8 results on '"Brijesh Rathi"'
Search Results
2. Metal-free construction of aminated isoquinoline frameworks from 2-(2-oxo-2-arylethyl) benzonitrile in an aqueous medium
- Author
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Himanshi Sharma, Manoj Kumar, Aaftaab Sethi, and Brijesh Rathi
- Abstract
Herein, we report a metal-free protocol for the activation of nitrile towards the nucleophilic addition and subsequent annulation under an aqueous medium for the first time. The protocol divulges an efficient route for the construction of diversified aminated isoquinolines. Differently substituted primary as well as secondary amines underwent the reaction in a highly regioselective manner. The reaction is operationally simple, shows high functional group tolerance, easier modification of well-known drugs, and successfully extended to gram-scale synthesis.
- Published
- 2022
3. Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane
- Author
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Meenakshi Bansal, Brijesh Rathi, Poonam, Vladimir Potemkin, Charu Upadhyay, Bhupender S. Chhikara, Sumit Kumar, and Maria Grishina
- Subjects
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.
- Published
- 2020
4. Discovery of New Hydroxyethylamine Analogs against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure–Activity Relationship Studies
- Author
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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
- Subjects
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.
- Published
- 2020
5. Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages
- Author
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Angela O. Achieng, Kailash C. Pandey, Amit Singh, Mansi Pandit, Poonam, Brajendra K. Singh, Daniel E. Goldberg, Ben M. Dunn, Ramesh Chandra, Brijesh Rathi, Prakasha Kempaiah, Latha Narayanan, Snigdha Singh, Jiang He, Afshana Quadiri, Akansha Pant, Agam P. Singh, Armiyaw S. Nasamu, Prahlad C. Ghosh, Vandana, Vinoth Rajendran, Jyoti Prakash Singh, and Nikesh Gupta
- Subjects
0301 basic medicine ,Plasmodium berghei ,Plasmodium falciparum ,030106 microbiology ,Plasmodium vivax ,Phthalimides ,Plasmodium ,Microbiology ,Antimalarials ,Inhibitory Concentration 50 ,Mice ,03 medical and health sciences ,In vivo ,Drug Discovery ,parasitic diseases ,Ethylamines ,medicine ,Gametocyte ,Animals ,Aspartic Acid Endopeptidases ,Life Cycle Stages ,biology ,Chloroquine ,biology.organism_classification ,medicine.disease ,In vitro ,030104 developmental biology ,Infectious Diseases ,Malaria - Abstract
The eradication of malaria remains challenging due to the complex life cycle of Plasmodium and the rapid emergence of drug-resistant forms of Plasmodium falciparum and Plasmodium vivax. New, effective, and inexpensive antimalarials against multiple life stages of the parasite are urgently needed to combat the spread of malaria. Here, we synthesized a set of novel hydroxyethylamines and investigated their activities in vitro and in vivo. All of the compounds tested had an inhibitory effect on the blood stage of P. falciparum at submicromolar concentrations, with the best showing 50% inhibitory concentrations (IC50) of around 500 nM against drug-resistant P. falciparum parasites. These compounds showed inhibitory actions against plasmepsins, a family of malarial aspartyl proteases, and exhibited a marked killing effect on blood stage Plasmodium. In chloroquine-resistant Plasmodium berghei and P. berghei ANKA infected mouse models, treating mice with both compounds led to a significant decrease in blood parasite load. Importantly, two of the compounds displayed an inhibitory effect on the gametocyte stages (III-V) of P. falciparum in culture and the liver-stage infection of P. berghei both in in vitro and in vivo. Altogether, our findings suggest that fast-acting hydroxyethylamine-phthalimide analogs targeting multiple life stages of the parasite could be a valuable chemical lead for the development of novel antimalarial drugs.
- Published
- 2018
6. Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2
- Author
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Dhruv Kumar, Brijesh Rathi, Sibin Raj, Prem Prakash Sharma, and Vaishali Chandel
- Abstract
Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, in vitro and in vivo validation of these findings will be helpful in bringing these molecules at the clinical settings.
- Published
- 2020
7. Potential Drugs Targeting Nsp16 Protein May Corroborates a Promising Approach to Combat SARSCoV-2 Virus
- Author
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Amit Kumar, Brijesh Rathi, Subodh Kumar Mishra, Prativa Majee, Neha Jain, and Uma Shankar
- Abstract
The recent ongoing pandemic caused by SARS-CoV-2 continues to impose devastating impacts and is accountable for the loss of more than 250,000 human lives within a short span of four months. This urges immediate therapeutic measures to control the impact of this disease. One of the most conserved and potentially druggable sites is the Nsp16 active site that performs the 2’-O-methyltransferase activity and puts a 5’ cap on the viral RNA molecules. This allows them to mimic endogenous transcripts for the efficient translation of viral proteins and evasion of the immune response. Herein, we screened three libraries of compounds (>5500) with chemical diversity to identify hits against Nsp16 active site of SARS-CoV-2. From each library a top hit was identified, namely Velpatasvir from the FDA compounds; JFD00244 from the LOPAC library and compound 6 from the SAM based analog library. Interestingly, all three hits showed higher affinity than the positive controls. Velpatasvir is a known anti-viral drug used against Hepatitis C virus, and JFD00244 is a SIRT2 inhibitor. 100ns molecular simulation studies showed all three molecules to have stable and energetically favourable interactions with the active site of Nsp16. In summary, this investigation identified three potential drug candidates that are predicted to be potent Nsp16 inhibitors and could be pursued further in cell-based studies.
- Published
- 2020
8. Catalyst Free, Nitromethane Assisted Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines
- Author
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Sumit Kumar, Poonam, Vladimir Potemkin, Maria Grishina, Charu Upadhyay, Meenakshi Bansal, and Brijesh Rathi
- Subjects
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.
- Published
- 2020
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