A Molecular Docking Study Reveals That Short Peptides Induce Conformational Changes in the Structure of Human Tubulin Isotypes αßI, αßII, αßIII and αßIV.

Microtubules are cylindrical protein polymers assembled in the cytoplasm of all eukaryotic cells by polymerization of aß tubulin dimers, which are involved in cell division, migration, signaling, and intracellular traffic. These functions make them essential in the proliferation of cancerous cells and metastases. Tubulin has been the molecular target of many anticancer drugs because of its crucial role in the cell proliferation process. By developing drug resistance, tumor cells severely limit the successful outcomes of cancer chemotherapy. Hence, overcoming drug resistance motivates the design of new anticancer therapeutics. Here, we retrieve short peptides obtained from the data repository of antimicrobial peptides (DRAMP) and report on the computational screening of their predicted tertiary structures for the ability to inhibit tubulin polymerization using multiple combinatorial docking programs, namely PATCHDOCK, FIREDOCK, and ClusPro. The interaction visualizations show that all the best peptides from the docking analysis bind to the interface residues of the tubulin isoforms αßl, αßll, αßlll, and αßlV, respectively. The docking studies were further confirmed by a molecular dynamics simulation, in which the computed root-mean-square deviation (RMSD), and root-mean-square fluctuation (RMSF), verified the stable nature of the peptide-tubulin complexes. Physiochemical toxicity and allergenicity studies were also performed. This present study suggests that these identified anticancer peptide molecules might destabilize the tubulin polymerization process and hence can be suitable candidates for novel drug development. It is concluded that wet-lab experiments are needed to validate these findings.

Development of Novel siRNA Therapeutics: A Review with a Focus on Inclisiran for the Treatment of Hypercholesterolemia.

Over the past two decades, it was discovered that introducing synthetic small interfering RNAs (siRNAs) into the cytoplasm facilitates effective gene-targeted silencing. This compromises gene expression and regulation by repressing transcription or stimulating sequence-specific RNA degradation. Substantial investments in developing RNA therapeutics for disease prevention and treatment have been made. We discuss the application to proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to and degrades the low-density lipoprotein cholesterol (LDL-C) receptor, interrupting the process of LDL-C uptake into hepatocytes. PCSK9 loss-of-function modifications show significant clinical importance by causing dominant hypocholesterolemia and lessening the risk of cardiovascular disease (CVD). Monoclonal antibodies and small interfering RNA (siRNA) drugs targeting PCSK9 are a significant new option for managing lipid disorders and improving CVD outcomes. In general, monoclonal antibodies are restricted to binding with cell surface receptors or circulating proteins. Similarly, overcoming the intracellular and extracellular defenses that prevent exogenous RNA from entering cells must be achieved for the clinical application of siRNAs. N-acetylgalactosamine (GalNAc) conjugates are a simple solution to the siRNA delivery problem that is especially suitable for treating a broad spectrum of diseases involving liver-expressed genes. Inclisiran is a GalNAc-conjugated siRNA molecule that inhibits the translation of PCSK9. The administration is only required every 3 to 6 months, which is a significant improvement over monoclonal antibodies for PCSK9. This review provides an overview of siRNA therapeutics with a focus on detailed profiles of inclisiran, mainly its delivery strategies. We discuss the mechanisms of action, its status in clinical trials, and its prospects.

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds.

Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

Mapping Scientific Productivity Trends and Hotspots in Remdesivir Research Publications: A Bibliometric Study from 2016 to 2021.

