57 results on '"Brijesh Rathi"'
Search Results
2. Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane
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Sumit Kumar, Charu Upadhyay, Meenakshi Bansal, Maria Grishina, Bhupender S. Chhikara, Vladimir Potemkin, Brijesh Rathi, and Poonam
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Chemistry ,QD1-999 - Published
- 2020
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3. Review of Atypical Organometallic Compounds as Antimalarial Drugs
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Samuel K. Kwofie, Emmanuel Broni, Bismark Dankwa, Kweku S. Enninful, Joshua Teye, Cedar R. Davidson, Josephine B. Nimely, J. Chioma Orizu, Prakasha Kempaiah, Brijesh Rathi, and Whelton A. Miller
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Chemistry ,QD1-999 - Abstract
Organometallic compounds are molecules that contain at least one metal-carbon bond. Due to resistance of the Plasmodium parasite to traditional organic antimalarials, the use of organometallic compounds has become widely adopted in antimalarial drug discovery. Ferroquine, which was developed due to the emergence of chloroquine resistance, is currently the most advanced organometallic antimalarial drug and has paved the way for the development of new organometallic antimalarials. In this review, a general overview of organometallic antimalarial compounds and their antimalarial activity in comparison to purely organic antimalarials are presented. Furthermore, recent developments in the field are discussed, and future applications of this emerging class of therapeutics in antimalarial drug discovery are suggested.
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- 2020
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4. Phytocompounds of Rheum emodi, Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor: In Silico Approach
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Vikas Kumar, Prem Prakash Sharma, Deeksha Salaria, Rajan Rolta, David J. Baumler, Kamal Dev, Mansi Verma, Bhanu Sharma, Anuradha Sourirajan, and Brijesh Rathi
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Emodin ,In silico ,Artemisia annua ,Phytocompounds ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Drug Discovery ,Genetics ,medicine ,Natural Products: From Chemistry to Pharmacology (C Ho, Section Editor) ,Artemisinin ,Receptor ,chemistry.chemical_classification ,biology ,Rheum emodi ,COVID-19 ,Chloroquine ,MD simulation ,AutoDock ,biology.organism_classification ,Thymol ,chemistry ,Antimalarial drugs ,Glycoprotein ,medicine.drug - Abstract
Graphical abstract COVID-19, the disease caused by SARS-CoV-2, has been declared as a global pandemic. Traditional medicinal plants have long history to treat viral infections. Our in silico approach suggested that unique phytocompounds such as emodin, thymol and carvacrol, and artemisinin could physically bind SARS-CoV-2 spike glycoproteins (6VXX and 6VYB), SARS-CoV-2 B.1.351 South Africa variant of Spike glycoprotein (7NXA), and even with ACE2 and prevent the SARS-CoV-2 binding to the host ACE2, TMPRSS2 and neutrapilin-1 receptors. Since Chloroquine has been looked as potential therapy against COVID-19, we also compared the binding of chloroquine and artemisinin for its interaction with spike proteins (6VXX, 6VYB) and its variant 7NXA, respectively. Molecular docking study of phytocompounds and SARS-CoV-2 spike protein was performed by using AutoDock/Vina software. Molecular dynamics (MD) simulation was performed for 50ns. Among all the phytocompounds, molecular docking studies revealed lowest binding energy of artemisinin with 6VXX and 6VYB, with Etotal −10.5 KJ mol−1 and −10.3 KJ mol−1 respectively. Emodin showed the best binding affinity with 6VYB with Etotal −8.8 KJ mol−1and SARS-CoV-2 B.1.351 variant (7NXA) with binding energy of −6.4KJ mol−1. Emodin showed best interactions with TMPRSS 2 and ACE2 with Etotal of −7.1 and −7.3 KJ mol−1 respectively, whereas artemisinin interacts with TMPRSS 2 and ACE2 with Etotal of −6.9 and −7.4 KJ mol−1 respectively. All the phytocompounds were non-toxic and non-carcinogenic. MD simulation showed that artemisinin has more stable interaction with 6VYB as compared to 6VXX, and hence proposed as potential phytochemical to prevent SARS-CoV-2 interaction with ACE-2 receptor. Supplementary Information The online version contains supplementary material available at 10.1007/s40495-021-00259-4.
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- 2021
5. In silico identification and validation of triarylchromones as potential inhibitor against main protease of severe acute respiratory syndrome coronavirus 2
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Brijesh Rathi, Seema A. Nayar, Dhruv Kumar, Abhijeet Kumar, Garima Tripathi, and Vaishali Chandel
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Drug ,medicine.medical_treatment ,media_common.quotation_subject ,In silico ,030303 biophysics ,Context (language use) ,Computational biology ,Virus ,03 medical and health sciences ,Structural Biology ,medicine ,Molecular Biology ,media_common ,ADME ,0303 health sciences ,Protease ,Chemistry ,Arylchromone ,COVID-19 ,General Medicine ,molecular docking ,In vitro ,Drug repositioning ,stomatognathic diseases ,molecular dynamics simulation ,main protease ,Research Article - Abstract
The ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The in silico studies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (–11.2 kcal/mol), TAC-4 (–10.5 kcal/mol), TAC-6 (–11.2 kcal/mol), TAC-7 (–10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the in vitro and preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma
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- 2021
6. The emerging paradigm of calcium homeostasis as a new therapeutic target for protozoan parasites
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Matthew C Weyenberg, Ravi Durvasula, Stefan M. Kanzok, Poonam, Catherine M. Pearce, Neha Sharma, Jesus G Romero, Raman Mathur, Steven Goicoechea, Brijesh Rathi, Prakasha Kempaiah, Yash Gupta, Hoseah M. Akala, Bharathi Daravath, and Samuel K. Kwofie
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Drug ,media_common.quotation_subject ,Cryptosporidiosis ,Cryptosporidium ,Cellular homeostasis ,Computational biology ,Drug resistance ,Chemical library ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,parasitic diseases ,Drug Discovery ,Animals ,Homeostasis ,Humans ,Parasites ,030304 developmental biology ,media_common ,Pharmacology ,0303 health sciences ,biology ,fungi ,Kinetoplastida ,biology.organism_classification ,Leishmania ,chemistry ,030220 oncology & carcinogenesis ,Trypanosoma ,Molecular Medicine ,Calcium ,Function (biology) - Abstract
Calcium channels (CCs), a group of ubiquitously expressed membrane proteins, are involved in many pathophysiological processes of protozoan parasites. Our understanding of CCs in cell signaling, organelle function, cellular homeostasis, and cell cycle control has led to improved insights into their structure and functions. In this article, we discuss CCs characteristics of five major protozoan parasites Plasmodium, Leishmania, Toxoplasma, Trypanosoma, and Cryptosporidium. We provide a comprehensive review of current antiparasitic drugs and the potential of using CCs as new therapeutic targets. Interestingly, previous studies have demonstrated that human CC modulators can kill or sensitize parasites to antiparasitic drugs. Still, none of the parasite CCs, pumps, or transporters has been validated as drug targets. Information for this review draws from extensive data mining of genome sequences, chemical library screenings, and drug design studies. Parasitic resistance to currently approved therapeutics is a serious and emerging threat to both disease control and management efforts. In this article, we suggest that the disruption of calcium homeostasis may be an effective approach to develop new anti-parasite drug candidates and reduce parasite resistance.
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- 2021
7. A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): in silico and in vitro investigations
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Prakasha Kempaiah, Yash Gupta, Vladimir Potemkin, Samantha E. Zak, Sumit Kumar, Charu Upadhyay, Andrew S. Herbert, John M. Dye, Ravi Durvasula, Poonam, Neha Sharma, and Brijesh Rathi
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Pharmacology ,chemistry.chemical_classification ,Virtual screening ,biology ,Chemistry ,In silico ,Organic Chemistry ,Endoribonuclease ,In vitro toxicology ,Pharmaceutical Science ,Active site ,Biochemistry ,Enzyme ,Viral replication ,Viral entry ,Drug Discovery ,biology.protein ,Molecular Medicine - Abstract
NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based '(2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol' (IV) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays. This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IV was not toxic to the cell lines up to a 50 μM concentration and exhibited IC50s of 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.
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- 2021
8. Phthalimide analogs for antimalarial drug discovery
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Poonam, Suresh Kumar, Charu Upadhyay, Meenakshi Bansal, and Brijesh Rathi
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Drug ,media_common.quotation_subject ,Pharmaceutical Science ,Disease ,Bioinformatics ,Biochemistry ,Phthalimide ,chemistry.chemical_compound ,parasitic diseases ,Drug Discovery ,Medicine ,Artemisinin ,media_common ,Pharmacology ,biology ,Drug discovery ,business.industry ,Organic Chemistry ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Chemistry ,chemistry ,Molecular Medicine ,Pharmacophore ,business ,Malaria ,medicine.drug - Abstract
Malaria remains one of the world's most life-threatening diseases and, thus, it is a major public health concern all around the world. The disease can become devastating if not treated with proper medication in a timely manner. Currently, the number of viable treatment therapies is in continuous decline due to compromised effectiveness, probably owing to the complex life cycle of Plasmodium falciparum. The factors responsible for the unclear status of malaria eradication programmes include ever-developing parasite resistance to the most effective treatments used on the frontline (i.e., artemisinin derivatives) and the paucity of new effective therapeutics. Due to these circumstances, the development of novel effective drug candidates with unique modes of action is essential for overcoming the listed obstacles. As such, the discovery of novel chemical compounds based on validated pharmacophores remains an unmet need in the field of medicinal chemistry. In this area, functionalized phthalimide (Pht) analogs have been explored as potential candidates against various diseases, including malaria. Pht presents a promising bioactive scaffold that can be easily functionalized and thus utilized as a starting point for the development of new antimalarial candidates suitable for preclinical and clinical studies. In this short review, we highlight a wide range of Pht analogs that have been investigated for their activity against various strains of Plasmodium falciparum.
