Design, synthesis, and biological evaluation of novel quinoline carboxylic acid based styryl/alkyne hybrid molecule as a potent anti-adipogenic and antidyslipidemic agent via activation of Wnt/β-catenin pathway

Abstract

Obesity has emerged as the root cause for various metabolic disorders worldwide and hence demands for urgent attention. In the same stride, a series of quinoline carboxylic acid-based styryl/alkyne hybrids were designed, synthesized, and evaluated for their anti-adipogenic activity. Based on the structure-activity relationship, functional groups and essential substituents to potentiate the anti-adipogenic activity were identified. The potent compound (E)-6-fluoro-2-(4-(4-methylstyryl)phenyl)quinoline-4-carboxylic acid (5m) suppresses the adipogenesis with IC₅₀ value of 0.330 μM. In vitro studies in 3T3-L1 preadipocytes cell line show that compound 5m prevents adipogenesis by stopping the cell cycle at the early phase of differentiation, which is caused by stimulation of the Wnt3a/β-catenin pathway. Further compound 5m improves the blood lipid profile and reduces adipogenic marker proteins in the epididymal white adipose tissue (eWAT) of dyslipidemic hamster at 100 mg/kg/day oral dose. Treatment with compound 5m reduces the hypertrophied adipose tissue along with the decrease in the levels of adipogenic marker proteins such as PPARγ and CEBPα. The pharmacokinetic result establishes the molecule 5m to be stable with significant oral bioavailability. Henceforth, the present study provides a unique insight into the anti-adipogenic/anti-dyslipidemic properties of a novel styryl-quinoline carboxylic acid scaffold with a scope to enhance the anti-adipogenic potency for therapeutic intervention of obesity.