In response to global efforts to control and exterminate infectious diseases, this study aims to provide insight into the productivity of remdesivir research and highlight future directions. To achieve this, there is a need to summarize and curate evidence from the literature. As a result, this study carried out comprehensive scientific research to detect trends in published articles related to remdesivir using a bibliometric analysis. Keywords associated with remdesivir were used to access pertinent published articles using the Scopus database. A total of 5321 research documents were retrieved, primarily as novel research articles (n = 2440; 46%). The number of publications increased exponentially from 2020 up to the present. The papers published by the top 12 institutions focusing on remdesivir accounted for 25.69% of the overall number of articles. The USA ranked as the most productive country, with 906 documents (37.1%), equivalent to one-third of the global publications in this field. The most productive institution was Icahn School of Medicine, Mount Sinai, in the USA (103 publications). The New England Journal of Medicine was the most cited, with an h-index of 13. The publication of research on remdesivir has gained momentum in the past year. The importance of remdesivir suggests that it needs continued research to help global health organizations detect areas requiring instant action to implement suitable measures. Furthermore, this study offers evolving hotspots and valuable insights into the scientific advances in this field and provides scaling-up analysis and evidence diffusion on remdesivir.

A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives.

Pyrazoles are five-membered heterocyclic compounds that contain nitrogen. They are an important class of compounds for drug development; thus, they have attracted much attention. In the meantime, pyrazole derivatives have been synthesized as target structures and have demonstrated numerous biological activities such as antituberculosis, antimicrobial, antifungal, and anti-inflammatory. This review summarizes the results of published research on pyrazole derivatives synthesis and biological activities. The published research works on pyrazole derivatives synthesis and biological activities between January 2018 and December 2021 were retrieved from the Scopus database and reviewed accordingly.

A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization.

Microtubules are cylindrical protein polymers formed from αß-tubulin heterodimers in the cytoplasm of eukaryotic cells. Microtubule disturbance may cause cell cycle arrest in the G2/M phase, and anomalous mitotic spindles will form. Microtubules are an important target for cancer drug action because of their critical role in mitosis. Several microtubule-targeting agents with vast therapeutic advantages have been developed, but they often lead to multidrug resistance and adverse side effects. Thus, single-target therapy has drawbacks in the effective control of tubulin polymerization. Molecular hybridization, based on the amalgamation of two or more pharmacophores of bioactive conjugates to engender a single molecular structure with enhanced pharmacokinetics and biological activity, compared to their parent molecules, has recently become a promising approach in drug development. The practical application of combined active scaffolds targeting tubulin polymerization inhibitors has been corroborated in the past few years. Meanwhile, different designs and syntheses of novel anti-tubulin hybrids have been broadly studied, illustrated, and detailed in the literature. This review describes various molecular hybrids with their reported structural-activity relationships (SARs) where it is possible in an effort to generate efficacious tubulin polymerization inhibitors. The aim is to create a platform on which new active scaffolds can be modeled for improved tubulin polymerization inhibitory potency and hence, the development of new therapeutic agents against cancer.

A Bibliometric Analysis of the Literature on Norovirus Disease from 1991-2021.

Norovirus (NoV) is one of the oldest recognized diseases and the leading causal pathogen for acute gastroenteritis (AGE) worldwide. Though numerous studies have been reported on NoV disease, limited research has explored the publication trends in this area. As a result, the objective of this work was to fill the void by conducting a bibliometric study in publication trends on NoV studies as well as discovering the hotspots. The Web of Science central assemblage database was hunted for publications from 1991 to 2021 with "norovirus" in the heading. Microsoft Excel 2016, VOSviewer, R Bibliometrix, and Biblioshiny packages were deployed for the statistical analysis of published research articles. A total of 6021 published documents were identified in the Web of Science database for this thirty-year study period (1991-2021). The analyses disclosed that the Journal of Medical Virology was the leading journal in publications on norovirus studies with a total of 215 published articles, the Journal of Virology was the most cited document with 11,185 total citations. The United States of America (USA) has the most significant productivity in norovirus publications and is the leading country with the highest international collaboration. Analysis of top germane authors discovered that X. Jiang (135) and J. Vinje (119) were the two top relevant authors of norovirus publications. The commonly recognized funders were US and EU-based, with the US emerging as a top funder. This study reveals trends in scientific findings and academic collaborations and serves as a leading-edge model to reveal trends in global research in the field of norovirus research. This study points out the progress status and trends on NoV research. It can help researchers in the medical profession obtain a comprehensive understanding of the state of the art of NoV. It also has reference values for the research and application of the NoV visualization methods. Further, the research map on AGE obtained by our analysis is expected to help researchers efficiently and effectively explore the NoV field.