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- 2021
9. Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane
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Meenakshi Bansal, Brijesh Rathi, Poonam, Vladimir Potemkin, Charu Upadhyay, Bhupender S. Chhikara, Sumit Kumar, and Maria Grishina
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chemistry.chemical_classification ,Nitromethane ,General Chemical Engineering ,Epoxide ,Aromatic amine ,Regioselectivity ,General Chemistry ,Ring (chemistry) ,Article ,Catalysis ,Solvent ,Chemistry ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Organic chemistry ,QD1-999 - Abstract
Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, convenient, green, and highly efficient regioselective ring opening reactions of sterically hindered (2R,3S)-3-(N-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involve the reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41–98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR experiments suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first-time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving an equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent, and simple workup procedures.
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- 2020
10. Discovery of New Hydroxyethylamine Analogs against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure–Activity Relationship Studies
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Poonam, Uma Shankar, Amit Kumar, Sanjeev Kumar Joshi, Prakasha Kempaiah, Ravi Durvasula, Brijesh Rathi, Prem Prakash Sharma, Sumit Kumar, Dhruv Kumar, and Lindomar Pena
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Virtual screening ,Protease ,010304 chemical physics ,Chemistry ,General Chemical Engineering ,medicine.medical_treatment ,General Chemistry ,Computational biology ,Library and Information Sciences ,medicine.disease_cause ,01 natural sciences ,Cysteine protease ,0104 chemical sciences ,Computer Science Applications ,chemistry.chemical_compound ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,Indinavir ,0103 physical sciences ,medicine ,Structure–activity relationship ,Pharmacophore ,Lead compound ,medicine.drug ,Coronavirus - Abstract
A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (Mpro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CLpro) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CLpro) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16 with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of 16 within the binding pocket. Largly, our results supported that this novel compound 16 binds to the domain I & II, and domain II-III linker of 3CLpro protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound 16 could pave incredible directions for the design of novel 3CLpro inhibitors and ultimately therapeutics against COVID-19 disease.
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- 2020
11. Fluorinated scaffolds for antimalarial drug discovery
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Charu Upadhyay, Anikó Borbás, Ronaldo N. de Oliveira, Brijesh Rathi, Prakasha Kempaiah, Monika Chaudhary, and Poonam Singh
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0303 health sciences ,Halogenation ,Drug discovery ,Chemistry ,Fluorine ,Combinatorial chemistry ,Malaria ,Antimalarials ,03 medical and health sciences ,0302 clinical medicine ,Drug Design ,030220 oncology & carcinogenesis ,Chemical diversity ,Drug Discovery ,Lipophilicity ,Animals ,Humans ,Organofluorine compounds ,030304 developmental biology - Abstract
The unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria.In this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery.Fluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F
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- 2020
12. Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations
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Vladimir Potemkin, Agam P. Singh, Snigdha Singh, Poonam, Raman Mathur, Prateek Pathak, Meenakshi Bansal, Brijesh Rathi, Maria Grishina, Jyoti Prakash Singh, Prakasha Kempaiah, Mohammad Kashif, Mohd Shahbaaz, Vinoth Rajendran, Yash Gupta, and Neha Sharma
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0303 health sciences ,education.field_of_study ,Chemistry ,General Chemical Engineering ,Population ,General Chemistry ,Pharmacology ,medicine.disease ,01 natural sciences ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Plasmepsin II ,In vivo ,parasitic diseases ,medicine ,Gametocyte ,education ,Cytotoxicity ,IC50 ,Malaria ,030304 developmental biology - Abstract
Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite's multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC50) in the low micromolar range. The compounds' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC50 values > 170 μM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC50 value of 1.89 μM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg−1 dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.
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- 2020
13. Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds
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Willyenne Marília Dantas, Gustavo M. Seabra, Ronaldo N. de Oliveira, Valentina Nascimento Melo de Oliveira, Diogo A L Santos, Brijesh Rathi, Prem Prakash Sharma, and Lindomar Pena
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Microcephaly ,Pharmaceutical Science ,Organic chemistry ,naphthoquinone ,Virus ,Analytical Chemistry ,Zika virus ,chemistry.chemical_compound ,Flaviviridae ,QD241-441 ,Drug Discovery ,medicine ,Physical and Theoretical Chemistry ,Cytotoxicity ,IC50 ,biology ,RNA ,MD simulation ,1H-1,2,3-triazoles ,biology.organism_classification ,medicine.disease ,Virology ,Naphthoquinone ,chemistry ,Chemistry (miscellaneous) ,Molecular Medicine ,cytotoxicity ,phthalimide - Abstract
Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flaviviridae family and is responsible for an exanthematous disease and severe neurological manifestations, such as microcephaly and Guillain-Barré syndrome. ZIKV has a single strand positive-sense RNA genome that is translated into structural and non-structural (NS) proteins. Although it has become endemic in most parts of the tropical world, Zika still does not have a specific treatment. Thus, in this work we evaluate the cytotoxicity and antiviral activities of 14 hybrid compounds formed by 1H-1,2,3-triazole, naphthoquinone and phthalimide groups. Most compounds showed low cytotoxicity to epithelial cells, specially the 3b compound. After screening with all compounds, 4b was the most active against ZIKV in the post-infection test, obtaining a 50% inhibition concentration (IC50) of 146.0 µM and SI of 2.3. There were no significant results for the pre-treatment test. According to the molecular docking compound, 4b was suggested with significant binding affinity for the NS5 RdRp protein target, which was further corroborated by molecular dynamic simulation studies.
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- 2021
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14. Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors
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Xinyong Liu, Peng Zhan, Zhao Wang, Xiangkai Ji, Kuo‐Hsiung Lee, Simon Cocklin, Chin Ho Chen, Jing Li, Xiangyi Jiang, Dongwei Kang, Alexej Dick, Prem Prakash Sharma, and Brijesh Rathi
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Stereochemistry ,Anti-HIV Agents ,Phenylalanine ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Random hexamer ,Molecular Dynamics Simulation ,Virus Replication ,Biochemistry ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,Viral life cycle ,Drug Discovery ,Humans ,Surface plasmon resonance ,Molecular Biology ,Cells, Cultured ,Dose-Response Relationship, Drug ,Molecular Structure ,Ligand binding assay ,Organic Chemistry ,Monomer ,chemistry ,Capsid ,Drug Design ,HIV-1 ,Molecular Medicine ,Capsid Proteins ,Lead compound - Abstract
The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 μM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 μM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.
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- 2021
15. A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15)
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Sumit, Kumar, Yash, Gupta, Samantha E, Zak, Charu, Upadhyay, Neha, Sharma, Andrew S, Herbert, Ravi, Durvasula, Vladimir, Potemkin, John M, Dye, Poonam, Prakasha, Kempaiah, and Brijesh, Rathi
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Chemistry - Abstract
NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2′-3′-cyclic phosphates 5′ to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based ‘(2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol’ (IV) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays. This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IV was not toxic to the cell lines up to a 50 μM concentration and exhibited IC(50s) of 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.
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- 2021
16. Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A
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I. V. Mikhura, Gunnar Westman, Vladimir A. Brylev, Brijesh Rathi, Alexey A. Chistov, Ilya O. Aparin, Liubov I. Kozlovskaya, Dmitry I. Osolodkin, Vladimir A. Palyulin, Philipp P. Streshnev, Vladimir A. Korshun, Nikita A. Slesarchuk, Alexey A. Orlov, Alexey V. Ustinov, Sergey V. Kutyakov, and Nidhi Jain
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Cell Survival ,Swine ,Microbial Sensitivity Tests ,Antiviral Agents ,01 natural sciences ,Virus ,Cell Line ,Encephalitis Viruses, Tick-Borne ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Chlorocebus aethiops ,Drug Discovery ,Animals ,Humans ,Moiety ,Structure–activity relationship ,Uracil ,Mode of action ,Vero Cells ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Biological activity ,General Medicine ,biology.organism_classification ,Enterovirus A, Human ,0104 chemical sciences ,Intestines ,Tick-borne encephalitis virus ,Biochemistry ,Blood-Brain Barrier ,Nucleoside - Abstract
Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC50 values vary from 0.077 μM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC50 50-100 μM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.
