Synthesis, Characterization, Bioactivity Screening and Computational Studies of Diphenyl−malonohydrazides and Pyridines Derivatives

Abstract

Abstract A series of new hydrazide ( 3 a – j ) and pyridine ( 11 a – j ) derivatives were synthesized using a convergent synthetic methodology by condensation of malono‐di(2‐phenylhydrazide) with arylidene malononitrile or arylidene ethyl cyanoacetate derivatives. The synthesized compounds ( 3 , 11 a – j ) were characterized using via IR, 1 H‐, 13 C‐NMR, and MS spectroscopies as well as elemental analysis. The biological activity of these molecules has been evaluated in vitro against two gram‐positive bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) and one‐gram negative bacteria ( Escherichia coli ), as well as one fungus ( Candida albicans ). The results of the bioactive assay revealed that the synthesized pyridine ( 11 a – j ) derivatives had greater antibacterial efficacy than the hydrazide ( 3 a – j ) derivatives and were comparable to the reference drug Augmentin. Furthermore, docking studies against the Staphylococcus aureus dihydrofolate reductase (DHFR) protein revealed that pyridine derivatives ( 11 a – j ) had higher binding interactions affinity (ΔG=−9.59∼−7.69 kcal/mol) than diphenyl−malonohydrazide derivatives ( 3 a – j ), which achieved a binding affinity in the range of (ΔG=−9.65∼−6.77 kcal/mol), supporting the experimental results. Finally, DFT and TD‐DFT were used to gain a better understanding of the structure‐activity relationship and biological activity of the new synthesized hydrazide/pyridine derivatives.