Synthesis and biological evaluation of nicotinamide derivatives with a diarylamine-modified scaffold as succinate dehydrogenase inhibitors

Abstract

Six novel nicotinamide derivatives bearing a diarylamine-modified scaffold with flexible heterocyclic patterns were designed, synthesized, and characterized in detail via Hydrogen nuclear magnetic resonance (¹H-NMR), Carbon nuclear magnetic resonance (¹³C-NMR), and Electrospray ionization mass spectrometry (ESI-MS). Their fungicidal activities and succinate dehydrogenase (SDH) enzymatic inhibitory abilities were evaluated. Preliminary fungicidal bioassay results showed that some of the target compounds exhibited moderate fungicidal activity. Among them, compound 4a showed 40.54% inhibition against Botrytis cinerea fungi. An SDH enzymatic inhibition assay revealed that the IC₅₀ of compound 4b was 3.18 µM. This result indicated that the enzymatic inhibition level of 4b was similar to that of boscalid. Compound 4f exhibited superior comprehensive fungicidal and SDH enzymatic inhibitory activities. Molecular docking results suggested that 4f could bind well to the substrate cavity and the entrance cavity of SDH (1YQ3). In particular, 4f could react with the key catalytic site Arg 297. This phenomenon implied that 4f could act as the lead compound for further optimization.