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- 2019
17. Oxygen mediated highly efficient cobalt(<scp>ii</scp>) porphyrin-catalyzed reduction of functional chromones: experimental and computational studies
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Brijesh Rathi, Poonam, Pratibha Kumari, Maria Grishina, Vladimir Potemkin, and Abhishek Verma
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Catalytic complex ,chemistry.chemical_element ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Redox ,Oxygen ,Porphyrin ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Sodium borohydride ,Reaction rate constant ,chemistry ,Materials Chemistry ,0210 nano-technology ,Cobalt - Abstract
The highly efficient oxygen mediated reduction of functional chromones with sodium borohydride (NaBH4) catalyzed by cobalt(II) porphyrins afforded biologically active chroman-4-ols as the reduction products in 80–98% yields. Oxygen assists in the formation of hydridocobalt(III) porphyrin as a key intermediate, which releases hydride rapidly to reduce the chromones. Additionally, the correlation between quantum calculation results of the catalysts’ conversions, yields, times and logarithms of the rate constants for the oxygen assisted reduction reaction was studied. The mechanism of the reaction was also justified by establishing a quantitative relationship between the rate constant, the α-HOMO orbital of the catalytic complex and the stabilization energy of the complex with oxygen.
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- 2019
18. Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach
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Prakasha Kempaiah, Brijesh Rathi, Krysten A. Jones, Ravi Durvasula, Charu Upadhyay, John M. Dye, Yash Gupta, Saara-Anne Azizi, Neha Sharma, Sumit Kumar, Samantha E. Zak, Poonam, Rahul S. Kathayat, Bryan C. Dickinson, and Andrew S. Herbert
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Virtual screening ,Cell Survival ,medicine.medical_treatment ,Clinical Biochemistry ,Protein Data Bank (RCSB PDB) ,Pharmaceutical Science ,Computational biology ,Molecular Dynamics Simulation ,Biochemistry ,Molecular Docking Simulation ,Antiviral Agents ,Article ,Hydroxyethylamine compound library ,Catalytic Domain ,Drug Discovery ,Chlorocebus aethiops ,medicine ,Ethylamines ,Animals ,Humans ,Protease Inhibitors ,Molecular Biology ,Vero Cells ,Coronavirus 3C Proteases ,ComputingMethodologies_COMPUTERGRAPHICS ,MM-GBSA ,Protease ,Binding Sites ,Chemistry ,Drug discovery ,SARS-CoV-2 ,Organic Chemistry ,COVID-19 ,3CLpro ,MD simulation ,computer.file_format ,Protein Data Bank ,Docking (molecular) ,Antiviral assay ,Molecular Medicine ,Thermodynamics ,Pharmacophore ,computer - Abstract
Graphical abstract, The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6 M03, 6LU7, 2GZ7, 6 W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n = 40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3′S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of ∼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.
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- 2021
19. Mutational heterogeneity in spike glycoproteins of severe acute respiratory syndrome coronavirus 2
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Niraj Kumar Jha, Dhruv Kumar, Brijesh Rathi, Aanchal Mathur, Saurabh Kumar Jha, and Sibi Raj
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chemistry.chemical_classification ,Multiple sequence alignment ,Phylogenetic tree ,SARS-CoV-2 ,Protein subunit ,In silico ,viruses ,COVID-19 ,Review Article ,Environmental Science (miscellaneous) ,Biology ,medicine.disease_cause ,Agricultural and Biological Sciences (miscellaneous) ,Genome ,Virology ,Virus ,Mutational heterogeneity ,chemistry ,medicine ,Glycoprotein ,Spike proteins ,Biotechnology ,Coronavirus ,Glycoproteins - Abstract
The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to a global crisis by infecting millions of people across the globe eventually causing multiple deaths. The prominent player of the virus has been known as the spike protein which enters the host system and leads to the infection. The S2 subunit is the most essential in this process of infection as it helps the SARS-CoV-2 to infect the host by binding to the human angiotensin converting enzyme 2 (hACE2), with the help of the receptor binding domain found at the S2 subunit of the virus. Studies also hypothesize that the S glycoproteins present in the virus interacts with different hosts in different ways which might be due to the mutations taking place in the genome of the virus over time. This work aims to decipher the similarities and differences in the sequences of spike proteins from samples of SARS-CoV-2 acquired from different infected individuals in different countries with the help of in silico methods such as multiple sequence alignment and phylogenetic analysis. It also aims to understand the differential infection rates among the infected countries by studying the amino acid composition and interactions of the virus with the host.
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- 2021
20. Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies
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Prakasha Kempaiah, Poonam, Charu Upadhyay, Sumit Kumar, Prem Prakash Sharma, and Brijesh Rathi
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Drug ,FDA-approved drugs ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,media_common.quotation_subject ,Diosmin ,Coronavirus Papain-Like Proteases ,Computational biology ,Molecular Dynamics Simulation ,Viral Nonstructural Proteins ,medicine.disease_cause ,Ligands ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Article ,Chemical library ,03 medical and health sciences ,Molecular dynamics ,chemistry.chemical_compound ,Drug Discovery ,Endoribonucleases ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Coronavirus ,media_common ,0303 health sciences ,Virtual screening ,Coronavirus RNA-Dependent RNA Polymerase ,SARS-CoV-2 ,030302 biochemistry & molecular biology ,COVID-19 ,RNA-Binding Proteins ,MD simulation ,COVID-19 Drug Treatment ,Molecular Docking Simulation ,chemistry ,Docking (molecular) ,Molecular docking ,medicine.drug ,Multi-targeting - Abstract
Novel coronavirus SARS-CoV-2continues tospread rapidly worldwide and causing serious health and economic loss. In the absence of any effective treatment, various in-silico approaches are being explored towards the therapeutic discovery against COVID-19. Targeting multiple key enzymes of SARS-CoV-2 with a single potential drug could be an important in-silico strategy to tackle the therapeutic emergency. A number of Food and Drug Administration (FDA) approved drugs entered into clinical stages were originated from multi-target approaches with an increased rate, 16-21% between 2015 and 2017. In this study, we selected an FDA-approved library (Prestwick Chemical Library of 1520 compounds) and implemented in-silico virtual screening against multiple protein targets of SARS-CoV-2 on the Glide module of Schrodinger software (release 2020-1). Compounds were analyzed for their docking scores and the top-ranked against each targeted protein were further subjected to Molecular Dynamics (MD) simulations to assess the binding stability of ligand-protein complexes. A multi-targeting approach was optimized that enabled the analysis of several compounds' binding efficiency with more than one protein targets. It was demonstrated that Diosmin (6) showed the highest binding affinity towards multiple targets with binding free energy (kcal/mol) values of -63.39 (nsp3); -62.89 (nsp9); -31.23 (nsp12); and -65.58 (nsp15). Therefore, our results suggests that Diosmin (6) possesses multi-targeting capability, a potent inhibitor of various non-structural proteins of SARS-CoV-2, and thus it deserves further validation experiments before using as a therapeutic against COVID-19 disease.
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- 2021
21. Synthesis of alkynylated 1,2,4-oxadiazole/1,2,3-1H-triazole glycoconjugates: Discovering new compounds for use in chemotherapy against lung carcinoma and Mycobacterium tuberculosis
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Vanessa Pinheiro Gonçalves Ferreira, Lílian Maria Lapa Montenegro Pimentel, Cybele Flávia do Amaral Moura, Valentina Nascimento Melo de Oliveira, Cláudia Pessoa, Héverton Mendes Araújo, Brijesh Rathi, Lindomar Pena, Roberto Nicolete, Aline dos Santos Peixoto, Prem Prakash Sharma, Janaína V. dos Anjos, Patrick Rollin, Arnaud Tatibouët, and Ronaldo N. de Oliveira
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Lung Neoplasms ,Glycoconjugate ,Cell Survival ,Triazole ,Antitubercular Agents ,Antineoplastic Agents ,Microbial Sensitivity Tests ,Cell Line ,Mycobacterium tuberculosis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Chlorocebus aethiops ,Drug Discovery ,Animals ,Humans ,Viability assay ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,chemistry.chemical_classification ,Oxadiazoles ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,INHA ,Organic Chemistry ,General Medicine ,Triazoles ,biology.organism_classification ,chemistry ,Cell culture ,Alkynes ,Cancer research ,Vero cell ,Carcinoma, Squamous Cell ,Glycoconjugates - Abstract
A total of forty-three compounds were synthesized, including thirty-two new ones. Among those compounds, seventeen were selected and tested on human tumor cell lines: PC-3 (prostate adenocarcinoma), HCT-116 (colorectal tumor), NCIH-460 (lung carcinoma), SKMEL-103 (melanoma) and AGP-01 (gastric tumor). Alkynylated 1,2,4-oxadiazoles 2m, 3g and 3k exhibited antiproliferative activities against NCIH-460 in culture. Alkynylated N-cyclohexyl-1,2,4-oxadiazoles 3a-m and bis-heterocycle glucoglycero-1,2,3-triazole-N-cyclohexyl-1,2,4-oxadiazole derivatives 5a-k and 6–11 were evaluated for their in vitro efficacy towards Mycobacterium tuberculosis (Mtb) H37Ra and H37Rv strains. In general, glycerosugars conjugated to 1,2,4-oxadiazole via a 1,2,3-triazole linkage (5a, 5e, 5j, 5k, and 7) showed in vitro inhibitory activity against Mtb (H37Rv). The largest molecules bis-triazoles 10 and 11, proved inactive against TB. Probably, the absence of the N-cyclohexyl group in compound 8 and 1,2,4-oxadiazole nucleus in compound 9 were responsible for its low activity. Glucoglycero-triazole-oxadiazole derivatives 5e (10 μM) and 7 (23.9 μM) were the most promising antitubercular compounds, showing a better selective index than when tested against RAW 264.7 and HepG2 cells. Vero cell were used to investigate cytotoxicity of compounds 5a, 5h, 5j, 5k, and these compounds showed good cell viability. Further, in silico studies were performed for most active compounds (5e and 7) with potential drug targets, DprE1 and InhA of Mtb to understand possible interactions aided with molecular dynamic simulation (100ns).
