Identification of chemotherapeutic agents against leishmaniasis and Chagas' disease
Patients with clinical manifestations of leishmaniasis and Chagas' disease rely on few drugs that have limited efficacy and considerable side effects. Expanding the diversity of available chemotherapeutic drugs for these diseases is of extreme medical importance. Enones or α,β-unsaturated ketones, initially developed as anti-cancer agents, are a worthy of class of compounds to test for activity against Leishmania major and Trypanosoma cruzi as these eukaryotic parasites share many of the characteristics exhibited by cancer cells. The anti-parasitic activity of a library of α,β-unsaturated ketones (136 derivatives) was screened against L. major as well as in mammalian cells. Three compounds (NC901, NC884, and NC2459) showed high leishmanicidal activity (EC50 = 456 nM, 1122 nM, and 20 nM, respectively), without mammalian cell toxicity, and were also highly toxic against. T. cruzi epimastigotes (EC50 = 468 nM, 475 nM, and 20 nM, respectively). When tested on in vitro infections of BALB/c intraperitoneal macrophages or human osteoblasts with metacyclic promastigote and trypomastigote forms of L. major and T. cruzi, respectively, these three compounds showed strong showed strong inhibition as well (Lm-IC 50 = 1870 nM, 937 nM, and 625 nM; Tc-IC50 = 301 nM, 987 nM, and 227 nM, respectively) Furthermore, these compounds were shown to be capable of significantly reducing the parasite burden of L. major induced cutaneous leishmaniasis in vivo with no apparent toxicity in BALB/c mice. Lastly, our experimental results strongly suggested that the mechanism of action of these compounds is through the induction of a mitochondria-dependent apoptosis-like effect in L. major promastigotes. These results indicate that enones may be considered as a safe alternative for current chemotherapeutic drugs used to combat leishmaniasis and Chagas' disease.
Vasquez, Miguel Abran, "Identification of chemotherapeutic agents against leishmaniasis and Chagas' disease" (2013). ETD Collection for University of Texas, El Paso. AAI3597262.