Synthesis, SAR Analysis, and Antifungal Potency against Plant Pathogenic Fungi of New Azidopyrazoles

Abstract

The development of potent synthetic antifungal agents for plants is an ongoing challenge of modern chemistry that impacts biological, medicinal and environmental sciences. Herein, a concise Structure–Activity Relationship (SAR) model involving seven synthetic azidopyrazoles toward three pathogens of agricultural products and ornamental plants: Fusarium oxysporum, Rhizoctonia sp., and Alternaria alternata is described. The set of azidopyrazoles 1–7 includes a central fragment of 3-azido-1H-pyrazole substitutes in different positions of the ring (5-substituted, R = H, 1; R = −CH3, 2; R = –Ph, 3; R = –PhOCH3, 5; 4-substituted, R = –Ph, 4; R = –(4-Cl-Ph), 6) and 3-substituted 5-azido-1H-pyrazole (R = thiophene, 7) which are prepared via a high-yielding (>85%), one-step synthesis from commercial cheap aminopyrazoles. Compounds 3 and 7 showed the greatest inhibition with IC50 values of 26.52 ± 1.14 and 26.75 ± 1.36 μg/mL for F. oxysporum; 18.63 ± 1.08 and 14.39 ± 1.09 μg/mL for Rhizoctonia sp.; and 15.53 ± 1.14 and 21.02 ± 1.37 μg/mL for A. alternata. SAR analysis revealed that aryl substitution at C5 increased markedly the antifungal potency. In contrast, unsubstituted and alkyl-substituted pyrazoles (1, 2) had low activity. Combining 3 with Ag-nanoparticles (NPs) doubled its efficacy only against Rhizoctonia sp. (AgNPs, 10 nm, 100 ng/mL). From IC50 = 18.63 ± 1.08 to 9.65 ± 1.38 μg/mL). Molecular docking with MEP36 supported these results: compound 3 had the highest binding affinity (−6.8 kcal/mol) due to π–alkyl interaction with Val274 residue. Furthermore, root mean square deviation analyses confirmed the tight binding mode.