Investigation of Novel Isatinylhydantoin Derivatives as Potential Anti-Kinetoplastid Agents.

Abstract

Neglected tropical diseases are a group of infectious diseases with a high endemicity in developing countries of Africa, Asia, and the Americas. Treatment for these diseases depends solely on chemotherapy, which is associated with severe side effects, toxicity, and the development of parasitic resistance. This highlights a critical need to develop new and effective drugs to curb these diseases. As a result, a series of novel isatinylhydantoin derivatives were synthesized and evaluated for in vitro anti-kinetoplastid activity against seven human- or animal-infective Trypanosoma and two human-infective Leishmania species. The synthesized derivatives were tested for potential cytotoxicity against human, animal, and parasite host-related cell lines. The isatinylhydantoin hybrid 4 b bearing 5-chloroisatin and p-bromobenzyl moieties, showed strong trypanocidal activity against blood-stage T. congolense parasites; however, the promising in vitro trypanocidal potency of 4 b could not be translated to in vivo treatment efficacy in a preliminary animal study. Compounds 5, 2 b, and 5 b, were the most active against amastigotes of L. donovani, showing higher leishmanicidal activity than the reference drug, amphotericin B. These compounds were identified as early antileishmanicidal leads, and future investigations will focus on confirming their antileishmanial potential through in vivo efficacy evaluation as well as their exact mechanism of action.