In silico modeling and experimental validation of 2-oxoimidazolidin-4-sulfonamides as low-toxicity fungicides against Phytophthora infestans

Phytophthora infestans control is a long-standing problem that has caused ongoing difficulties and brought limited success for over a century. Traditional methods, such as fungicides, have drawbacks including high cost, restrictions on organic farming, potential risks to the environment and human health, and the development of resistant strains. In this study, we employed cutting-edge computer-based techniques, including Quantitative Structure-Activity Relationship (QSAR) modeling and molecular docking simulations, to uncover new fungicidal compounds and gain insights into their specific mechanisms of action against P. infestans . QSAR modeling on the number of compounds tested as P . infestans inhibitors was performed using an interactive OCHEM web platform. The predictive ability of the developed classification models had a balanced accuracy (BA) of 77–85 % for the training set and BA = 89–93 % for the validation external test set. During the in vitro testing against P. infestans , thirteen synthesized 2-oxoimidazolidine-4-sulfonamides demonstrated inhibition rates, ranging from 23.6 % to 87.4 %. The fungicidal potential of six of these fungicides ranged from 79.3 % to 87.4 %, which is comparable to the activity of known fungicides. Acute toxicity results using the well-known aquatic marker Daphnia magna showed that the most active sulfonamides 3d, 3f, 3h, 3j, 3k, and 3l, with LC 50 values ranging from 13.7 to 52.9 mg/L, are low-toxicity compounds. The molecular docking results demonstrated a potential mechanism of the antifungal action of the studied 2-oxoimidazolidin-4-sulfonamide derivatives via the inhibition of fungal CYP51, a sterol biosynthesis enzyme. • QSAR models were designed to screen new Phytophthora infestans inhibitors. • QSAR methodologies used various Neural Networks. • The fungicidal potential of six designed compounds ranged from 79.3 % to 87.4 %. • Acute toxicity results showed that most active sulfonamides have low toxicity. • The proposed approach can be a potential tool for designing new fungicides.