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.

Keywords: Inflammation; Molecular docking; Pharmacophore model; Pyrrole-indazole derivatives; Soybean lipoxygenase; Virtual screening.