Design, synthesis and antifungal activity of amide hybrid molecules containing the structure of phenolic monoterpene

Aiming to discover the amides with high antifungal activity, thirty amide hybrid molecules were designed and synthesized by combining natural phenolic monoterpene (carvacrol and thymol) with the functional groups of succinate dehydrogenase inhibitors (SDHI). The structures of the synthesized compounds were characterized by the ¹H NMR, ¹³C NMR and high resolution mass spectrometry (HRMS). The antifungal activity of the hybrid molecules against five plant pathogenic fungus were determined by mycelial growth rate method. The results showed that the synthesized hybrid molecules exhibited excellent antifungal activity against Alternaria solani and Botrytis cinerea. Among of them, the compound 7e (N-(4-hydroxy-5-isopropyl-2-methylphenyl)-3-methylthiophene-2-carboxamide) showed the highest antifungal activity, with EC₅₀ values of 3.28 and 15.06 μg/mL against A. solani and B.cinerea, respectively. In addition, there was no cross-resistance between compound 7e and boscalid. Succinate dehydrogenase (SDH) activity assay showed that the compound 7e had strong SDH inhibitory activity against sensitive, resistant and B-P225F mutant strains of B. cinerea. Molecular docking studies showed that compound 7e had a strong affinity with both wild-type and mutant B. cinerea succinate dehydrogenase (BcSDH). Therefore, it was speculated that compound 7e was a potential novel SDHI. The difference in SDH inhibitory activity and binding modes with wild-type and mutant BcSDH, which may account for the lack of cross-resistance between the compound 7e and boscalid.