Synthesis and non-clinical studies of potentially antiprotozoal reciprocal prodrugs

Abstract

For more than a century, Chagas Disease is one of the most epidemiological significant disease in Brasil, and nowadays it still remains neglected by the global pharmaceutical industries, that invest primarily on the development of new drugs for the treatment of globally more incident pathologies, mainly those that afflict the developed countries, in order to guaranty the monetary returns once invested. Albeit a number of works have been published every year, showing promising compounds with high trypanocidal activity, only a few of them go forward into non-clinical studies in way to turn them real drug candidates. Thus, this project aims not only the development of new antiprotozoal compounds, but also the first steps to non-clinical studies, in way to determine their toxicities and efficacy, and so to afford the basis of future clinical assays.The proposed compounds will be obtained through prodrug approach, which present the advantage to employ already known molecules, with prior biological and toxicological data, making faster the development of new derivatives, and with more chances of success. The compound 2-amine-1-(4-nitro)acetophenone thiosemicarbazone was elected by presenting a superior trypanocidal activity than benznidazol, the only drug against Chagas Disease in therapeutics today, and is an important inhibitor of cruzain, its probable molecular target. Additionally, there are a number of natural products, relatively abundant in plants and easily purchased from the market, that exhibit great antiprotozoal activity, including trypanocidal action, whose mechanism of action are not even completely elucidated, although preliminary studies showed that they are not able to inhibit the enzyme cruzain.The non-activity of these compound against cruzain makes them ideal for the purpose of this work, once the union through a hydrolysable binding to 2-amine-1-(4-nitro)acetophenone thiosemicarbazone leads to the obtainment of a prodrug that aims more than one metabolic pathway to plays its antiprotozoal activity, what represents an important goal to the prevention of resistance to the treatment and, possible, to improve the pharmacokinetic profiles of both active compounds. (AU)