Design, synthesis, and biological evaluation of quinoline derivatives as dual-target inhibitors of chitin synthase and glucosamine-6-phosphate synthase.

Two series of compounds were designed and synthesized based on a glycine methyl ester-quinoline core scaffold combined with a fragment containing nitrogen using either an isoxazole or a piperidine carboxamide fragment as a linker as dual inhibitors targeting both chitin synthase (CHS) and glucosamine-6-phosphate synthase (GlmS). The inhibition percentage (IP) values of these compounds against CHS ranged from 29.9% to 84.5%, while their inhibition percentages against GlmS spanned 38.1% to 86.9% at the concentration of 300 μg mL-1. The IC50(CHS)/IC50(GlmS) ratios of compounds 8c, 9, 14c, 14g, and 14i, which were approximately equal to 1 (between 0.97 and 1.15), demonstrated that these compounds were dual inhibitors targeting both CHS and GlmS. Kinetic analysis revealed that compounds 8c (K i = 0.109 mM) and 14e (K i = 0.125 mM) acted as noncompetitive inhibitors of CHS, exhibiting stronger binding affinities for CHS than that of UDP-GlcNAc (K m = 4.11 mM). Similarly, 8c (K i = 0.227 mM) and 14e (K i = 0.248 mM) displayed higher binding affinities for GlmS than that of UDP-GlcNAc (K m = 6.28 mM). Antifungal activity assays in vitro demonstrated that compounds 8c, 8i, 9, 14d, 14e, and 14g exhibited potent antifungal effects comparable to those of fluconazole or polyoxin B. The results of antifungal activity experiments against drug-resistant fungal strains and sorbitol protection assays, coupled with the results of drug combination studies, further indicated that the target of these compounds is the chitin in the cell wall. Molecular docking showed that compounds had good affinities with both CHS and GlmS. Furthermore, ADME (absorption, distribution, metabolism, excretion) profiling revealed that these compounds possess favorable pharmacokinetic properties and drug-likeness, representing viable lead compounds for the development of novel antifungal agents.