The Role of Nitro (NO2-), Chloro (Cl), and Fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds.

Abstract

Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas diseases are among the most severe NTDs, and are caused by the Leishmania sp and Trypanosoma cruzi, respectively. Glucantime, pentamidine, and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, are known to improve biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluorosynthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand-searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth mentioning that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro-, and chloro-groups in the compound backbone. All in all, nitro and halogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as the baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts in in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.