Novel 1,2,4-oxadiazole-pyrimidine hybrids: Design, synthesis, and mechanistic insights into potent anti-rust agents via integrated in vivo and in silico approaches

Rust diseases, caused by Puccinia species, pose a persistent threat to global crop production, necessitating the continuous development of novel, safer, and more effective fungicides. In this study, we designed and synthesized a series of twenty-nine novel 1,2,4-oxadiazole derivatives incorporating a pyrimidine motif, leveraging a molecular hybridization strategy that merges the pharmacophores of the commercial fungicide flufenoxadiazam and insecticide flufenerim. All synthesized compounds were fully characterized by 1 H NMR, 13 C NMR, and HRMS. In vivo fungicidal screening against corn rust ( Puccinia sorghi ) identified several potent candidates. Notably, compound XII17 exhibited outstanding activity, achieving 100% inhibition at 200 mg/L, while compounds XII8 and XII9 showed significant inhibition rates of 90% and 70%, respectively. Structure-activity relationship (SAR) analysis revealed that the presence of a 5-chloro substituent on the pyrimidine ring and a 3-(trifluoromethyl)benzyl moiety are crucial for enhanced activity. To elucidate the potential mechanism of action, molecular docking studies were performed, suggesting that XII17 may act through chelation with the zinc ion in the active sites of histone deacetylases (HDACs), with calculated Zn–F distances of 2.7 Å (HDAC1) and 2.3 Å (HDAC4/6). Density functional theory (DFT) calculations provided further insights, indicating that XII17 possesses a higher chemical hardness (η = 2.52 eV) and a favorable HOMO-LUMO energy gap (ΔE = 5.05 eV) compared to reference compounds. In silico ADMET predictions highlighted a distinct pharmacokinetic and toxicity profile for XII17 , including non-mutagenicity, though optimization for absorption is needed. This work not only identifies XII17 as a promising lead compound for anti-rust development but also provides a robust framework for the rational design of next-generation 1,2,4-oxadiazole-pyrimidine hybrids.