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

Journal of Enzyme Inhibition and Medicinal Chemistry

Amany F. Mohamed¹  Shaimaa M. Hafez¹  Ayman Abo Elmaaty²  Seham K. Khirala³  Azza Ali Althoqapy³  Ahmed A. Al-Karmalawy⁴  Mona M. Amin⁵  Azza H. AbdElwahab⁶  Yousuf A. F⁶  Feras A. Alshehri⁷  Yahya A. Alzahrani⁷  Reem K. Alsuair⁷  Mohammad Hayal Alotaibi⁷  Mohamed S. Alesawy⁸  Marwa A. Saleh⁹  Rogy R. Ezz Eldin^1,10 

[1] Department of Anatomy and Embryology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt;Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt;Department of Microbiology and Immunology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt;Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt;Department of Pharmacology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt;Department of Physiology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt;National Center for Chemical Technologies, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia;Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al‐Azhar University, Cairo, Egypt;Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt;Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt;

关键词: N'-benzylidene-3,4-dimethoxybenzohydrazide;    antibacterial;    antifungal;    in vitro;    in vivo;    SAR;   

DOI  :  10.1080/14756366.2022.2063282

来源: DOAJ

【 摘 要 】

Herein, a series of N'-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised to target the multidrug efflux pump (MATE). The antibacterial activities were screened against S. aureus, Acinetobacter, S. typhi, E. coli, and P. aeruginosa, whereas their antifungal activities were screened against C. albicans. Compounds 4a, 4h, and 4i showed the most promising antibacterial and antifungal activities. Moreover, compounds 4h and 4i being the broader and superior members regarding their antimicrobial effects were selected to be further evaluated via in vivo 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 N'-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 in vitro, in vivo, and in silico approaches.Using the agar well diffusion assay, the antibacterial activities of the synthesised compounds were screened against S. aureus, Acinetobacter, S. typhi, E. coli, and P. aeruginosa, whereas, their antifungal activities were screened against C. albicans.The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of the synthesised compounds were investigated on variable microbial species.Compounds (4h and 4i) -as the broader and superior members regarding their antimicrobial effects- were further evaluated via in vivo testing using bio-chemical analysis and liver/kidney histological examination.A molecular docking study and ADMET in silico studies were performed.A structure-antimicrobial activity relationship study was established to facilitate further structural modifications in the future.

【 授权许可】

Unknown