Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies.

Background/

Objectives

Vector-borne diseases like malaria remain a major global health concern, worsened by insecticide resistance in mosquito populations. Quinoline-based compounds have been extensively studied for their pharmacological effects, including antimalarial and larvicidal properties. Modifying quinoline structures with hydrazone groups may enhance their biological activity and physicochemical properties. This study reports the synthesis, structural characterization, and larvicidal testing of a new series of aryl hydrazones (6a-i) derived from 8-trifluoromethyl quinoline.

Methods

Compounds 6a-i were prepared via condensation reactions and characterized using 1H NMR, 19F-NMR, 13C NMR, and HRMS techniques. Their larvicidal activity was tested against Anopheles arabiensis. Single-crystal X-ray diffraction (XRD) was performed on compound 6d to determine its three-dimensional structure. Hirshfeld surface analysis, fingerprint plots, and interaction energy calculations (HF/3-21G) were used to examine intermolecular interactions. Quantum chemical parameters were computed using density functional theory (DFT). Molecular docking studies were performed for the synthesized compounds 6a-i against the target acetylcholinesterase from the malaria vector (6ARY). In silico ADMET properties were also calculated to evaluate the drug-likeness of all the tested compounds.

Results

Compound 6a showed the highest larvicidal activity, causing significant mortality in Anopheles arabiensis larvae. Single-crystal XRD analysis of 6d revealed a monoclinic crystal system with space group P21/c, stabilized by N-H···N intermolecular hydrogen bonds. Hirshfeld analysis identified H···H (22.0%) and C···H (12.1%) interactions as key contributors to molecular packing. Density functional theory results indicated a favorable HOMO-LUMO energy gap, supporting molecular stability and good electronic distribution. The most active compounds, 6a and 6d, also showed strong binding interactions with the target protein 6ARY and satisfactory ADMET properties. The BOILED-Egg model is a powerful tool for predicting both blood-brain barrier (BBB) and gastrointestinal permeation by calculating the lipophilicity and polarity of the reported compounds 6a-i.

Conclusions

The synthesized arylhydrazone derivatives demonstrated promising larvicidal activity. Combined crystallographic and computational studies support their structural stability and suitability for further development as eco-friendly bioactive agents in malaria vector control.