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- 2021
22. Computational study of novel inhibitory molecule, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea, with high potential to competitively block ATP binding to the RNA dependent RNA polymerase of SARS-CoV-2 virus
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Nikolay Yu. Gorobets, Martin Zoltner, Babban Jee, Dhruv Kumar, Brijesh Rathi, Sumit Kumar, Prem Prakash Sharma, Peng Zhang, Sukrit Srivastava, Poonam, Shailendra Asthana, Mukesh Kumar, and Mitul Srivastava
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Drug discovery ,Chemistry ,Stereochemistry ,In silico ,RNA ,RNA-dependent RNA polymerase ,General Medicine ,chemistry.chemical_compound ,Structural Biology ,Docking (molecular) ,RNA polymerase ,Pharmacophore ,Molecular Biology ,Adenosine triphosphate - Abstract
For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silico screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski’s rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz. docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1 displayed higher docking score (−8.069 kcal/mol) and MM-GBSA binding free energy (−49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1 as better inhibitor. Overall, our systematic in silico study predicts the potential of compound 1 to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies. Communicated by Ramasawamy H. Sarma
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- 2021
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23. Phytocompounds from Himalayan Medicinal Plants as Potential Drugs to Treat Multidrug-Resistant Salmonella typhimurium: An In Silico Approach
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Prem Prakash Sharma, Deeksha Salaria, Brijesh Rathi, Oladoja A Awofisayo, Jyoti Mehta, Adity Chopra, Neha Kaushik, Nagendra Kumar Kaushik, Eun Ha Choi, Rajan Rolta, and Olatomide A. Fadare
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phytocompounds ,biology ,Chemistry ,QH301-705.5 ,In silico ,Medicine (miscellaneous) ,toxicity ,MD simulation ,molecular docking ,drug likeness ,AutoDock ,biology.organism_classification ,Antimicrobial ,General Biochemistry, Genetics and Molecular Biology ,Article ,Multiple drug resistance ,Biochemistry ,Docking (molecular) ,Salmonella enterica ,multidrug resistance ,efflux pump ,Efflux ,Target protein ,Biology (General) ,medicinal plants - Abstract
Medicinal plants can be used as natural therapeutics to treat diseases in humans. Enteric bacteria possess efflux pumps to remove bile salts from cells to avoid potential membrane damage. Resistance to bile and antibiotics is associated with the survival of Salmonella enterica subspecies enterica serovar Typhimurium (S. typhimurium) within a host. The present study aimed to investigate the binding affinity of major phytocompounds derived from 35 medicinal plants of the North Western Himalayas with the RamR protein (PDB ID 6IE9) of S. typhimurium. Proteins and ligands were prepared using AutoDock software 1.5.6. Molecular docking was performed using AutoDock Vina and MD simulation was performed at 100 ns. Drug likeness and toxicity predictions of hit phytocompounds were evaluated using molinspiration and ProTox II online servers. Moreover, docking, drug likeness, and toxicity results revealed that among all the selected phytocompounds, beta-sitosterol exhibited the most efficacious binding affinity with RamR protein (PDB ID 6IE9) and was nontoxic in nature. MD simulation data revealed that beta-sitosterol in complex with 6IE9 can be used as an antimicrobial. Furthermore, beta-sitosterol is stable in the binding pocket of the target protein, hence, it can be further explored as a drug to inhibit resistance-nodulation-division efflux pumps.
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- 2021
24. Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays
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Dawid Maciorowski, Raman Mathur, Yash Gupta, Krysten A. Jones, Saara Anne Azizi, David J. Ilc, John M. Dye, Bryan C. Dickinson, Daniel P. Becker, Rahul S. Kathayat, Ajay R. Bharti, Samantha E. Zak, Brijesh Rathi, Hamza Husein, Catherine M. Pearce, Prakasha Kempaiah, Ravi Durvasula, and Andrew S. Herbert
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Indoles ,COACH, Meta-server approach to protein-ligand binding site prediction ,Drug Evaluation, Preclinical ,Protein Structure, Secondary ,Maleimides ,Drug Delivery Systems ,SARS, Severe Acute Respiratory Syndrome ,RdRP, RNA-directed RNA polymerase ,ExoN, exoribonuclease ,Coronavirus 3C Proteases ,0303 health sciences ,MD simulations ,drug repurposing ,Chemistry ,030302 biochemistry & molecular biology ,3CLpro ,ExoN ,NendoU ,Ligand (biochemistry) ,Molecular Docking Simulation ,CoronaVirus Disease-2019 (COVID-19), SARS Corona Virus2 (SARS-CoV-2) ,Drug repositioning ,PLpro ,Proteome ,Target protein ,and 2'-O-MT ,BIM IX, bisindolylmaleimide IX ,2'-O-MT, 2’-O-Methyltransferase ,Computational biology ,Molecular mechanics ,Antiviral Agents ,PLpro, Papain-like proteinase ,General Biochemistry, Genetics and Molecular Biology ,Article ,Helicase ,03 medical and health sciences ,Humans ,MOA, mechanism of action ,Binding site ,Molecular Biology ,030304 developmental biology ,MM-GBSA ,Virtual screening ,RdRP ,Dose-Response Relationship, Drug ,SARS-CoV-2 ,Drug Repositioning ,3CLpro, 3-Chymotrypsin-Like Protease ,Reproducibility of Results ,COVID-19 ,virtual screening ,NendoU, Nonstructural Uridylate-specific endoribonuclease ,High-Throughput Screening Assays ,Docking (molecular) ,MERS, Middle Eastern Respiratory Syndrome ,Bisindolylmaleimide (BIM) IX, Anti-Viral assay, 3CLpro enzymatic assay ,HTVS, high throughput virtual screening ,CAD, computer-aided drug design - Abstract
Highlights • Seven enzymes of Covid19 virus proteome were comprehensively targeted; 3CLPro, PlPro, RdRP, Helicase, NandoU, ExoN and 2O-MT. • Virtual screening (VS) was performed with world approved/investigational drug libraries (n=5903) • Two tier anti-viral assay with nuclei counting for reliable activity. • Bisindolylmaleimide IX reported here is an advanced investigational molecule and has 80% viral blocking at 50 µM. • Specific highly sensitive FRET based main protease (3ClPro) enzymatic assays. • This drug discovery effort solely targets to understand drug targetability of Covid-19 as well as to enrich the candidates for future drugs that have acceptable/investigated safety profiles., SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n=5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.
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- 2020
25. Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays
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David J. Ilc, Hamza Husein, Rahul S. Kathayat, Brijesh Rathi, Samantha E. Zak, Yash Gupta, Daniel P. Becker, Dawid Maciorowski, Raman Mathur, Ajay R. Bharti, Prakasha Kempaiah, Ravi Durvasula, Andrew S. Herbert, Catherine M. Pearce, John M. Dye, Krysten A. Jones, Bryan C. Dickinson, and Saara-Anne Azizi
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Virtual screening ,Protease ,Chemistry ,medicine.medical_treatment ,In vitro toxicology ,medicine ,Bisindolylmaleimide IX ,Virology - Abstract
The emergence of SARS/MERS drug-resistant SARS-CoV2 comes with higher rates of transmission and mortality. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral multiplication cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard(Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 inhibition. Among eight molecules included in our evaluation, we found inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.
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- 2020
26. Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines
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Sumit Kumar, Poonam, Vladimir Potemkin, Maria Grishina, Charu Upadhyay, Meenakshi Bansal, and Brijesh Rathi
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Solvent ,chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Nitromethane ,Nucleophile ,Epoxide ,Aromatic amine ,Regioselectivity ,Organic chemistry ,Ring (chemistry) ,Catalysis - Abstract
Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, a convenient, green and highly efficient regioselective ring opening of sterically hindered (2R,3S)-3-(N-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involves reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41-98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR and UV-visible spectroscopic studies suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent and simple workup procedures.
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- 2020
27. Oseltamivir analogs with potent anti-influenza virus activity
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Sonu Kumar, Catherine M. Pearce, Steven Goicoechea, Poonam, Brijesh Rathi, Sumit Kumar, Prakasha Kempaiah, and Ravi Durvasula
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0301 basic medicine ,Oseltamivir ,Neuraminidase ,Endogeny ,medicine.disease_cause ,Antiviral Agents ,Virus ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Orthomyxoviridae Infections ,Oral administration ,Drug Discovery ,Viral neuraminidase ,medicine ,Animals ,Humans ,Pharmacology ,Life Cycle Stages ,business.industry ,virus diseases ,Orthomyxoviridae ,Virology ,Influenza A virus subtype H5N1 ,Bioavailability ,Vaccination ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,business - Abstract
Influenza A and B viruses cause seasonal worldwide influenza epidemics each winter, and are a major public health concern and cause of morbidity and mortality. A substantial reduction in influenza-related deaths can be attributed to both vaccination and administration of oseltamivir (OS), which is approved for oral administration and inhibits viral neuraminidase (NA), a transmembrane protein. OS carboxylate (OSC), the active form of OS, is formed by the action of endogenous esterase, which targets NA and is shown to significantly reduce influenza-related deaths. However, the development of resistance in various viral variants, including H3N2 and H5N1, has raised concern about the effectiveness of OS. This comprehensive review covers a range of OS analogs shown to be effective against influenza virus, comparing different types of substituent group that contribute to the activity and bioavailability of these compounds.
