In Pursuit of Lead Innovation: Pharmaceutically Important and Distinct Amide-Free Succinate Dehydrogenase Inhibitors.

Though succinate dehydrogenase inhibitors (SDHIs) are quite successful in the modern agrochemical industry, the Fungicide Resistance Action Committee has classified the resistance risk as "medium to high". Structural analysis reveals that these antifungal chemotypes are highly conserved with amides as a consistent feature. This chemical factor may be a potential factor for the ever-increasing resistance risk. Introducing new antifungal structures or models may be a potent method to tackle this and find new bioactive compounds. In this Perspective, the recent progress in SDHIs without amide functionality from either synthetic endeavors or natural sources is showcased, focusing on their biological activities and a brief introduction of their mechanism. Synthetic advances in complex natural products are discussed, aiming to inspire new pharmaceutical discoveries and efficient synthesis methods. The challenges and strategies for the development of SDHIs are also discussed. This may offer insights for developing new SDHIs or chemical entities to combat the increasing resistance to commercial agrochemicals.