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Background: DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as ‘dormancy regulon’. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB. Objective: We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches. Methods: The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB. Results: Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature. Conclusion: The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.

Herein, we report a metal/additive-free protocol for the activation of nitrile towards nucleophilic addition and subsequent annulation under an aqueous medium for the first time.

The role of functional group in discovery of Nirmatrelvir is valuable and interesting for development of various inhibitors against viral diseases.

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a critical need for treatments to reduce morbidity and mortality associated with this disease. However, traditional drug development takes many years, which is not practical solution given the current pandemic. Therefore, a viable option is to repurpose existing drugs. The structural data of several proteins vital for the virus became available shortly after the start of the pandemic. In this review, we discuss the importance of these targets and their available potential inhibitors predicted by the computational approaches. Among the hits identified by computational approaches, 35 candidates were suggested for further evaluation, among which ten drugs are in clinical trials (Phase III and IV) for treating Coronavirus 2019 (COVID-19).

Abstract: Synthetic pesticides, crucial compounds for agricultural production, degrade quickly and damage the environment, hence solutions for their decreased usage or formulations with prolonged efficacy at low dosages are needed. Nanotechnology for nanosized formulations may reduce pesticide adverse effects. Nano-encapsulated pesticides made from nanocapsules, nanoemulsions, micelles, and nanogels outperform traditional pesticides with minimum environmental impact. Nanopesticides allowed target-based administration to decrease leaching and drainage into water bodies, and lower pesticide active component dosages. Nanocapsules with a core-shell configuration and a pesticide in the core are the most advantageous nanomaterials. Nanocapsules shield the active component. Stimuli-responsive nanocapsules may limit pesticide release by responding to pH, temperature, light, enzyme, or redox reactions. Toxicity prevents their use. This review discusses the latest developments in nanocapsule fabrication methods, their relevance, contemporary synthetic approaches to developing pesticide-loaded nanocapsules, and the features of these nanocomposites, with an emphasis on sustainable agricultural applications.

Diagnosis and treatment of lung diseases pose serious challenges. Currently, diagnostic as well as therapeutic methods show poor efficacy toward drug-resistant bacterial infections, while chemotherapy causes toxicity and nonspecific delivery of drugs. Advanced treatment methods that cure lung-related diseases, by enabling drug bioavailability via nasal passages during mucosal formation, which interferes with drug penetration to targeted sites, are in demand. Nanotechnology confers several advantages. Currently, different nanoparticles, or their combinations, are being used to enhance targeted drug delivery. Nanomedicine, a combination of nanoparticles and therapeutic agents, that delivers drugs to targeted sites increases the bioavailability of drugs at these sites. Thus, nanotechnology is superior to conventional chemotherapeutic strategies. Here, the authors review the latest advancements in nanomedicine-based drug-delivery methods for managing acute and chronic inflammatory lung diseases.

Compound VI exhibits potent activity against Zika virus infection combined with favorable cellular uptake and biodistribution without apparent cytotoxicity in a mouse model.

We optimized a solvent-free mechanochemical grinding procedure for the synthesis of N-substituted amines. The method involves mild reaction conditions and isolation of products without column chromatography.

Matrix Metalloproteinases-9 (MMP-9) is one of the important targets that play a vital role in various diseases such as cancer, Alzheimer’s, arthritis, etc. Traditionally, MMP-9 inhibitors have been unable to achieve selectivity to get around this target; thereby, novel mechanisms such as inhibition of activated MMP-9 zymogen (pro-MMP-9) have been discovered. The JNJ0966 was one of the few compounds that attained the requisite selectivity by inhibiting the activation of MMP-9 zymogen (pro-MMP-9). Since JNJ0966, no other small molecules have been identified. Herein, extensive in silico studies were called upon to bolster the prospect of exploring potential candidates. The key objective of this research is to identify the potential hits from the ChEMBL database via molecular docking and dynamics approach. Protein with PDB ID: 5UE4, having a unique inhibitor in an allosteric binding pocket of MMP-9, was chosen for the study. Structure-based virtual screening and MMGBSA binding affinity calculations were performed, and five potential hits were finalized. Detailed analysis of the best-scoring molecules was performed with ADMET analysis and molecular dynamics (MD) simulation. All five hits outperformed JNJ0966 in the docking assessment, ADMET analysis, and molecular dynamics simulation. Accordingly, our research findings imply that these hits can be investigated for in vitro and in vivo studies against proMMP9 and might be explored as potential anticancer drugs. The outcome of our research might contribute in expediting the exploration of drugs that inhibits proMMP-9. Communicated by Ramaswamy H. Sarma