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- 2020
28. Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty
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Elizabeth A. Winzeler, Nelly El-Sakkary, Danielle E. Skinner, Brijesh Rathi, Prem Prakash Sharma, Sabine Ottilie, Snigdha Singh, Conor R. Caffrey, Prashant Kumar, Yevgeniya Antonova-Koch, and Poonam
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0301 basic medicine ,030231 tropical medicine ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,Schistosomiasis ,Pharmacology ,Article ,benzimidazole ,drug discovery ,Phthalimide ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,parasitic diseases ,medicine ,EC50 ,Schistosoma ,ADME ,biology ,lcsh:R ,biology.organism_classification ,medicine.disease ,tropical disease ,Bioavailability ,anti-schistosomal activity ,030104 developmental biology ,chemistry ,Toxicity ,click chemistry ,Molecular Medicine ,Schistosoma mansoni ,schistosoma ,phthalimide - Abstract
The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µ, M against both somules and adults (6d, 6f, 6i&ndash, 6l, 6n&ndash, 6p, 6s, 6r&rsquo, 6t&rsquo, and 6w). Against somules, the majority caused degeneracy and/or death after 72 h, whereas against adult parasites, five compounds (6l, 6d, 6f, 6r&rsquo, and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC50 values &ge, 50 µ, M). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.
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- 2020
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29. Review of Atypical Organometallic Compounds as Antimalarial Drugs
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Brijesh Rathi, Cedar R. Davidson, Samuel K. Kwofie, J. Chioma Orizu, Kweku S Enninful, Emmanuel Broni, Joshua Teye, Whelton A. Miller, Josephine B. Nimely, Bismark Dankwa, and Prakasha Kempaiah
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Drug ,010405 organic chemistry ,Drug discovery ,Chemistry ,media_common.quotation_subject ,Plasmodium parasite ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Ferroquine ,Chloroquine resistance ,QD1-999 ,media_common ,Group 2 organometallic chemistry - Abstract
Organometallic compounds are molecules that contain at least one metal-carbon bond. Due to resistance of the Plasmodium parasite to traditional organic antimalarials, the use of organometallic compounds has become widely adopted in antimalarial drug discovery. Ferroquine, which was developed due to the emergence of chloroquine resistance, is currently the most advanced organometallic antimalarial drug and has paved the way for the development of new organometallic antimalarials. In this review, a general overview of organometallic antimalarial compounds and their antimalarial activity in comparison to purely organic antimalarials are presented. Furthermore, recent developments in the field are discussed, and future applications of this emerging class of therapeutics in antimalarial drug discovery are suggested.
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- 2020
30. Characterization of immobilized tyrosinase – an enzyme that is stable in organic solvent at 100 °C
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Brijesh Rathi, Huan Liu, Jincheng Li, Lidong Wu, Gang Han, Xiuhong Wu, Anjie Ming, and Yi Chen
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chemistry.chemical_classification ,Aqueous solution ,010405 organic chemistry ,General Chemical Engineering ,Tyrosinase ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Hexane ,chemistry.chemical_compound ,Pigment ,Enzyme ,chemistry ,visual_art ,Anhydrous ,visual_art.visual_art_medium ,Organic chemistry ,Methanol ,Derivative (chemistry) - Abstract
Tyrosinase is a copper-containing enzyme present in plant and animal tissues, which catalyzes the production of melanin and other pigments. In organic solvent, tyrosinase can convert N-acetyl-L-tyrosine ethyl ester (insoluble in aqueous) to a derivative of L-dopamine (a drug used for the treatment of Parkinson's disease). Thus, the performances of tyrosinase in organic solvent have attracted scientific attention since 1980. In this work, we investigated the stability of immobilized tyrosinase at high temperature in anhydrous organic solvent. Triethylaminoethyl cellulose (TEAE-Cellulose) performed the best out of six immobilization platforms. The dry immobilized tyrosinase became extremely thermostable in organic solvent, and the half-life of the dry immobilized tyrosinase in organic solvent is strongly related to the polarity of the organic solvent than their log P value. The immobilized tyrosinase loses its activity instantaneously in aqueous solution at 100 °C, but it keeps enzymatic activity within 10 min in hydrophilic methanol and over one month in hydrophobic hexane (log P: 4.66, non-polar) even incubating at 100 °C. This research provides valuable information for the design of new biocatalysts.
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- 2018
31. Theoretical and experimental studies of an oseltamivir-triazole-based thermoresponsive organogel
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Kumar Kaushik, Sumit Kumar, Neha Sharma, Bhupendra S. Chhikara, Poonam, Lidong Wu, Ayushee, Vladimir Potemkin, Maria Grishina, and Brijesh Rathi
- Subjects
chemistry.chemical_classification ,Alkane ,General Chemical Engineering ,Triazole ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Micelle ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Amide ,Drug delivery ,Lipophilicity ,0210 nano-technology ,Alkyl ,Conjugate - Abstract
Low-molecular weight organic gelators have been of significant interest in recent years because of their interesting properties and potential applications in sensing technology, biomedicine and drug delivery. Herein, the synthesis, characterization and gelation properties of new oseltamivir conjugates are reported. The oseltamivir–triazole conjugate 1 was synthesized via a click-reaction in a 75% yield. The key features of this conjugate include the presence of amide, flexible ester linkages and a triazole scaffold linking a hydrophobic alkyl chain. The conjugate 1, possessing a long alkyl chain, showed gelation properties in various apolar organic solvents. This gelation behavior was not observed in the case of the deesterified conjugate 2; this indicated the necessity of the alkyl chain for gelation. The gelator 1 showed thermoreversible gelation properties in a range of linear alkane solvents (from n-pentane to n-dodecane). A scanning electron microscopic study suggests that the gelator 1 exists as cross-linked structures, which are self-aggregated in the range of submicrometers, as supported by extensive 1H-NMR studies. The rheological parameters supported the occurrence of a soft gelation process, and the gel formed in n-decane was found to be stiffer than that formed in n-hexane. Computational studies suggested that the gelation behavior was indeed due to micelle formation and dependent on the lipophilicity of solvents.
- Published
- 2019
32. Molecules Effective against Infectious Diseases - Part II
- Author
-
Poonam, Yogesh Kumar, Suresh Kumar, and Brijesh Rathi
- Subjects
Text mining ,Chemistry ,business.industry ,Drug Discovery ,General Medicine ,Computational biology ,business - Published
- 2019
33. Functionalized organic frameworks explored as second order NLO agents
- Author
-
Taruna Singh, Anil K. Singh, V. Balachandran, Brijesh Rathi, Brajendra K. Singh, Nikolay Yu. Gorobets, Volodymyr V. Medviediev, Oleg V. Shishkin, N. Vijayan, and Vijay Bahadur
- Subjects
Phthalimides ,Supramolecular chemistry ,Hyperpolarizability ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Crystal engineering ,Photochemistry ,01 natural sciences ,0104 chemical sciences ,Phthalimide ,Crystallography ,chemistry.chemical_compound ,chemistry ,Orthorhombic crystal system ,0210 nano-technology ,Chirality (chemistry) ,Monoclinic crystal system - Abstract
A new class of chiral phthalimides functionalized with aryl piperazines was designed anticipating their strong candidature for crystal engineering and technological applications. Five new phthalimides were synthesized, characterized and subjected to single crystal X-ray diffraction study that directed their non-centrosymmetric structures. Four phthalimides crystallized in P21 space group with monoclinic crystal system, however, one was found to possess P212121 space group with orthorhombic system. The supramolecular architectures of phthalimide crystals were analysed by an approach based on consideration of energy of intermolecular interaction. The molecular hyperpolarizability (β) calculation for all the listed phthalimides indicated their promising candidature for NLO materials. Further, the crystalline form of all phthalimides was evaluated for their second harmonic generation (SHG) response. A significant response of 16.4 mV was measured for phthalimide possessing t-butyl substituent at the para position of 4-benzylpiperazine. This high SHG response may be attributed to the molecular chirality and helical supramolecular frameworks stabilized by C-H ⋯O hydrogen bonds in the solid state. The current study attests chiral phthalimides possessing arylpiperazines as effective nominees to the area of crystal engineering and nonlinear optics.
