DESIGN AND SYNTHESIS OF NOVEL DIARYL ETHER LINKED BENZOTHIAZOLE DERIVATIVES WITH ENHANCED IN VITRO ANTI-INFLAMMATORY POTENTIAL

Abstract

The development of safe, targeted therapeutics remains a major clinical challenge due to the adverse effects of non steroidal anti-inflammatory drugs. In this study, a novel series of diaryl ether-linked benzothiazole derivatives (5a-5l) was designed, synthesized, and rigorously evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro enzymatic assays identified compound 5c, bearing a para-nitro substitution, as the most potent candidate, exhibiting an exceptional COX-2 IC50 of 0.48 µM and a remarkable Selectivity Index of 237.9, vastly outperforming indomethacin. Biological evaluation in LPS-stimulated RAW 264.7 macrophages demonstrated that compound 5c significantly and dose-dependently suppressed pro-inflammatory nitric oxide (NO) production. Crucially, the MTT assay confirmed an excellent safety profile with negligible cytotoxicity, proving the therapeutic effect is entirely independent of cell death. Comprehensive structure-activity relationship (SAR) analysis and molecular docking studies revealed that the V-shaped conformation of 5c enables optimal penetration into the COX-2 secondary pocket, forming critical hydrogen bonds with Arg513. Supported by highly favorable in silico ADMET predictions, including high oral bioavailability and zero Lipinski violations, compound 5c emerges as a highly promising, fundamentally safe lead for advanced preclinical anti-inflammatory drug development.