Design, Synthesis, DFT, docking Studies, and antimicrobial evaluation of novel benzimidazole containing sulphonamide derivatives.

In silico approaches have been employed to design a new series of benzimidazole-containing sulphonamide derivatives and qualified compounds have been synthesized to analyze their potential as antimicrobial agents. Antibacterial screening of all synthesized compounds was done using the broth microdilution method against several human pathogenic bacteria, viz. Gram-positive bacteria [B. cerus (NCIN-2156), B. subtilis (ATCC-6051), S. aureus (NCIM-2079)] and Gram-negative bacteria [P. aeruginosa (NCIM-2036), E. coli (NCIM-2065), and a drug-resistant strain of E. coli (U-621)], and the compounds presented admirable MIC values, ranging between 100-1.56 µg/mL. The combinatorial analysis showed the magnificent inhibitory efficiency of the tested compounds, acquired equipotent to ten-fold more potency compared to original MIC values. An immense synergistic effect was exhibited by the compounds during combination studies with reference drugs chloramphenicol and sulfamethoxazole was presented as fractional inhibitory concentration (∑FIC). Enzyme inhibition studies of all synthesized compounds were done by using peptidyl transferase and dihydropteroate synthase enzymes isolated from E. coli and S. aureus and each of the compound presented the admirable IC50 values, where the lead compound 3 bound to peptidyl transferase (of S. aureus with IC50 363.51 ± 2.54 µM and E. coli IC50 1.04 ± 0.08 µM) & dihydropteroate synthase (of S. aureus IC50 3.51 ± 0.82 µM and E. coli IC50 2.77 ± 0.65 µM), might account for the antimicrobial effect, exhibited excellent inhibition potential. Antifungal screening was also performed employing food poisoning methods against several pathogenic fungal species, viz A. flavus, F. oxysporum, A. niger, and A. brassicae. The obtained result indicated that few compounds can prove to be a potent drug regimen against dreaded MDR strains of microbes. Structural activity relationship (SAR) analysis and docking studies reveal that the presence of electron-withdrawing, polar, and more lipophilic substituents positively favor the antibacterial activity, whereas, electron-withdrawing, more polar, and hydrophilic substituents favor the antifungal activities. A robust coherence has been found in in-silico and in-vitro biological screening results of the compounds.

COVID-19: Pathophysiology, Transmission, and Drug Development for Therapeutic Treatment and Vaccination Strategies.

COVID-19, a dreaded and highly contagious pandemic, is flagrantly known for its rapid prevalence across the world. Till date, none of the treatments are distinctly accessible for this life-threatening disease. Under the prevailing conditions of a medical emergency, one creative strategy for the identification of novel and potential antiviral agents gaining momentum in research institutions and progressively being leveraged by pharmaceutical companies is target-based drug repositioning/repurposing. Continuous monitoring and recording of results offer anticipation that this strategy may help to reveal new medications for viral infections. This review recapitulates the neoteric illation of COVID-19, its genomic dispensation, molecular evolution via phylogenetic assessment, drug targets, the most frequently worldwide used repurposed drugs and their therapeutic applications, and a recent update on vaccine management strategies. The available data from solidarity trials exposed that the treatment with several known drugs, viz. lopinavir-ritonavir, chloroquine, hydroxychloroquine, etc. had displayed various antagonistic effects along with no impactful result in the diminution of mortality rate. The drugs, like remdesivir, favipiravir, and ribavirin, have proved to be quite safer therapeutic options for treatment against COVID-19. Similarly, dexamethasone, convalescent plasma therapy and oral administration of 2DG are expected to reduce the mortality rate of COVID-19 patients.

Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2.

A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme.Communicated by Ramaswamy H. SarmaHighlightsQuinoline derivatives have been designed as protease inhibitors against SARS-CoV-2.The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex.Docking studies indicated the stable ligand-protein complexes for all designed compounds.The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives.Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.

Molecular modelling, synthesis and antimicrobial evaluation of benzimidazole nucleoside mimetics.

A series of new N-1-(ß-d-ribofuranosyl) benzimidazole derivatives has been designed using in silico methods and synthesized as probable antimicrobial agents. Further, the compounds were assessed for their antibacterial and antifungal activity. Antibacterial screening was done by employing broth micro-dilution method and compounds exhibited excellent inhibitory activity (MIC, 50-1.56 µg/mL) against different human pathogenic bacteria, viz. B. cerus, B. subtilis, S. aureus, E. coli and P. aeruginosa and drug resistant strain (DRS) of E. coli. A great synergistic effect was observed during evaluation of ∑FIC, where a combination study was performed using standard references, viz. chloramphenicol and kanamycin. The MIC data obtained from different methods of combination approach revealed 4-128 fold more potency compared to compounds tested alone. The results clearly indicated the possibility of these compounds as active ingredients of drug regimen used against MDR strains. Antifungal screening were also performed employing two different methods, viz. serial dilution method and zone inhibition method, clearly indicated that compounds were also potentially active against several species of pathogenic fungal strains, viz. A. flavus, A. niger, F. oxysporum and C. albicans. The assessment of structure activity relationship (SAR) clearly revealed that presence of less polar and more hydrophobic substituents positively favours the antibacterial activity, conversely, more polar and hydrophilic substituents favours the antifungal activities. Thus, the results positively endorsed the compounds as potent antibacterial and antifungal agents which could be developed as possible drug regimens.

Anti-HIV potential of diarylpyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors: design, synthesis, docking, TOPKAT analysis and molecular dynamics simulations.

In view of the low toxicity of NNRTIs in comparison to NRTIs, a new series of diarylpyrimidine derivatives has been designed as NNRTIs against HIV-1. In silico studies using DS 3.0 software have shown that these compounds behaved as NNRTIs while interacting at the allosteric site of HIV-RT. The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Tyr181, Tyr318 and π- interactions with Tyr181, Tyr188, Phe227 and Trp229 amino acid residues located in the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-RT protein. The intended molecules have shown high binding affinity with HIV-1 RT, analogous to standard drug molecule-etravirine. TOPKAT results confirmed that the designed compounds were found to be less toxic than the reference drug. Further, employing molecular dynamics simulations, the complexes of the best screened compound 6 and etravirine with the HIV-1 RT protein were analyzed by calculating the RMSD, RMSF, Rg, number of hydrogen bonds, principal components of the coordinates, molecular mechanics-Poisson-Boltzmann surface area-based binding free energy and their decomposition for different interactions. The analysis demonstrated the higher stability of compound 6 than the standard drug etravirine with HIV-1 RT. The interactions like hydrogen-bonding, van-der-Waals, electrostatic and the solvent accessible surface energy have favorable contributions to the complex stability. Thus, the shortlisted designed compound has great promise as a potential inhibitor against HIV-1 RT.