Design, Synthesis, Biological Evaluation and SARs of Novel N-Substituted Sulfoximines as Potential Ryanodine Receptor Modulators

The sulfoximine group has been evaluated as a pharmacophore. Introducing the sulfoximine structure into medicinal compounds as exciting motifs has brought opportunities in drug discovery. In order to develop new ryanodine receptor (RyR) modulators, a series of phthalamides containing sulfoximine derivatives were designed, synthesized, and evaluated against oriental armyworm and diamondback moth for their insecticidal activities. These studies helped to elucidate the electronic and structural requirements around the sulfoximine motif for insecticidal activity. All new structures were synthesized and characterized by H-1 NMR, C-13 NMR, HRMS and bioassay and a preliminary structure - activity relationship (SAR) was discussed. The biological assessment indicated that most title compounds showed good to excellent larvicidal activities. Compounds Ia, Ie, and If gave excellent insecticidal activity against oriental armyworm, which showed 100% larvicidal activity at 0.5 mg/L. All compounds showed 100% larvicidal activity at 0.1 mg/L against diamondback moth. In particular, the larvicidal activities of Ie, If, and Ih at 0.0001 mg/L were 50%, 20%, and 40%, respectively, reaching an activity as high as that of the commercial flubendiamide (40%, 0.0001 mg/L). Therefore, Ia, Ie, If and Ih could be considered as new lead structures for the development of new ryanodine receptor (RyR) modulators.