SYNTHESIS AND BIOLOGICAL EVALUATION OF DIMETHYLETHYL)-4-HYDROXYPHENYL]METHYLENE]OXAZOLES, -THIAZOLES, AND -IMIDAZOLES - NOVEL DUAL 5-LIPOXYGENASE AND CYCLOOXYGENASE INHIBITORS WITH ANTIINFLAMMATORY ACTIVITY

A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhib itors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selecti vity toward the two enzymes. Several Compounds are orally active in th e rat carageenan footpad edema (CFE) and mycobacterium footpad edema ( MFE) antiinflammatory models. Structure-activity relationships are dis cussed. From this work, hydroxyphenyl]-methylene]-2-imino-4-thiazolidi none methanesulfonate salt (CI-1004) was identified as a potent. dual inhibitor of 5-lipoxygenase (IC50 = 0.77 mu M) and cyclooxygenase (IC5 0 = 0.39 mu M), with Oral activity (ID4(0) = 0 6 mg/kg) in the rat MFE model of inflammation.