Unveiling of Pyrimidindinones as Potential Anti-Norovirus Agents-A Pharmacoinformatic-Based Approach.

The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.

Curcumin modulates multiple cell death, matrix metalloproteinase activation and cardiac protein release in susceptible and resistant Plasmodium berghei-infected mice.

Pro-inflammatory signaling, cell death, and metalloproteinases activation are events in Plasmodium infection. However, it is not known if treatment with mefloquine (MF), and curcumin (CM) supplementation, will modulate these conditions. Malaria was induced in two different studies using susceptible (NK 65, study 1) and resistant (ANKA, study 2) strains of mouse malaria parasites (Plasmodium berghei) in thirty male Swiss mice (n = 5) in each study. Following confirmation of parasitemia, mice received 10 mL/kg distilled water (infected control), MF (10 mg/kg), MF and CM (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (not infected) were used as control. After treatment, the animals were sacrificed, serum obtained and liver mitochondria were isolated. Serum Tumour Necrosis Factor alpha (TNF-α), C-reactive protein (CRP), Interleukins-1 beta (IL-1ß) and Interleukins-6 (IL-6) as well as caspases-3, 9 (C3 and C9), p53, serum troponin I (TI) and creatine kinase (CK), were assayed using ELISA techniques. Mitochondrial membrane permeability transition (mPT) pore opening, mitochondrial F0F1 ATPase activity, and lipid peroxidation (mLPO) were determined spectrophotometrically. Matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) expressions were determined using electrophoresis. CM supplementation (25 mg/kg) significantly decreased serum p53, TNF-α, CRP and IL-6 compared with MF. In the resistant model, CM prevented mPT pore opening, significantly decreased F0F1 ATPase activity and mLPO. MF activated caspase-3 while supplementation with CM significantly decreased this effect. Furthermore, MMP-2 and MMP-9 were selectively expressed in the susceptible model. Malarial treatment with mefloquine elicits different cell death responses while supplementation with curcumin decreased TI level and CK activities.

Medicinal plants with anti-SARS-CoV activity repurposing for treatment of COVID-19 infection: A systematic review and meta-analysis.

The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus) has emerged as a significant threat to public health with startling drawbacks in all sectors globally. This study investigates the practicality of some medicinal plants for SARS-CoV-2 therapy using a systematic review and meta-analysis of their reported SARS-CoV-1 inhibitory potencies. Relevant data were systematically gathered from three databases, viz., Web of Science, PubMed and Scopus. The information obtained included botanical information, extraction method and extracts concentrations, as well as the proposed mechanisms. Fourteen articles describing 30 different plants met our eligibility criteria. Random effects model and subgroup analysis were applied to investigate heterogeneity. According to subgroup analysis, the substantial heterogeneity of the estimated mean based on the IC 50 values reporting the most potent anti-SARS-CoV 3C--like protease (3CLpro) inhibitors (10.07 %, p < 0.0001), was significantly higher compared to the most active anti-SARS-CoV papain-like protease (PLpro) inhibitors (6.12 %, p < 0.0001). More importantly, the literature analysis revealed that fruit extracts of Rheum palmatum L. and the compound cryptotanshinone isolated from the root of Salvia miltiorrhiza (IC 50 = 0.8 ± 0.2 µmol L-1) were excellent candidates for anti--SARS-CoV targeting PLpro. Meanwhile, iguesterin (IC 50 = 2.6 ± 0.6 µmol L-1) isolated from the bark of Tripterygium regelii emerged as the most excellent candidate for anti-SARS--CoV targeting 3CLpro. The present systematic review and meta-analysis provide valuable and comprehensive information about potential medicinal plants for SARS-CoV-2 inhibition. The chemotypes identified herein can be adopted as a starting point for developing new drugs to contain the novel virus.

