2-Phenylbenzothiazoles featuring heteroaryl sulfonamide end-capping substructures as developable mPGES-1 inhibitors.

The inhibition of human microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) is a promising therapeutic modality for developing next-generation anti-inflammatory medications. In this study, we present novel 2-phenylbenzothiazole derivatives featuring heteroaryl sulfonamide end-capping substructures as inhibitors of human mPGES-1, with IC50 values in the range of 0.72-3.40 µM in a cell-free assay of PGE2 formation. Notably, compound 21, featuring a quinoxalinedione ring in its sulfonamide segment, effectively suppresses PGE2 biosynthesis at a low micromolar concentration (IC50 = 0.72 µM) with exceptional selectivity against cyclooxygenase (COX)-1, COX-2, 5-lipoxygenase (5-LOX), and FLAP. This compound offers a novel chemical scaffold for developing safer and more effective anti-inflammatory agents.