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.

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.

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

In the recent past, chitosan demonstrated intriguing applications in the different domains of biomedical science, probably due to its biodegradability, biocompatibility, minimal toxicity, cost-effectiveness, and easy-going synthetic procedures. Chitosan is the second most prevalent amino polysaccharide after cellulose, generated from a deacetylated version of chitin. This short review briefly explains the preparation methods for chitosan from chitin and its role as a drug carrier for biomedical applications.

Nowadays, about 14% of couples have difficulty in conceiving, and half of the cases are attributed to men. Asthenozoospermia or poor sperm motility is considered as the cause of infertility in males which is most common. Even though energy metabolism is considered the main reason for the etiology of asthenospermia, few attempts are made to determine the pathway of its metabolic potential. Recognition of cellular as well as molecular pathways that lead to reduced sperm motility may lead to the implementation of new therapeutic strategies to eliminate low sperm motility in people with asthenozoospermia. This review article discusses the key causes of decreased sperm motility and some of the muted genes and metabolic causes of the same.

Plasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, Plasmodium falciparum (Pf). Plm V is required for cleaving the PEXEL motifs of many Pf proteins...

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.

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.

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.

The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is responsible for the COVID-19 outbreak. The highly contagious COVID-19 disease has spread to 216 countries in less than six months. Though several vaccine candidates are being claimed, an effective vaccine is yet to come. A novel reverse epitomics approach, ‘overlapping-epitope-clusters-to-patches’ method is utilized to identify the antigenic regions from the SARS-CoV-2 proteome. These antigenic regions are named as ‘Ag-Patch or Ag-Patches’, for Antigenic Patch or Patches. The identification of Ag-Patches is based on the clusters of overlapping epitopes rising from SARS-CoV-2 proteins. Further, we have utilized the identified Ag-Patches to design Multi-Patch Vaccines (MPVs), proposing a novel method for the vaccine design. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and cDNA constructs. We identified 73 CTL (Cytotoxic T-Lymphocyte) and 49 HTL (Helper T-Lymphocyte) novel Ag-Patches from the proteome of SARS-CoV-2. The identified Ag-Patches utilized to design MPVs cover 768 overlapping epitopes targeting 55 different HLA alleles leading to 99.98% of world human population coverage. The MPVs and Toll-Like Receptor ectodomain complex shows stable complex formation tendency. Further, the cDNA analysis favors high expression of the MPVs constructs in a human cell line. We identified highly immunogenic novel Ag-Patches from the entire proteome of SARS CoV-2 by a novel reverse epitomics approach and utilized them to design MPVs. We conclude that the novel MPVs could be a highly potential novel approach to combat SARS-CoV-2, with greater effectiveness, high specificity and large human population coverage worldwide., Graphical Abstract Communicated by Ramaswamy H. Sarma

In December 2019, outbreak of novel coronavirus (COVID-19) occurred in Wuhan, Hubei Province, China and exported across the world leading to thousands of deaths and millions of suspected cases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection into the host undergoes a huge number of complex replicative machineries which still remains unclear. Understanding the mechanism (s) of replication and mode of infection of SARS-CoV2 to human cells will help us in the development of novel vaccines or drugs for the eradication and prevention of the disease. This review compiles the knowledge of SARS-CoV2 replicative machinery, mode of infection to the human cells and the development of drugs and vaccines which are currently under clinical trials.

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins., Graphical 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.

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.

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

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.