Discovery of Novel Nicotinamide Derivatives by a Two-Step Strategy of Azo-Incorporating and Bioisosteric Replacement

Azobenzene moieties can serve as active fragments in antimicrobials and exert trans/cis conversions of molecules. Herein, a series of novel nicotinamide derivatives (<b>NTMs</b>) were developed by employing a two-step strategy, including azo-incorporating and bioisosteric replacement. Azo-incorporation can conveniently provide compounds that can be easily optically interconverted between trans/cis isomers, enhancing the structural diversity of azo compounds. It is noteworthy that the replacement of the azo bond with a 1,2,4-oxadiazole motif through further bioisosteric replacement led to the discovery of a novel compound, <b>NTM18</b>, which made a breakthrough in preventing rice sheath blight disease. A control effect value of 94.44% against <i>Rhizoctonia solani</i> could be observed on <b>NTM18</b>, while only 11.11% was determined for boscalid at 200 mg·L^-1. Further mechanism validations were conducted, and the molecular docking analysis demonstrated that compound <b>NTM18</b> might have a tight binding with SDH via an extra π-π interaction between the oxadiazole ring and residue of D_Y586. This work sets up a typical case for the united applications of azo-incorporating and bioisosteric replacement in fungicide design, posing an innovative approach in structural diversity-based development of pesticides.