Design, Synthesis, And Evaluation Of Novel Isothiazole-Purines As A Pyruvate Kinase-Based Fungicidal Lead Compound

Target identification is one of the most important bases for novel pesticide development; pyruvate kinase (PK) was discovered as a potent fungicide target in our previous studies. To continue the PK-based fungicide development, novel isothiazolepurine derivatives were rationally designed and synthesized. Bioassay results showed that compound 5ai displayed excellent in vitro activity against Rhizoctonia solani with an EC50 of 1.5 mu g/mL, which was superior to those of positive controls diflumetorim with its EC50 of 19.8 mu g/mL and PK-based lead YZK-C22 with its EC50 of 4.2 mu g/mL. Compounds 3b (5.2 mu g/mL) and 3c (4.5 mu g/mL) displayed better activities against Gibberella zeae with their EC(50)s falling between 4.0 and 5.5 mu g/mL, while YZK-C22 showed an EC50 of 6.4 mu g/mL. In addition, 5ah exhibited promising in vivo activity against Erysiphe graminis and Puccinia sorghi Schw. with 100% efficacy at 10 mu g/mL and 90% efficacy at 2 mu g/mL against P. sorghi Schw. Compound Sai showed good PK inhibitory activity with an IC50 of 38.8 mu mol/L, and it was well docked into the active site of the target enzyme PK, which was slightly more active than YZK-C22 with its IC50 of 42.4 mu mol/L. Our studies discovered that isothiazole-purines were PK-based fungicidal leads deserving of further study.