Novel 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene analogues as selective COX-2 inhibitors: Design, synthesis, anti-inflammatory evaluation, and molecular docking studies

Chetan K Khatri; Krishna S Indalkar; Chandragouda R Patil; Sameer N Goyal; Ganesh U Chaturbhuj

doi:10.1016/j.bmcl.2017.02.076

Novel 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene analogues as selective COX-2 inhibitors: Design, synthesis, anti-inflammatory evaluation, and molecular docking studies

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1721-1726. doi: 10.1016/j.bmcl.2017.02.076. Epub 2017 Mar 8.

Authors

Chetan K Khatri¹, Krishna S Indalkar¹, Chandragouda R Patil², Sameer N Goyal², Ganesh U Chaturbhuj³

Affiliations

¹ Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, Maharashtra, India.
² Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist-Dhule 425405, Maharashtra, India.
³ Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, Maharashtra, India. Electronic address: [email protected].

PMID: 28284805
DOI: 10.1016/j.bmcl.2017.02.076

Abstract

A series of 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene derivatives were synthesized and evaluated for in vitro COX inhibitory potential. Within the series, compounds 4a, 4j, 4k, and 4q were identified as potential and selective COX-2 inhibitors with COX-2 IC₅₀ in 0.31-1.40µM range; COX-2 selectivity index (SI)=48.8-183.8 range and they showed percent PGE-2 inhibitory activity in the range of 25.4-46.9. Further, compounds 4a, 4j, 4k and 4q displayed potent anti-inflammatory activity with percentage rise in paw volume ranging from 21.1-30.5 at 180min, while celecoxib demonstrated 19.6 percentage rise at the same dose at 180min in carrageenan-induced rat paw edema assay. Cell viability via MTT assay showed no cytotoxicity up to 80µM concentrations. Molecular docking study of potent compounds in the series showed Gscore comparable to celecoxib with similar binding orientation for the COX-2 active site which also corroborates the observed in vitro COX-2 inhibition.

Keywords: 4,5,6,7-Tetrahydro[b]benzothiophene; Anti-inflammatory activity; COX-2 selective; Carrageenan-induced rat paw edema; Molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Carrageenan
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry*
Cyclooxygenase 2 Inhibitors / pharmacology
Cyclooxygenase 2 Inhibitors / therapeutic use*
Drug Design
Edema / drug therapy*
Edema / pathology
Mice
Molecular Docking Simulation
RAW 264.7 Cells
Rats
Thiophenes / chemical synthesis
Thiophenes / chemistry*
Thiophenes / pharmacology
Thiophenes / therapeutic use*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Thiophenes
benzothiophene
Carrageenan