Synthesis, characterization, crystallography insights, and larvicidal activity of 4-substituted-8-(trifluoromethyl)quinoline derivatives against Anopheles arabiensis

Abstract

A new series of 8-trifluoromethyl quinoline derivatives bearing substituted saturated amines has been synthesized by standard conventional reflux methods. The structures of the novel saturated amine derivatives 4a–4h were characterized by 1H and 13C-NMR and mass spectrometry. Among the designed compounds 4a–4h, compound 4a was subjected to the single-crystal X-ray diffraction technique (SCXRD). According to the SCXRD analysis, the compound crystallized in a monoclinic lattice structure with the space group P21/n. The crystal structure is stabilized through intermolecular C–H⋯O interactions. Hirshfeld surface analysis is performed to validate the intermolecular interactions of compound 4a. Density functional theory (DFT) calculations are performed to study the optimized structure, molecular geometry, and molecular electrostatic potential (MEP) of compound 4a using the B3LYP/6–311++G(d,p) level of theory in the gas phase. We evaluated the title compounds for larvicidal activity using Temephos as the standard reference against Anopheles arabiensis. Compound 4b exhibited the highest larval mortality, at 97%, after 48 h of exposure. The synthesized compounds were generally non-toxic to normal fibroblasts. To further validate the biological activity, molecular docking studies were performed on the designed title compounds 4a–4h against five malaria vectors (PDB IDs: 1ZP4, 2CH2, 4JBV, 5V13, and 6ARY). In silico ADMET profiles were also screened to evaluate the drug-likeness and toxicity of the tested compounds.