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A Series of Furan-based Hydrazones: Design, Synthesis, and Evaluation of Antimicrobial Activity, Cytotoxicity and Genotoxicity



Hydrazones, frequently occurring motifs in many bioactive molecules, have
attracted a great deal of interest as potent antimicrobial agents.



The aim of this work was to design and synthesize new hydrazone-based antimicrobial
agents.



4-[2-((5-Arylfuran-2-yl)methylene)hydrazinyl]benzonitrile derivatives (1-10) were obtained
via the reaction of 4-cyanophenylhydrazine hydrochloride with 5-arylfurfurals. Compounds 1-10
were evaluated for their antimicrobial effects using a broth microdilution method. Their cytotoxic
effects on NIH/3T3 mouse embryonic fibroblast cell line were determined using XTT assay. The
most effective antimicrobial agents were investigated for their genotoxic effects using Ames MPF
assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies
were also performed using Schrödinger’s Maestro molecular modeling package.



The antifungal effects of the compounds were more significant than their antibacterial effects.
Compound 5 bearing 3-nitrophenyl moiety was the most potent antifungal agent against Candida
albicans, Trichoderma harzianum and Fusarium species, whereas compound 10 bearing 4-
chloro-2-nitrophenyl moiety was the most effective antifungal agent on Aspergillus ochraceus. According
to XTT and Ames MPF assays, these compounds were neither cytotoxic nor genotoxic at the
concentrations tested. Docking studies suggested that these compounds showed good affinity to the
active site of lanosterol 14α-demethylase (CYP51) (PDB code: 5V5Z) and interacted with the key
residues such as Hem601 and Cys470. Based on in silico ADME studies, the compounds are expected
to have high oral bioavailability.



According to the in vitro and in silico studies, compounds 5 and 10 stand out as potential
orally bioavailable antifungal agents for further studies.
