Computer-Assisted Improvement of Sulfonylureas with Antifungal Properties and Limited Herbicidal Activity: Potential Application in Forage Conservation

Abstract

This work reports studies at the molecular level of a series of modified sulfonylureas to determine the chemophoric sites responsible for their antifungal and herbicidal activities. For forage conservation, high antifungal potency and low phytotoxicity are required. A molecular modeling study based on multivariate image analysis applied to quantitative structure–activity relationship (MIA-QSAR) was performed to model these properties, as well as to guide the design of new agrochemical candidates. As a result, the MIA-QSAR models were reliable, robust, and predictive; for antifungal activity, the averages of the main validation parameters were r 2 = 0.936, q 2 = 0.741, and r 2 pred = 0.720, and for herbicidal activity, the model was very predictive (r 2 pred = 0.981 and r 2 m = 0.944). From the interpretation of the MIA-plots, 46 novel sulfonylureas with likely improved performance were proposed, from which 9 presented promising calculated selectivity indexes. Docking studies were performed to validate the QSAR predictions and to understand the interaction mode of the proposed ligands with the acetohydroxyacid synthase enzyme.

Novel [1,2,4]-Triazolo[3,4-b]-[1,3,4]thiadizoles as Potent Pyruvate Kinase Inhibitors for Fungal Control

“…Studies on the structure–activity relationship (SAR) would provide adequate guidance for lead optimization. − Generally, a trend of activity variation was discussed based on changes in the molecular structures of similar drugs. , Based on the target enzyme PK and the lead compound YZK-C22 , a combination of computational techniques ( e.g ., homology modeling and molecular docking), and continuously adding new SAR, information obtained from subsequent studies will improve the efficiency of molecular design. In particular, the open source of the AlphaFold 2 provides convenience for obtaining more accurate three-dimensional (3D) structures of the target proteins without crystal structures disclosed.…”