Design, Synthesis and Bio-Evaluation of Novel Chalcones Bridged with 1,3,4-Oxadiazole Linkers: ADMET and Docking Analysis.

Abstract

In this article, we prepared a novel series of 1,3,4-oxadiazoles containing chalcone analogs via replacement of phthalazine which had increased antibacterial activity and the final compounds were confirmed by proton, carbon nuclear magnetic resonance spectroscopy, infrared and mass spectral analysis. Two sets of 1,3,4-oxadiazoles like 2-methyl-5-substitutedbenzylthio-1,3,4-oxadiazolyl-4-methylphthalazine-2-ones (3a-f), (E)-substituted phenyl acryloylphenyl-4-methyl-1-oxophthalazine-1,3,4-oxadiazolylthioacetamides (5a-f) were designed, synthesized and evaluated for their in vitro antibacterial potency against different Gram-(+ve), Gram-(-ve) microorganisms and fungal strains. The synthesized 4-methyl-2-{[5-({[2-(trifluoromethyl)phenyl]methyl}sulfanyl)-1,3,4-oxadiazol-2-yl]methyl}phthalazin-1(2H)-one (3c), 4-methyl-2-[(5-{[(4-nitrophenyl)methyl]sulfanyl}-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2H)-one (3d), N-(4-{(2E)-3-[2-(dimethylamino)phenyl]prop-2-enoyl}phenyl)-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5d), and N-{4-[(2E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoyl]phenyl}-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5e) displayed improved activity with MICs 1.41, 0.87, 2.16, 0.89 μg/mL as compared to the standard drugs rifamycin, ciprofloxacin, fluconazole (MIC=1.52, 1.94, 3.02 μg/mL). The prepared compounds were also analyzed with better target binding towards bacterial bioavailability, 5e exhibited highest bonds with amino acids ArgA45 , LysA20 , LysA17 , ArgA171 , AspA49 , IleA14 , HisA18 and having docking energy -8.68 Kcal/mol and dissociation constant 432.48 nM, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.