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  3. 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

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

  • Eur J Med Chem. 2025 Apr 15:288:117346. doi: 10.1016/j.ejmech.2025.117346.
Richa Singh 1,  Vinita Kushwaha 2,  Sumit K Rastogi 3,  Prashant Rai 4,  Santosh Kumar 5,  Nilesh Khandelwal 6,  Sanchita Gupta 7,  Amol Chhatrapati Bisen 8,  Salil Varshney 9,  Astha Singh 10,  Vishal M Balaramnavar 11,  Rabi Sankar Bhatta 12,  Ravindra Kumar 13,  Anil N Gaikwad 14,  Arun K Sinha 15
Affiliations

Affiliations

  • 1 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: richasingh225@gmail.com.
  • 2 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: vk74508@gmail.com.
  • 3 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: rastogisumitkumar1995@gmail.com.
  • 4 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: prashantarjunrai@gmail.com.
  • 5 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: santoshprajapati234@gmail.com.
  • 6 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: khandelwaln27@gmail.com.
  • 7 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: sanchitagupta2691@gmail.com.
  • 8 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: amolbisen@gmail.com.
  • 9 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: salil.varshney1989@gmail.com.
  • 10 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: asthasingh8855@gmail.com.
  • 11 Sanskriti University, School of Pharmacy and Research Center, 28 KM. Stone, Mathura-Delhi Highway, Chhata, Mathura, Uttar Pradesh (UP), 281401, India. Electronic address: v.balaramnavar@gmail.com.
  • 12 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: rabi_bhatta@cdri.res.in.
  • 13 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: ravindra.kumar1@cdri.res.in.
  • 14 Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: anil_gaikwad@cdri.res.in.
  • 15 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P., India. Electronic address: aksinha08@rediffmail.com.
PMID: 39954348 DOI: 10.1016/j.ejmech.2025.117346
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.

Keywords

Anti-adipogenic; Anti-dyslipidemic; Hybrid Molecules; Pharmacokinetic; Wnt/β-Catenin Pathway.

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