Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors


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Abstract

Background:Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases.

Objectives:The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits.

Methods:Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities.

Results:The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 µM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 µM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90.

Conclusion:The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

About the authors

Nahid Ahmadi

Department of Pharmaceutical Chemistry, School of Pharmacy,, Shahid Beheshti University of Medical Sciences

Email: info@benthamscience.net

Mona Khoramjouy

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences

Email: info@benthamscience.net

Mahsa Azami Movahed

Department of Pharmaceutical Chemistry, School of Pharmacy,, Shahid Beheshti University of Medical Sciences

Email: info@benthamscience.net

Salimeh Amidi

Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences

Email: info@benthamscience.net

Mehrdad Faizi

Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences

Email: info@benthamscience.net

Afshin Zarghi

Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

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