Synthesis, Antifungal Activity, and Establishment of 3D‐QSAR Model of Heterocyclic Substituted Diaminothiourea Derivatives

Five 1‐heterocyclic substituted diaminothiourea compounds ( 1a–e ) were synthesized and characterized by FT‐IR, NMR, and high‐resolution mass spectrometry (HR‐MS) (ESI). Compound 1d with the highest antifungal activity against Fusarium graminearum (EC 50 = 25.791 mg/L) was reacted with substituted 2‐pyridinecarboxaldehyde to obtain seven 1,5‐heterocyclic substituted diaminothiourea compounds ( 2a–g ). In vitro fungal activity revealed that the antifungal activities (values of EC 50 [22.058–25.684]) of compounds ( 2a–g ) were better than that of compound 1d (EC 50 = 25.791 mg/L), with 2d (6‐fluoropyridine substitution) demonstrating the best antifungal activity (EC 50 = 22.058 mg/L). On the basis of previous research results, a stable and reliable 3D‐QSAR model ( q 2 = 0.660, ONC = 4, r 2 = 0.973, F = 181.556, SEE = 1.669) was established, and 36 compounds were further designed. Among these, PRE‐1 emerged as a promising candidate, and the synthetic route was also designed. Molecular docking confirmed 2d ’s lowest docking energy and formation of hydrogen bonds with 10 amino acids. The ADMET predictions indicated mild eye irritant for 2f and favorable pharmacokinetics for all derivatives, including low inhibition of Cytochrome P450 enzymes (CYP2D6) and minimal blood–brain barrier penetration.