Ligand-based design and synthesis of <i>N'</i> -Benzylidene-3,4-dimethoxybenzohydrazide derivatives as potential antimicrobial agents; evaluation by <i>in vitro</i> , <i>in vivo, and in silico</i> approaches with SAR studies

Abstract

Herein, a series of <i>N'</i>-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised to target the multidrug efflux pump (MATE). The antibacterial activities were screened against <i>S. aureus</i>, <i>Acinetobacter</i>, <i>S. typhi</i>, <i>E. coli</i>, and <i>P. aeruginosa</i>, whereas their antifungal activities were screened against <i>C. albicans</i>. Compounds <b>4a</b>, <b>4h</b>, and <b>4i</b> showed the most promising antibacterial and antifungal activities. Moreover, compounds <b>4h</b> and <b>4i</b> being the broader and superior members regarding their antimicrobial effects were selected to be further evaluated via <i>in vivo</i> testing using biochemical analysis and liver/kidney histological examination. Additionally, molecular docking was carried out to attain further deep insights into the synthesised compounds' binding modes. Also, ADMET studies were performed to investigate the physicochemical/pharmacokinetics features and toxicity parameters of the synthesised derivatives. Finally, a structure-antimicrobial activity relationship study was established to facilitate further structural modifications in the future. HighlightsA series of new <i>N'</i>-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised targeting the multidrug efflux pump (MATE) guided by the pharmacophoric features of the co-crystallized native inhibitor of the target protein.The newly synthesised compounds were assessed through <i>in vitro</i>, <i>in vivo</i>, and <i>in silico</i> approaches.Using the agar well diffusion assay, the antibacterial activities of the synthesised compounds were screened against <i>S. aureus</i>, <i>Acinetobacter</i>, <i>S. typhi</i>, <i>E. coli</i>, and <i>P. aeruginosa</i>, whereas, their antifungal activities were screened against <i>C. albicans</i>.The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of the synthesised compounds were investigated on variable microbial species.Compounds (<b>4h</b> and <b>4i</b>) -as the broader and superior members regarding their antimicrobial effects- were further evaluated via <i>in vivo</i> testing using bio-chemical analysis and liver/kidney histological examination.A molecular docking study and ADMET <i>in silico</i> studies were performed.A structure-antimicrobial activity relationship study was established to facilitate further structural modifications in the future.