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, H-1-, C-13-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 (Delta G=-9.59 similar to-7.69 kcal/mol) than diphenyl-malonohydrazide derivatives (3 a-j), which achieved a binding affinity in the range of (Delta G=-9.65 similar to-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.