3D-QSAR-Directed Synthesis of Halogenated Coumarin-3-Hydrazide Derivatives: Unveiling Their Potential as SDHI Antifungal Agents
Peng Dai, Zihua Ma, Yu Xiang, Wei Chen, Peng Teng, Yufei Li, Zhaojun Xu, Qing Xia, Zewen Liu, Weihua Zhang
Abstract
The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure–activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 μg/mL), 6ae (0.32 μg/mL), and 6ah (0.48 μg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani, outperforming the commonly used fungicide boscalid (0.52 μg/mL). Furthermore, compounds 4ak (0.88 μg/mL), 6ae (0.61 μg/mL), 6ah (0.65 μg/mL), and 6ak (1.11 μg/mL) showed significant activity against Colletotrichum orbiculare, surpassing both the SDHI fungicide boscalid (43.45 μg/mL) and the broad-spectrum fungicide carbendazim (2.15 μg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.