Promising inhibitors against main protease of SARS CoV-2 from medicinal plants: In silico identification.

Some compounds reported as active against SARS CoV were selected, and docking studies were performed using the main protease of SARS CoV-2 as the receptor. The docked complex analysis shows that the ligands selectively bind with the target residues and binding affinity of amentoflavone (-10.1 kcal mol-1), isotheaflavin-3'-gallate (-9.8 kcal mol-1), tomentin A and D (-8.0 and -8.8 kcal mol-1), theaflavin-3,3'-digallate (-8.6 kcal mol-1), papyriflavonol A (-8.4 kcal mol-1), iguesterin (-8.0 kcal mol-1) and savinin (-8.3 kcal mol-1) were ranked above the binding affinity of the reference, co-crystal ligand, ML188, a furan-2-carboxamide-based compound. To pinpoint the drug-like compound among the top-ranked compounds, the Lipinski's rule of five and pharmacokinetic properties of all the selected compounds were evaluated. The results detailed that savinin exhibits high gastrointestinal absorption and can penetrate through the blood-brain barrier. Also, modifying these natural scaffolds with excellent binding affinity may lead to discovering of anti-SARS CoV agents with promising safety profiles.

Predicting New Anti-Norovirus Inhibitor With the Help of Machine Learning Algorithms and Molecular Dynamics Simulation-Based Model.

Hepatitis C virus (HCV) inhibitors are essential in the treatment of human norovirus (HuNoV). This study aimed to map out HCV NS5B RNA-dependent RNA polymerase inhibitors that could potentially be responsible for the inhibitory activity of HuNoV RdRp. It is necessary to develop robust machine learning and in silico methods to predict HuNoV RdRp compounds. In this study, Naïve Bayesian and random forest models were built to categorize norovirus RdRp inhibitors from the non-inhibitors using their molecular descriptors and PubChem fingerprints. The best model observed had accuracy, specificity, and sensitivity values of 98.40%, 97.62%, and 97.62%, respectively. Meanwhile, an external test set was used to validate model performance before applicability to the screened HCV compounds database. As a result, 775 compounds were predicted as NoV RdRp inhibitors. The pharmacokinetics calculations were used to filter out the inhibitors that lack drug-likeness properties. Molecular docking and molecular dynamics simulation investigated the inhibitors' binding modes and residues critical for the HuNoV RdRp receptor. The most active compound, CHEMBL167790, closely binds to the binding pocket of the RdRp enzyme and depicted stable binding with RMSD 0.8-3.2 Å, and the RMSF profile peak was between 1.0-4.0 Å, and the conformational fluctuations were at 450-460 residues. Moreover, the dynamic residue cross-correlation plot also showed the pairwise correlation between the binding residues 300-510 of the HuNoV RdRp receptor and CHEMBL167790. The principal component analysis depicted the enhanced movement of protein atoms. Moreover, additional residues such as Glu510 and Asn505 interacted with CHEMBL167790 via water bridge and established H-bond interactions after the simulation. http://zinc15.docking.org/substances/ZINC000013589565.

Antimalarial and Erythrocyte Membrane Stability Properties of Globimetula braunii (Engle Van Tiegh) Growing on Cocoa in Plasmodium berghei-Infected Mice.

