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Published on: July 18, 2012
Core Emulating Optimization (CEO) of Alangiobussinine for Distinctive and Tractable Antifungal Leads
Xian Ming1, Wenlong Kong1, Shengxin Sun1
1State Key Laboratory of Green Pesticide, Center for R&D of Fine Chemicals of Guizhou University, Guiyang550025, China.
Abstract:
The discovery of novel antifungal chemotypes is vital for agrochemical science. Leveraging the unique scaffold of the natural product alangiobussinine, we utilized a core-emulating optimization (CEO) strategy to deconstruct the β-carboline framework. This approach generated 54 new amides by introducing substituted heterocyclic acids and rigidifying the β-arylamine to mimic the N-distribution of the parent compound. Structure-activity relationship studies emphasized the importance of combining 3-aryl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid with biaryl amine for antifungal activity. Compound D14 (LEX-M01) demonstrated potent activity against Gaeumannomyces graminis (EC50 = 0.7 μM), 16.4-fold more potent than boscalid. Compound D32 (LEX-M02) effectively inhibited Pyricularia oryzae (EC50 = 3.4 μM), while boscalid was nearly inactive (EC50 > 50 μM). Molecular docking confirmed strong interactions between LEX-M01 and succinate dehydrogenase (SDH). Mechanistic studies verified that LEX-M01 disrupts cell membrane integrity. Biosafety assessments showed no adverse effects on wheat. This will facilitate the discovery of patentable entities with high antifungal potentials.
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