Design, Synthesis, and Insecticidal and Antimicrobial Evaluation of Novel Pyrimidine Derivatives against Aphis gossypii (Glover, 1887) with DFT Calculations and Molecular Docking Validation

The escalating impact of Aphis gossypii (Glover, 1887) on global agriculture, together with the rapid emergence of resistance to conventional insecticides, underscores the urgent need for innovative pest-control agents with distinct modes of action. In this study, nine new pyrimidine-based heterocycles ( 2a − 2f, 3 – 5 ) were rationally designed, synthesized, and biologically evaluated. These compounds feature diverse amine substituents at the C-4 position of a 6-(4-methoxyphenyl)–2-morpholinopyrimidine-5-carbonitrile scaffold. Synthesis was achieved via nucleophilic aromatic substitution of a chlorocyanopyrimidine intermediate with primary and secondary amines under mild reflux, affording yields of 45–90%. Further structural diversification from the hydrazinyl intermediate ( 2e ) enabled the preparation of a triazolopyrimidine ( 3 ), a benzylidenehydrazinyl Schiff base ( 4 ), and a dimethylpyrazolyl derivative ( 5 ). All compounds were structurally confirmed using FTIR, 1 H/ 13 C NMR, and HRMS analyses. Bioassays against nymph and adult stages of A. gossypii revealed that compound 2c, bearing a phenylamino substituent, exhibited the highest activity, with a nymph LC 50 of 0.113 mg/L, approaching that of acetamiprid (0.039 mg/L). Also, antimicrobial screening demonstrated selective antifungal activity against Candida albicans, particularly for compounds 2d and 2a . Furthermore, density functional theory calculations at the B3LYP-D3(BJ)/6-31G(d) level provided frontier orbital energies (HOMO−LUMO gaps of 3.83−4.45 eV) and MESP maps, thereby identifying reactive sites correlated with biological performance. Molecular docking with the nicotinic acetylcholine receptor (PDB: 3SQ6) showed strong binding affinities (−8.0 to −9.3 kcal/mol), with compound 2c forming hydrophobic, hydrogen-bonding, and cation−π interactions. These findings highlight arylamine-functionalized pyrimidines as promising candidates for the development of environmentally sustainable insecticides.