Discovery of Novel\nNicotinamide Derivatives by a Two-Step\nStrategy of Azo-Incorporating and Bioisosteric Replacement

Azobenzene\nmoieties can serve as active fragments in antimicrobials\nand exert trans/cis conversions of molecules. Herein, a series of\nnovel nicotinamide derivatives (<b>NTMs</b>) were developed\nby employing a two-step strategy, including azo-incorporating and\nbioisosteric replacement. Azo-incorporation can conveniently provide\ncompounds that can be easily optically interconverted between trans/cis\nisomers, enhancing the structural diversity of azo compounds. It is\nnoteworthy that the replacement of the azo bond with a 1,2,4-oxadiazole\nmotif through further bioisosteric replacement led to the discovery\nof a novel compound, <b>NTM18</b>, which made a breakthrough\nin preventing rice sheath blight disease. A control effect value of\n94.44% against Rhizoctonia solani could\nbe observed on <b>NTM18</b>, while only 11.11% was determined\nfor boscalid at 200 mg·L<sup>–1</sup>. Further mechanism\nvalidations were conducted, and the molecular docking analysis demonstrated\nthat compound <b>NTM18</b> might have a tight binding with SDH\nvia an extra π–π interaction between the oxadiazole\nring and residue of D_Y586. This work sets up a typical case for the\nunited applications of azo-incorporating and bioisosteric replacement\nin fungicide design, posing an innovative approach in structural diversity-based\ndevelopment of pesticides.