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

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, 1H‐, 13C‐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. Twenty new malonohydrazides and poly‐substituted pyridine derivatives were successfully synthesized by using a convenient and effective convergent synthetic route. The target molecules demonstrated promising in vitro antibacterial and antifungal inhibition, making them stand out as motifs for upcoming developments in the field of drug discovery.