Synthesis, structure–activity relationships, and bioactivity evaluation of 6-bromo-quinazolinone derivatives

Abstract

6-Bromo-quinazolinone derivatives were prepared and evaluated for the ability to inhibit cyclooxygenase-2 (COX-2). An extensive structure-activity relationship work was carried out, thus some potent and selective COX-2 inhibitors were identified. The key compound isothiocyanate was prepared through a simple and ecological method using di-2-pyridyl thionocarbonate in substitution of the thiophosgene, a potential air pollutant. The cyclization reaction of intermediate derivatives was developed through the methods reporting by Wamhoff. The anti-inflammatory activity of the derivatives (5-12) was evaluated by determining (by Western blot) the expression of cyclooxygenase (COX)-2, of inducible NO synthase (iNOS) and of intercellular adhesion molecule-1 (ICAM-1). The biological assays showed that the derivatives 7, 9, 10, 12 act as potent inhibitors of COX-2, iNOS, and ICAM-1 expression in human keratinocytes NCTC-2544 cells. This work showed that the new derivatives could be used as a novel class of antiinflammatory agents.