Design, synthesis, and pharmacological evaluation of indazole carboxamides of N-substituted pyrrole derivatives as soybean lipoxygenase inhibitors.

ABSTRACT

In this paper, we attempted to develop a novel class of compounds against lipoxygenase, a key enzyme in the biosynthesis of leukotrienes implicated in a series of inflammatory diseases. Given the absence of appropriate human 5-lipoxygenase crystallographic data, solved soybean lipoxygenase-1 and -3 structures were used as a template to generate an accurate pharmacophore model which was further used for virtual screening purposes. Eight compounds (1-8) have been derived from the in-house library consisting of N-substituted pyrroles conjugated with 5- or 6-indazole moieties through a carboxamide linker. This study led to the discovery of hit molecule 8 bearing a naphthyl group with the IC50 value of 22 µM according to soybean lipoxygenase in vitro assay. Isosteric replacement of naphthyl ring with quinoline moieties and reduction of carbonyl carboxamide group resulted in compounds 9-12 and 13, respectively. Compound 12 demonstrated the most promising enzyme inhibition. In addition, compounds 8 and 12 were found to reduce the carrageenan-induced paw edema in vivo by 52.6 and 49.8%, respectively. In view of the encouraging outcomes concerning their notable in vitro and in vivo anti-inflammatory activities, compounds 8 and 12 could be further optimized for the discovery of novel 5-lipoxygenase inhibitors in future. A structure-based 3D pharmacophore model was used in the virtual screening of in-house library to discover novel potential 5-lipoxygenase inhibitors.