Synthesis and Biological Activity Evaluation of Naringenin Derivatives Incorporating 1,3,4‐Oxadiazole Acylhydrazone Moieties as Antifungal Agents

Abstract

The global rise of antimicrobial resistance (AMR) has reduced the effectiveness of existing antibiotics, highlighting the urgent need for novel antimicrobial agents. In this study, a series of eighteen naringenin‐based derivatives incorporating 1,3,4‐oxadiazole acylhydrazone moieties were synthesized and evaluated for antimicrobial activity. The compounds were tested against Staphylococcus aureus ( S. aureus ), Bacillus subtilis ( B. subtilis ), and Candida albicans ( C. albicans ) using the broth microdilution assay, with norfloxacin and fluconazole as reference agents, while no significant inhibitory activity was observed against S. aureus and B. subtilis (MIC > 512 µg/mL), several compounds displayed pronounced antifungal effects against C. albicans . Notably, compounds 6h , 6l , and 6p exhibited the most potent antifungal activity, each displaying an MIC 80 value of 8 µg/mL. Furthermore, growth curve analysis revealed that compound 6h exerted a concentration‐dependent inhibitory effect on C. albicans , indicating its potential as a promising antifungal lead. Scanning electron microscopy (SEM) imaging of treated cells revealed membrane deformation and surface wrinkling, consistent with a membrane‐disruptive mode of action. Collectively, these results support continued structural refinement of naringenin‐based 1,3,4‐oxadiazole derivatives and highlight this chemotype as a promising scaffold for antifungal drug development.