Design, synthesis and biological evaluation of isoflavones as antigiardial agents.

摘要

Pathogenic diseases have been a subject of research interest for a long time in medicinal chemistry. Giardiasis is one of the major intestinal diseases caused by a pathogenic unicellular protozoan, Giardia lamblia. Giardiasis is found worldwide, infecting an estimated of 280 million people each year. Recent reports on drug toxicity and Giardia resistant against current therapy have necessitated an urgent need to develop novel, safe and effective antigiardial agents.;It has been cited in the literature that isoflavones isolated from the bark of Dalbergia frutescens, namely formononetin and pseudobaptigenin, exhibited potent antigiardial activity that was higher than that of metronidazole, the current drug of choice (0.1mug/ml). Furthermore, formononetin showed remarkable selectivity as no cytotoxicity was observed to the mammalian cell line. However, formononetin failed to show significant in vivo antigiardial activity due to poor bioavailability issues.;In order to conduct structure activity studies towards discovery of novel antigiardial agents, a library of isoflavone analogs was designed and synthesized by solid-phase parallel synthesis. Several synthesized isoflavone analogs were identified as promising antigiardial agents. Computational studies were initiated in order to get key insights and identify structural features essential for antigiardial activity. An additional goal of this research was to design isoflavone prodrugs that would help in delivering the drug to the site of action.