Synthesis of novel benzimidazole derivatives and the studies on their leukotriene biosynthesis inhibitory activities

LTs have important pathophysiological roles in inflammatory, cardiovascular and allergic diseases. The first committed step in the synthesis of leukotrienes involves the function of integral membran protein FLAP to transfer AA to 5-LO. The recent elucidation of FLAP x-ray crystal structure caused increased interest for development of new LT biosynthesis inhibitors for treatment of inflammatory diseases. For this purpose, we decided to synthesize new compounds that may exhibit the inhibition of LT biosynthesis in human PMNL. By keeping the main benzimidazole structure, thirty two novel compunds were synthesized. Their sturctures were fully elucidated using spectral techniques and elemental analysis.The obtained thirty two final compunds reported herein were evaluated for their ability to inhibit LT biosynthesis in human PMNL. The compund 6e (1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1H-benzimidazole) was found to be a potent inhibitor of LT biosynthesis with 0.12 µM. In addition, 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzdimidazol-5-ol (7e) and 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-5-(pyridin-2-ylmethoxy)-1H-benzimidazole (9e) derivatives also potently inhibited LT biosynthesis with IC50 values 0.19 µM and 0.18 µM, respectively. By using molecular modeling approaches, molecular binding patterns of selected compounds with FLAP active site resulted insight for further studies.