INTRODUCTION: Resistant malaria is a fatal disease. Globimetula braunii (African Mistletoe) is traditionally used for malarial treatment but this fact has not been scientifically reported. METHODS: Plasmodium berghei (NK65)-infected male Swiss mice (20±2 g) were treated orally and once daily with 100, 200, and 400 mg/kg BW of methanol extract and its respective hexane, dichloromethane and ethyl acetate fractions for 9 days. P-alaxin was used as control drug P. berghei (ANKA)-infected mice were then treated with the most potent fraction for 5 days. Parasitemia and parasite clearance were determined by microscopy, while hematological parameters, heme, hemozoin, and mouse erythrocyte membrane stabilisation were assayed. The phytochemicals in the most potent fraction were identified using gas chromatography-mass spectrometry. RESULTS: Hexane fraction (HF)-treated mice (400 mg/kg BW) had the least mean parasite load (0.00 ± 0.00; 0.14 ± 0.05%) and highest clearance (100 ± 0.00; 75.50 ± 4.95%) compared with infected control (9.81 ± 0.09; 6.84 ± 0.09%) in susceptible and resistant models, respectively. Hexane fraction modulated hematological indices, minimised erythrocyte membrane damage in heat-induced (2.18 ± 0.94%) and hypotonic solution-induced (7.93 ± 0.93%) compared to artequin (5.05 ± 2.18; 6.38 ± 0.33%) and P-alaxin (67.45 ± 5.15; 56.78 ± 1.10%) in both models of membrane stabilisation, respectively. Hexane fraction (P<0.01) increased heme and decreased hemozoin contents. Friedelan-3-one was identified as the most abundant triterpene. CONCLUSION: The results indicated that G. braunii has anti-plasmodial properties and minimally dis-stabilised erythrocyte membrane. The major findings in this study are that n-hexane fraction of G. braunii possess excellent and moderate antiplasmodial activity against susceptible and resistant P. berghei, respectively. This was reflected via decreased parasite load, improved hematological parameters, increased heme and decreased hemozoin contents. Friedelan-3-one, a major constituent of the n-hexane fraction, may be responsible for this activity.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition.

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 µM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.

Studies on the mitochondrial, immunological and inflammatory effects of solvent fractions of Diospyros mespiliformis Hochst in Plasmodium berghei-infected mice.

The use of medicinal plants in the treatment of malaria is gaining global attention due to their efficacy and cost effectiveness. This study evaluated the bioactivity-guided antiplasmodial efficacy and immunomodulatory effects of solvent fractions of Diospyros mespiliformis in mice infected with a susceptible strain of Plasmodium berghei (NK 65). The crude methanol extract of the stem of D. mespiliformis (DM) was partitioned between n-hexane, dichloromethane, ethyl acetate and methanol. Male Swiss mice (20 ± 2 g) infected with P. berghei were grouped and treated with vehicle (10 mL/kg, control), Artemether lumefantrine (10 mg/kg), 100, 200 and 400 mg/kg of n-hexane, dichloromethane, ethyl acetate and methanol fractions of D. mespiliformis for seven days. Blood was obtained for heme and hemozoin contents while serum was obtained for inflammatory cytokines and immunoglobulins G and M assessments. Liver mitochondria were isolated for mitochondrial permeability transition (mPT), mitochondrial F1F0 ATPase (mATPase) and lipid peroxidation (mLPO) assays. The GC-MS was used to identify the compounds present in the most potent fraction. The dichloromethane fraction had the highest parasite clearance and improved hematological indices relative to the drug control. The heme values increased, while the hemozoin content significantly (P < 0.05) decreased compared with the drug control. The highest dose of HF and MF opened the mPT pore while the reversal effects of DF on mPT, mATPase and mLPO were dose-dependent. The levels of IgG, IgM and TNFα in the DF group were significantly higher than the drug control, while the IL-1ß and IL-6 values did not vary linearly with the dose. Lupeol and Stigmastan-3,5-diene were the most abundant phytochemicals in the DF. The outcome of this study showed that the DF has immunomodulatory effects in infected mice, reduced proliferation of the malaria parasite and thus protect liver cells.

Antibacterial evaluation and molecular docking studies of pyrazole-thiosemicarbazones and their pyrazole-thiazolidinone conjugates.

A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested for anti-microbial activity against two Gram-positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) and four Gram-negative bacteria (Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa). Among the compounds tested, 3-((2,4-dichlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-yl)methylene)hydrazinecarbothioamide (3a) and 2-((3-(2-chlorophenyl)-1-(2,4 dinitrophenyl)-1H-pyrazol-4-yl)methyleneamino)thiazolidin-4-one (4b) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and S. aureus. Structure-activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds 3a and 4b preferably interact with the targets through hydrogen bonding.