- Published
- 2016
34. Magnetic iron oxide nanoparticles encapsulating horseradish peroxidase (HRP): synthesis, characterization and carrier for the generation of free radicals for potential applications in cancer therapy
- Author
-
Chetna Gupta, Seema Sharma, Himadri B. Bohidar, Nikesh Gupta, Rakesh Kumar Sharma, and Brijesh Rathi
- Subjects
biology ,Chemistry ,General Chemical Engineering ,Radical ,Kinetics ,food and beverages ,Substrate (chemistry) ,02 engineering and technology ,General Chemistry ,Prodrug ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Horseradish peroxidase ,0104 chemical sciences ,chemistry.chemical_compound ,biology.protein ,Organic chemistry ,MTT assay ,0210 nano-technology ,Iron oxide nanoparticles ,Oxidative decarboxylation ,Nuclear chemistry - Abstract
This article reports a method of preparation of iron oxide nanoparticles using a reverse micellar (water-in-oil) approach. We have encapsulated horseradish peroxidase (HRP) in iron oxide nanoparticles. HRTEM, XRD, and DLS analyses showed that the average diameter of these particles was around 20 nm, 20.5 nm, and 30 nm, respectively, and the particles were highly monodispersed with spherical morphology. The entrapment efficiency of HRP was found to be as high as 92%. Practically, the entrapped enzyme shows zero leachability for up to 30 days. Enzyme entrapped in iron oxide nanoparticles followed Michaelis–Menten kinetics and showed higher stability towards temperature change as compared to free enzyme. Entrapped enzyme is stable at up to 65 °C; however, the free enzyme starts to lose its activity above 38 °C. The entrapped enzyme, HRP, has been used to convert a benign prodrug, indole-3-acetic acid (IAA), to a toxic oxidized product, and its toxic effect has been tested on cancerous cell lines through thiazolyl blue tetrazolium blue (MTT) assay. MTT assay on two cancer cell lines revealed that indole acetic acid (IAA), the prodrug alone, had no cytotoxic effect, and it became active only after oxidative decarboxylation by HRP. The benign substrate IAA reaches the cells and is oxidized by HRP. IAA, on reacting with HRP, forms free radicals such as indolyl, skatole and peroxyl radicals. This creates severe oxidative stress in the cancer cells, resulting in cell death.
- Published
- 2016
35. Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors
- Author
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Poonam, Vladimir Potemkin, Ben M. Dunn, Archana Singh, Brajendra K. Singh, Prakasha Kempaiah, Yogesh Kumar, Ravi Durvasula, Whelton A. Miller, Maria Grishina, Amit Singh, Nikesh Gupta, Prashant Kumar, Vinoth Rajendran, Snigdha Singh, and Brijesh Rathi
- Subjects
0301 basic medicine ,Cell Survival ,Clinical Biochemistry ,Plasmodium falciparum ,Plasmepsin ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Antimalarials ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Plasmepsin II ,Drug Discovery ,Chlorocebus aethiops ,Ethylamines ,Structure–activity relationship ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Molecular Biology ,IC50 ,Vero Cells ,chemistry.chemical_classification ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Biological activity ,Hep G2 Cells ,biology.organism_classification ,0104 chemical sciences ,Protein Structure, Tertiary ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Enzyme ,Drug Design ,Molecular Medicine ,Growth inhibition - Abstract
Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 ± 0.29 µM for Plm II; Ki, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 ± 0.95 µM for 10f; IC50, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.
- Published
- 2018
36. Potentials of Hydrogels in Cancer Therapy
- Author
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Brijesh Rathi, Brajendra Singh, Ravindra Kumar, Ajay Kumar, Prem Prakash Sharma, and Anil K. Singh
- Subjects
Cancer Research ,Oncology ,Chemistry ,Self-healing hydrogels ,Cancer therapy ,Cancer research ,Molecular Medicine - Published
- 2015
37. Synthesis and nucleation studies on<scp>L</scp>-leucine hydrobromide: a promising nonlinear optical material
- Author
-
Radha Rani, Brijesh Rathi, G. Bhagavannarayana, Geetanjali Sharma, Anuj Krishna, Kanika Thukral, and N. Vijayan
- Subjects
Crystal ,Supersaturation ,symbols.namesake ,Chemistry ,Analytical chemistry ,Nucleation ,symbols ,Crystal growth ,Atmospheric temperature range ,Raman spectroscopy ,General Biochemistry, Genetics and Molecular Biology ,Surface energy ,Gibbs free energy - Abstract
To achieve good quality bulk size crystal growth, an assessment of the nucleation kinetics of a semi-organic L-leucine hydrobromide (L-LHBr) crystal was carried out using double-distilled water as solvent medium. The effect on metastable zone width (MSZW) with increasing temperature and on induction period with varied supersaturation level was determined experimentally and was found to be very well in accordance with the nucleation theory prospects. Thereafter, various other nucleation parameters, such as Gibbs free energy and interfacial energy, were also determined. The knowledge of these nucleation parameters indicated the requisite temperature domain and the appropriate growth technique, leading to the successful single-crystal growth of L-LHBr by slow cooling in the temperature range 298–291 K. The cooling rate of 0.25 K per day was optimized after repeated trials. X-ray diffraction and Raman analysis were performed on grown crystals for the verification of the material. High-resolution X-ray diffraction analysis was used to assess the crystalline perfection of the grown crystals. To further explore the properties of the grown crystals, photoluminescence and time decay studies, etching analysis, andZ-scan measurements were performed.
- Published
- 2014
38. Biochemical characterization of unusual cysteine protease of P. falciparum, metacaspase-2 (MCA-2)
- Author
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Ajay K. Saxena, Agam P. Singh, Rajnikant Dixit, Vandana, Kailash C. Pandey, Jitendra Singh, Mymoona Akhter, Ruby Sharma, Brijesh Rathi, Anju Katyal, and Pradyumna Kumar Mishra
- Subjects
0301 basic medicine ,Proteases ,Proteolysis ,030106 microbiology ,Plasmodium falciparum ,Cysteine Proteinase Inhibitors ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,Cysteine Proteases ,Leucine ,parasitic diseases ,medicine ,Molecular Biology ,Caspase ,medicine.diagnostic_test ,biology ,Gene Expression Profiling ,Dipeptides ,Ketones ,Cysteine protease ,Metacaspase ,Z-FA-FMK ,030104 developmental biology ,chemistry ,Biochemistry ,Apoptosis ,biology.protein ,DNA fragmentation ,Parasitology - Abstract
Earlier studies on Plasmodium apoptosis revealed the presence of proteases with caspases like- activity, which are known as “metacaspases”. Although this family of cysteine proteases is structurally similar to caspases with Cys-His dyad but their evolutionary significance and functional relevance remains largely unknown. These proteases are considered to be an important target against malaria due to their absence in humans. In this report, we have biochemically characterized metacaspase-2 (PfMCA-2) of P.falciparum. Enzymatic assay showed that PfMCA-2 efficiently cleaved arginine/lysine specific peptide, but not caspase-specific substrate. Consistently, PfMCA-2 activity was sensitive to effector caspases inhibitor, Z-FA-FMK, and mildly inhibited by aprotinin and E-64. However, general caspase inhibitors such as Z-VAD-FMK and Z-DEVD-FMK had no effect on PfMCA-2 activity. Z-FA-FMK inhibits parasite growth with an IC50 value of 2.7 μM along with the notable morphological changes. PfMCA-2 specifically expressed in schizonts and gametocyte stages and there was a notable depletion of PfMCA-2 expression in Z-FA-FMK treated schizonts and gametocytes stages of parasite. Notably, PfMCA-2 cleaves a phylogenetically conserved protein, TSN (Tudor staphylococcal nuclease) and the proteolysis of PfTSN did not occur after treatment with the Z-FA-FMK. The production of large amount of reactive oxygen species in presence of Z-FA-FMK caused oxidative stress which in turn leads to loss of cell viability. The oxidative stress further generates positive feedback for the occurrence of cell death in term of phosphatidylserine externalization and DNA fragmentation in vitro.
- Published
- 2017
39. Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model
- Author
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Brajendra K. Singh, Brijesh Rathi, Douglas J Perkins, Vinoth Rajendran, Prashant Kumar, Angela O. Achieng, Prakasha Kempaiah, Prahlad C. Ghosh, and Manmeet Rawat
- Subjects
0301 basic medicine ,Erythrocytes ,Plasmodium berghei ,Science ,medicine.medical_treatment ,Plasmodium falciparum ,030106 microbiology ,Dihydroartemisinin ,Phthalimides ,Parasite load ,Article ,Phthalimide ,Antimalarials ,Inhibitory Concentration 50 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Chloroquine ,medicine ,Animals ,Humans ,Antimalarial Agent ,Author Correction ,Life Cycle Stages ,Multidisciplinary ,biology ,Drug Synergism ,biology.organism_classification ,Artemisinins ,Malaria ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Biochemistry ,Medicine ,Drug Therapy, Combination ,Female ,Growth inhibition ,medicine.drug - Abstract
A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC50 values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.
