Design, synthesis, and evaluation of antifungal and antibacterial activities of novel quinazolinone–formononetin derivatives

Abstract

BACKGROUND Plant pathogenic fungi and bacteria cause substantial losses in agricultural production worldwide, and escalating resistance to conventional agrochemicals necessitates the development of novel, environmentally benign pesticides. Formononetin, a naturally occurring isoflavone, exhibits promising bioactivities, while quinazolinone and piperidine moieties serve as privileged pharmacophores in agrochemical discovery. RESULTS A series of novel formononetin derivatives bearing piperidine–quinazolinone scaffolds were designed, synthesized, and assessed for antifungal and antibacterial activities. Among them, T6 exhibited the strongest antifungal activity against Fusarium oxysporum f. sp. capsicum ( Fo ), with a median effective concentration (EC 50 ) of 8.2 μg/mL, which was markedly superior to that of azoxystrobin (Az, 79.7 μg/mL). T9 showed outstanding antibacterial activity against Xanthomonas axonopodis pv. citri ( Xac ), with an EC 50 of 1.8 μg/mL, far exceeding the activities of thiodiazole‐copper (TC, 79.6 μg/mL) and formononetin (FMN, 96.8 μg/mL). Notably, T6 primarily exerts an antifungal effect, whereas T9 mainly exhibits an antibacterial effect. Mechanistic studies revealed that T6 compromised plasma membrane integrity, triggered oxidative stress, and induced leakage of intracellular components in Fo . Meanwhile, T9 suppressed Xac growth, showed significant protective and curative activities in vivo against Xac , reduced swarming motility, inhibited biofilm formation, and decreased extracellular cellulase and amylase activities in a dose‐dependent manner. Density functional theory calculations clarified the electronic features governing the reactivity and stability of these compounds. CONCLUSION These findings provide both theoretical and experimental foundations for the rational design of next‐generation antifungal and antibacterial agents aimed at sustainable crop protection. © 2026 Society of Chemical Industry.