Facile synthesis of novel quinolin-8-amine derivatives: crystallographic study, in silico and antifungal investigation

Background

Quinoline, an important nitrogen-containing heterocycle, is frequently found in both natural and synthetic compounds. Numerous quinoline derivatives have been developed as commercial pharmaceuticals and pesticides. Due to quinoline derivatives having exhibited various bioactivities, this research aims to investigate novel quinolin-8-amine derivatives as potential antifungal agents. Elucidating the structure–activity relationships (SAR) provides insights to facilitate the discovery of new agrochemicals.

Results

A series of quinolin-8-amine derivatives were designed, synthesized, and structurally characterized by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). Single-crystal X-ray diffraction analysis confirmed the molecular architecture of compound 3n (4-chloro-N-(4-fluorophenyl)-2,3-dimethylquinolin-8-amine). Biological evaluation revealed several synthesized derivatives exhibited fungicidal activity against ten phytopathogenic fungi. Structural analysis of compound 3n revealed two distinct intermolecular hydrogen-bonding motifs: N–H···Cl and C–H···Cl interactions. Hirshfeld surface analysis identified H···H (37.0%) and C···H (12.2%) contacts as the major intermolecular interactions, while energy framework calculations revealed their respective contributions to crystal packing stability. Computational investigations including energy framework analysis, and density functional theory (DFT) calculations consistently emphasized the critical role of the quinoline scaffold in the antifungal activity.

Conclusions

This study provides an improved understanding of the SAR of quinoline-based fungicides, which is valuable for synthesizing novel quinoline derivatives and discovering more potent quinoline-based fungicides.

Graphical Abstract