- Published
- 2017
40. Effect of Oxygen Ion Irradiation on the Structural and Optical Properties of L-Arginine Acetate Single Crystals
- Author
-
R. Ramesh Babu, N. Renuka, Kanika Thukral, Brijesh Rathi, and N. Vijayan
- Subjects
010302 applied physics ,Diffraction ,Photoluminescence ,Arginine ,Chemistry ,Inorganic chemistry ,Analytical chemistry ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,Evaporation (deposition) ,Spectral line ,0103 physical sciences ,Irradiation ,Fourier transform infrared spectroscopy ,0210 nano-technology ,Single crystal - Abstract
In the present work, a potential nonlinear optical single crystal, L-arginine acetate (LAA) was grown by slow evaporation solution growth technique. The grown LAA single crystal was irradiated with oxygen ions at the dose rate of 600 krad and 1 Mrad in order to tune the structural and optical properties . The structural properties of pristine and oxygen ions irradiated LAA single crystals were studied using Powder X-ray diffraction and Fourier Transform Infrared spectroscopy. The results obtained reveal the structural changes that are generated due to irradiation. Optical behavior of prisitine and oxygen ions irradiated crystals was studied by UV-Vis-NIR and photoluminescence spectra recorded at room temperature.
- Published
- 2017
41. Synthesis, structural aspects and nonlinear optical properties of novel phthalimide derivatives: theoretical and experimental approach
- Author
-
Anil K. Singh, N. Vijayan, Ram Kishan, Brajendra K. Singh, Vadivelu Balachandran, Hemandra K. Tiwari, Brijesh Rathi, and Vijay Bahadur
- Subjects
Phthalimides ,Stereochemistry ,Hydrogen bond ,Chemistry ,Organic Chemistry ,Hyperpolarizability ,Crystal structure ,Triclinic crystal system ,Phthalimide ,chemistry.chemical_compound ,Crystallography ,Asymmetric carbon ,Orthorhombic crystal system ,Physical and Theoretical Chemistry - Abstract
Novel phthalimides (1, 2, 3) possessing variability of cyclic amines have been synthesized and characterized by analytical and spectroscopic techniques. Phthalimide 1 and 2 crystallized in a triclinic system with space group P; however, an orthorhombic system with a chiral space group of P2(1)2(1)2(1) was observed for 3 possessing piperidine cyclic amine. The hydrogen atoms attached to the central chiral carbon were oriented anti to each other resulting in minimum steric repulsion. The occurrence of C-H center dot center dot center dot O hydrogen bonds in 1, 2, 3 enabled the building of several supramolecular structures. Hyperpolarizability 197.6096 Debye angstrom(2) calculated for 1 was found to be higher than the hyperpolarizabilities, 138.0836 and 165.2521 Debye angstrom(2) measured for 2 and 3, respectively. Subsequently, phthalimides (1, 2, 3) were assessed for second harmonic generation (SHG) response, and a negligible response was recorded for 1 and 2; however, 3 showed a significant response of 14.2 mV. In addition to acentric structure, helical structural motifs identified in 3 could be responsible for its enhanced SHG response.
- Published
- 2014
42. 'Phloem sap analysis of Schleichera oleosa (Lour) Oken, Butea monosperma (Lam) Taub. and Ziziphus mauritiana (Lam) and hemolymph of Kerria lacca (Kerr) using HPLC and tandem mass spectrometry'
- Author
-
Amit Vashishtha, K. K. Sharma, Brijesh Rathi, Suman Lakhanpaul, and Sandeep Kaushik
- Subjects
chemistry.chemical_classification ,biology ,Physiology ,Host (biology) ,media_common.quotation_subject ,fungi ,Plant Science ,Ziziphus ,Insect ,biology.organism_classification ,Amino acid ,Biochemistry ,chemistry ,Hemolymph ,Botany ,Butea ,Phloem ,Molecular Biology ,Kerria lacca ,Research Article ,media_common - Abstract
Females of lac insects especially of Kerria lacca (Kerr) secret a resin known as lac for their own protection, which has tremendous applications. Lac insect completes its lifecycle on several host taxa where it exclusively feeds on phloem sap but Schleichera oleosa (Lour.) Oken, Butea monosperma (Lam.) and Ziziphus mauritiana (Lam.) are its major hosts. Analysis of phloem sap constituents as well as hemolymph of lac insect is important because it ultimately gets converted into lac by insect intervention. Main phloem sap constituent’s viz. sugars and free amino acids and hemolymph of lac insect were analyzed using HPLC and tandem mass spectrometry, respectively. The results were transformed to relative percentage of the total sugars and free amino acids analyzed in each sample for comparison among lac insect hemolymph and the phloem sap of the three different host taxa. Sucrose (58.9 ± 3.6–85.6 ± 0.9) and trehalose (62.3 ± 0.4) were the predominant sugars in phloem sap of three taxa and hemolymph of lac insect, respectively. Glutamic acid (33.1 ± 1.4–39.8 ± 1.4) was found to be main amino acid among the phloem sap of three taxa while tyrosine (61 ± 2.6) was the major amino acid in hemolymph of lac insect. The relative percentage of non-essential amino acids (60.8 %–69.9 %) was found to be more in all the three host taxa while essential amino acids (30.1 %–35.4 %) were present at a lower relative percentage. In contrast to this, the relative percentage of essential amino acids (81.9 %) was observed to be higher as compared to non-essential amino acids (17.7 %) in lac insect hemolymph. These results led to the detection of lac insect’s endosymbionts. Moreover, this study revealed a clue regarding the importance of development of a synthetic diet for this insect so that a precise pathway of lac biosynthesis could be investigated for thorough understanding.
- Published
- 2013
43. Evaluation of phytochemical and pharmacological aspects of Holarrhena antidysenterica (Wall.): A comprehensive review
- Author
-
Amit Vashishtha, Brijesh Rathi, Aishwarye Sharma, N.V.S.R.K. Prasad, P. Hemalatha Reddy, and Snehadri Sinha
- Subjects
Phytochemistry ,biology ,Apocynaceae ,Traditional medicine ,fungi ,food and beverages ,Pharmacognosy ,biology.organism_classification ,Conessine ,chemistry.chemical_compound ,Phytochemical ,chemistry ,Botany ,Natural Product Research ,Medicinal plants ,Holarrhena - Abstract
Medicinal plants are generating an ever-increasing amount of interest due to the effectiveness, low cost and minimal side-effects associated with drugs derived from them. Holarrhena antidysenterica (syn. H. pubescens) WALL., belonging to the family Apocynaceae, is commended for the medicinal applications of its stem bark, leaves and seeds in Ayurveda. During the past century, studies on the phytochemical and pharmacological nature of the plant have yielded important results regarding the chemical constituents present and have also verified the traditionally claimed properties associated with the plant viz. analgesic, antibacterial, anti-diarrhoeal, anti-amoebic, anti-inflammatory and anti-haemorrhoidal activities. Moreover, recently some other properties have also been discovered viz. anti-malarial, anti-diabetic, anti-oxidant, anti-urolithic, anti-mutagenic, CNS-stimulating, Angiotensin-converting-enzyme inhibitory and acetylcholinesterase inhibitory activity. This review discusses the findings of studies on the aforementioned properties of the plant in detail and 68 alkaloids isolated from various parts of plant to justify its widespread use in the treatment of a variety of diseases and suggests future lines of research.
- Published
- 2013
44. Synthesis, growth, and characterization of iminodiacetic acid monohydrochloride
- Author
-
S. C. Mojumdar, K. Safakath, Brijesh Rathi, Neelam Rani, Reji Philip, G. Bhagavannarayana, G. Madhurambal, and N. Vijayan
- Subjects
Diffraction ,Materials science ,Iminodiacetic acid ,Analytical chemistry ,Crystal structure ,Condensed Matter Physics ,Chemical reaction ,chemistry.chemical_compound ,chemistry ,Elemental analysis ,Grain boundary ,Z-scan technique ,Physical and Theoretical Chemistry ,Spectroscopy - Abstract
The title compound of iminodiacetic acid hydrochloride (IDAAMHCL) has been successfully synthesized by adopting conventional chemical reaction and the single crystals have been grown by solvent evaporation method at room temperature and studied its various properties and reported for the first time. The lattice dimension and the crystal structure were identified from the powder X-ray diffraction analysis. The crystalline perfection assessed by high resolution X-ray diffraction technique shows that the specimen is free from structural grain boundaries. The presence of functional groups and the protons in IDAAMHCl was confirmed by Fourier transform infra-red and NMR (1H and 13C) spectroscopic techniques. The presence of carbon, hydrogen, and nitrogen was confirmed by elemental analysis. The optical behavior of IDAAMHCl was assessed by UV-visible spectroscopy and it is found that there is no absorption in the entire visible region of the spectrum. The Z scan measurements at 532 nm with 5 ns laser pulses show that IDAAMHCL is a very good candidate for optical limiting applications.
- Published
- 2013
45. Depletion of the Ozone Layer and Its Consequences: A Review
- Author
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Kuldeep Sharma, Neeti Mehla, Brijesh Rathi, K. K. Sharma, Vashishtha Amit, Rishi Pal Singh, Deepali, Sonal Bhatnagar, Anjali Aggarwal, and Reeta Kumari
- Subjects
Bronchial Diseases ,Ozone ,food and beverages ,Biosphere ,General Medicine ,Ozone depletion ,Crop productivity ,chemistry.chemical_compound ,chemistry ,Environmental chemistry ,Ozone layer ,Environmental science ,Ecosystem ,Plant system - Abstract
Ozone (O3) is a stratospheric layer that plays important role in providing support to humans for their survival. It is an essential factor for many global, biological and environmental phenomena. The ultra-violet (UV) rays emitted from sun are captured by ozone and thereby provide a stable ontological structure in the biosphere. Various anthropogenic activities such as emissions of CFCs, HCFCs and other organo-halogens lead to the depletion of ozone. The ozone depletion resulted in secondary production of an ozone layer near the ground (terrestrial ozone layer), which is responsible for adverse effects on plants, humans and environment with increased number of bronchial diseases in humans. The mutations caused by UV rays result in variation in morphogenic traits of plants which ultimately decreases crop productivity. However, UV radiation is required in optimum intensity for both plants and animals. This review takes into an account the wide ranging effects of ozone depletion with a majority of them being detrimental to the plant system.
