Synthesis of 5-lipoxygenase inhibitors and studies on biological activities

SUMMARYLT?s are proinflammatory lipid mediators which play an important role in a number of human diseases. The first step in LT biosynthesis is the transformation of AA to the 5-HPETE catalyzed by the 5-LO enzyme, which subsequently converted to LTA4 by LTA4 hydrolase. In addition, a helper protein FLAP has been observed to aid the transfer of substrate AA to the 5-LO. Hence, inhibition of LT biosynthesis can be accomplished either by direct inhibition of 5-LO or indirectly by the inhibiton of FLAP. Recently illimunated crystal structure of 5-LO provided an opportunity to develop the novel 5-LO inhibitors, which can prevent LT biosynthesis at early stages to develop novel therapies for inflammatory disorders, cardiovascular diseases and cancer. With this aim, by keeping the isoxazole ring as a main structure, a series of twenty nine compounds including linear isoxazole, 4,5-diaryl-3-methylisoxazole and 4,5-diaryl-3-carboxylic acidisoxazole derivatives were designed and synthesized. Their structures were fully elucidated using spectral techniques and elemental analysis.Twenty nine final compounds reported herein were evaluated for their ability to inhibit LT biosynthesis in human PMNL. Compound 7e, tert-butyl 4[({5-[4-(benzyloxy)phenyl]isoxazole-3-yl}methyl)amino]piperidine-1-carboxylate was found to be a potent inhibitor of LT biosynthesis with 1.5 µM IC50 value in PMNL. In addition, 1[({5-[4-(benzyloxy)phenyl]isoxazole-3-yl}methyl)4-(2-furoyl)piperazine (7d), 1[({5-[4-(benzyloxy)phenyl]isoxazole-3-yl}methyl)]-4-[4-(trifluoromethyl)benzyl]piperazine (7a) and 1[({5-[4-(benzyloxy)phenyl]isoxazole-3-yl}carbonyl)-4-(4-tert-butylbenzyl) piperazine (8) also potently inhibited LT biosynthesis in PMNL with IC50 values of 5, 8 and 8 µM, respectively. Judging from the results of carboxylic acid derivatives, its seen that derivatives with phenyl group bearing 2-CH3 at 5th position of isoxazole ring, are the most active compounds at 10 µM. according to promising results, further studies are in progress.