Synthesis of 1H-1,2,3-Triazole-Linked Quinoline-Isatin Molecular Hybrids as Anti-Breast Cancer and Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents.

BACKGROUND: The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to tamoxifen, the standard endocrine therapy for the disease, exacts continuous attention. To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profiles. OBJECTIVE: The primary goal of this study was to examine the potential of 1H-1,2,3-triazole linked quinolineisatin molecular hybrids as drug candidates against breast cancer and Methicillin-Resistant Staphylococcus aureus (MRSA) cells. METHODS: The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using Estrogen-Responsive (ER+) MCF-7 and MDA-MB-231 (Triple-Negative Breast Cancer -TNBC) cells, while antimicrobial efficacy was established via the broth dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney cells (HEK293) and human Red Blood Cells (hRBCs). In silico techniques were employed to predict the druglike properties of potent compounds and understand their binding modes with Estrogen Receptor alpha (ERα). RESULTS: Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50µM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDAMB- 231 and MRSA cells with IC50=71.40µM and MIC80=27.34µM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7-disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligandbinding domain of ERα. CONCLUSION: These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.

Discovery of Potential Inhibitors for RNA-Dependent RNA Polymerase of Norovirus: Virtual Screening, and Molecular Dynamics.

Noroviruses are non-enveloped viruses with a positive-sense single-stranded RNA (ssRNA) genome belonging to the genus Norovirus, from the family Caliciviridae, which are accountable for acute gastroenteritis in humans. The Norovirus genus is subdivided into seven genogroups, i.e., (GI-GVII); among these, the genogroup II and genotype 4 (GII.4) strains caused global outbreaks of human norovirus (HuNov) disease. The viral genome comprises three open reading frames (ORFs). ORF1 encodes the nonstructural polyprotein that is cleaved into six nonstructural proteins, which include 3C-like cysteine protease (3CLpro) and a viral RNA-dependent RNA polymerase. ORF2 and ORF3 encode the proteins VP1 and VP2. The RNA-dependent RNA polymerase (RdRp) from noroviruses is one of the multipurpose enzymes of RNA viruses vital for replicating and transcribing the viral genome, making the virally encoded enzyme one of the critical targets for the development of novel anti-norovirus agents. In the quest for a new antiviral agent that could combat HuNov, high throughput virtual screening (HTVS), combined with e-pharmacophore screening, was applied to screen compounds from the PubChem database. CMX521 molecule was selected as a prototype for a similarity search in the PubChem online database. Molecular dynamics simulations were employed to identify different compounds that may inhibit HuNov. The results predicted that compound CID-57930781 and CID-44396095 formed stable complexes with MNV-RdRp within 50 ns; hence, they may signify as promising human norovirus inhibitors.

Design, Synthesis, Antiproliferative Evaluation, and Molecular Docking Studies of N-(3-Hydroxyindole)-Appended ß-Carbolines/Tetrahydro-ß-Carbolines Targeting Triple-Negative and Non-Triple-Negative Breast Cancer.

The present manuscript pertains to the design and synthesis of a series of 3-hydroxyindole-substituted ß-carbolines/tetrahydro-ß-carbolines with an aim to explore their antiproliferative structure-activity relationship against breast cancer. The conjugate with an optimum combination of a flexible tetrahydro-ß-carboline core, a tertiary alcoholic group along with a chloro substituent on the indole ring, proved to be the most active compound. It displayed IC50 values of 13.61 and 22.76 µM against MCF-7 (ER+) and MDA-MB-231 (ER-) cells, respectively. The docking studies were found to be consistent with experimental results owing to the stronger binding affinity of the synthesized conjugates via hydrophobic and H-bonding interactions.

Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads as potential anti-mycobacterials.

A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities against the mc26230 strain of M. tuberculosis with MIC in the range of 5.1-11.9 µM and were non-cytotoxic against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present study.