- Published
- 2013
46. Asymmetric Reductive Amination of Carbonyl Compounds by Using N,N,N-Tributylpropanaminium Based Novel Chiral Ionic Liquid
- Author
-
Sharda Pasricha, Brijesh Rathi, and B Rupini
- Subjects
chemistry.chemical_compound ,Sodium borohydride ,Dual role ,chemistry ,Bromide ,Reducing agent ,Ionic liquid ,Polymer chemistry ,Ammonium ,Reductive amination - Abstract
Asymmetric reductive amination of carbonyl compounds was carried out using a novel class of aliphatic quarternary ammonium based chiral ionic liquid. S-(+)-2,3-dihydroxy-N,N,N-tributylpropanaminum bromide chiral ionic liquid has been synthesized, characterized and used for asymmetric reductive amination of carbonyl compounds in the presence of sodium borohydride. These preliminary results are encouraging and advocate dual role of novel ionic liquid as a medium and reducing agent for proficient conversion of ketones to amines, however, reductive amination reaction needs to be established for other substituents.
- Published
- 2013
47. Design, synthesis and biological evaluation of Arylpiperazine-based novel Phthalimides: active inducers of testicular germ cell apoptosis
- Author
-
Anil K. Singh, Ankur Maheshwari, Avijit Podder, Yogesh Kumar, Brijesh Rathi, Helena Tomás, B Rupini, N. Latha, Ram Kishan, Jitender Kumar Bhardwaj, Ana Olival, Renuka Agrawal, Brajendra K. Singh, and João Rodrigues
- Subjects
0301 basic medicine ,Phthalimides ,Programmed cell death ,TUNEL assay ,Cancer cells ,Chemistry ,Acridine orange ,Apoptosis ,General Chemistry ,In vitro ,03 medical and health sciences ,chemistry.chemical_compound ,Faculdade de Ciências Exatas e da Engenharia ,030104 developmental biology ,0302 clinical medicine ,Aryl piperazine ,Biochemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular docking ,Cancer research ,DNA fragmentation - Abstract
Understanding of apoptosis or programmed cell death has provided the basis for novel therapeutics that has resulted in rationally designed anticancer strategies. Recently, inducers of apoptosis have been used in cancer therapy. In this work, we describe the role of chiral phthalimides functionalized with piperazines as potential apoptotic inducers. The listed twenty phthalimides were assessed for their in vitro apoptotic activity against testicular germ cells. All phthalimides showed a significant apoptotic response (∼39 to ∼68%). TUNEL assay and acridine orange fluorescence staining were carried out to investigate the molecular mechanisms responsible for the cell death. Phthalimides exhibited substantial apoptotic induction following the intrinsic pathway mechanism. Studies advocated that the apoptotic induction was mediated through caspase-9, caspase-3, JNK MAP kinase and tumor suppressor p53, which was accompanied by DNA fragmentation and nuclear condensation. Besides, the best five phthalimides regarding apoptotic action were evaluated for in vitro cytotoxic effects against CAL-72 and MCF-7 cancer cell lines. Compounds showed efficient killing of cancer cells. This discovery of functionalized phthalimides as apoptotic inducers would be highly valuable in understanding the mechanism of apoptosis at the molecular level and opens up new possibilities for therapeutic strategies.
- Published
- 2016
48. Synthesis and conformational features of sym N,N′,N″-triarylguanidines
- Author
-
Natesan Thirupathi, Kanniyappan Gopi, and Brijesh Rathi
- Subjects
chemistry.chemical_classification ,Negative hyperconjugation ,chemistry.chemical_compound ,chemistry ,Stereochemistry ,Aryl ,Steric factor ,Substituent ,Non-covalent interactions ,General Chemistry ,Crystal structure ,Guanidine ,Single crystal - Abstract
A one pot reaction involving sym N,N′-diarylthiourea and the respective arylamine in the presence of aq. KOH in nitrobenzene at ≥105°C afforded sym N,N′,N″-triarylguanidine in fair to good yield and the products have been characterized. Sym N,N′,N″-tri(4-tolyl)guanidine possesses (7) anti-anti conformation, sym N,N′,N″-tri(2-tolyl)guanidine (8) and sym N,N’,N″-tris(2,4-xylyl)guanidine (11) each possess anti-anti αβα conformation whereas sym N,N′,N″-tris(2-anisyl)guanidine possesses (9) syn-anti αββ conformation as determined by single crystal X-ray diffraction data. The observed conformations appear to result from a subtle balance between steric factor associated with the aryl substituent and multiple electronic factors namely n-π conjugation/negative hyperconjugation and non-covalent interactions in the crystal lattice.
- Published
- 2010
49. Self-assembled peptide nanoarchitectures: applications and future aspects
- Author
-
João Rodrigues, Prem Prakash Sharma, Nikolay Yu. Gorobets, and Brijesh Rathi
- Subjects
Peptide nanoube ,Dendrimers ,Human welfare ,Computer science ,Static Electricity ,Nanotechnology ,Peptide ,Peptide nanosphere ,Biosensing Techniques ,Regenerative Medicine ,Peptides, Cyclic ,Self assembled ,Faculdade de Ciências Exatas e da Engenharia ,Drug Delivery Systems ,Drug Discovery ,Humans ,Peptide nanofiber ,chemistry.chemical_classification ,Peptide dendrimer ,Tissue Engineering ,Gene Transfer Techniques ,Hydrogels ,General Medicine ,Nanostructures ,chemistry ,Peptide self-assembly ,Thermodynamics ,Hydrophobic and Hydrophilic Interactions ,Peptide hydrogel - Abstract
Among the diversity of natural and synthetic compounds being studied and applied for human welfare, peptides able to develop nanostructures are currently under special attention of scientists. In this review, we focus on such properties of peptides and various kinds of intramolecular interactions allowing their ability to form different shapes of nanoassemblies. We have also discussed the applications of self-assembled peptides in various biomedical fields where they can be employed as cargo to target delivery of drugs, genes, in tissue engineering, regenerative medicines, and biosensors.
- Published
- 2015
50. Design, synthesis and biological evaluation of functionalized phthalimides: a new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite
- Author
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Neelu Singh, Brajendra K. Singh, N. Latha, Akansha Pant, Kailash C. Pandey, Brijesh Rathi, Prahlad C. Ghosh, Anil K. Singh, Vinoth Rajendran, and Sandeep Garg
- Subjects
Stereochemistry ,Clinical Biochemistry ,Plasmodium falciparum ,Pharmaceutical Science ,Phthalimides ,Biochemistry ,Piperazines ,Phthalimide ,chemistry.chemical_compound ,Antimalarials ,Chloroquine ,Drug Discovery ,medicine ,Humans ,Antimalarial Agent ,Artemisinin ,Malaria, Falciparum ,Molecular Biology ,Hypoxanthine ,biology ,Organic Chemistry ,biology.organism_classification ,Molecular Docking Simulation ,Piperazine ,Cysteine Endopeptidases ,chemistry ,Molecular Medicine ,medicine.drug - Abstract
Phthalimides functionalized with cyclic amines were synthesized, characterized and screened for their in vitro antimalarial efficacy against Plasmodium falciparum (Pf3D7). Of all the listed phthalimides evaluated, 14 and 24 were identified as potent antimalarial agents as advocated by assessment of their ability to inhibit [3H] hypoxanthine incorporation in the nucleic acid of parasites. In addition, phthalimides 14 and 24 were incubated for 60 and 90 h and an enhanced antimalarial effect was noticed with increase in time to great extent. A reduction in IC50 values was observed with increase in exposure time of the parasite to the compounds. A symmetric phthalimide, 24 possessing piperazine as linker unit was identified as the most potent antimalarial agent with IC50 values of 5.97 ± 0.78, 2.0 ± 1.09 and 1.1 ± 0.75 μM on incubation period of 42, 60 and 90 h, respectively. The abnormal morphologies such as delay in developmental stages, growth arrest and condensed nuclei of parasite were observed with the aid of microscopic studies upon exposure with 14 and 24. The evaluation of 14 and 24 against chloroquine resistant strain, (Pf7GB) of P. falciparum afforded IC50 values, 13.29 ± 1.20 and 7.21 ± 0.98 μM, respectively. The combination of 24 with artemisinin (ART) showed enhanced killing of parasite against Pf3D7. Further, all phthalimides were evaluated for their activity against falcipain-2 (FP2), a major hemoglobinase of malarial parasite. The enzymatic assay afforded 6 as most active member against FP2. To the best of our knowledge this is the initial study represents phthalimide protected amino acids functionalized with cyclic amines as potent antimalarial agents.
- Published
- 2014
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