Descubrimiento racional de nuevos compuestos químicos para el tratamiento de la Leishmaniosis y la enfermedad de Chagas

SIFONTES-RODRÍGUEZ, S; MOLLINEDA-DIOGO, N; MONZOTE-FIDALGO, L; MENESES-MARCEL, A; GULIN, E; ESCARIO, JA; ARÁN-REDÓ, V

La Habana

Congreso; IX Congreso Cubano de Microbiología y Parasitología. VI Congreso Nacional de Medicina Tropical. VI Seminario Internacional sobre la infección por el VIH y el SIDA en Cuba.; 2017

Chagas? disease and Leishmaniasis are two neglected diseases of high prevalence and impact on public health worldwide. They primarily affect poor countries; there are no safe and efficacious vaccines to prevent them; the available drugs are expensive, toxic, ineffective and the emergence of drug-resistant parasite strains is of major concern. The aim of the present research work was searching for potentially active compounds against these two protozoa by using chemo-informatics techniques coupled with biological assays and focused on drugs already licensed for indications other than Leishmaniasis and Chagas? disease.Two datasets resulting from the high throughput screening of two different libraries of hundreds of thousands compounds tested against Leishmania major promastigotes and Trypanosoma cruzi intracellular amastigotes were modeled. 0-2D descriptors implemented in DRAGON software were calculated and Linear Discriminant Analysis and k-Nearest Neighbors techniques were used to obtain classification models (active/inactive). The most diverse models satisfying minimum accuracy criteria were combined into multi-classifier systems with adequate accuracy, robustness, predictive power and applicability domain coverage. Such model systems were used to classify compounds of unknown activity in order to identify potentially active compounds among a dataset of pharmacologically active ingredients of already licensed drugs. A selection of compounds based on model predictions so as pharmacological and toxicological properties was tested against the parasites in vitro and in vivo.Six compounds (clomiphene, meclozine, thioridazine, droperidol, furvine and toxiflavine) out of the 20 compounds (30%) selected for in vitro testing against L. amazonensis promastigotes were active. Two (10%) -meclozine and thioridazine Ŕ were also active against intracellular amastigotes and showed a selectivity index above 15. Moreover, three compounds (furvine, thioridazine and UC245) were active in an experimental model of murine cutaneous leishmaniasis.Alprazolam was the only active compound against T. cruzi intracellular amastigotes out of the five (20%) initially tested; however, it showed low specificity. Other two active compounds, one against L. amazonensis promastigotes (cyproheptadine, IC50=5.8±0.2μM) and the other against T. cruzi intracellular amastigotes (MbA, CI50=5.7±1.1 μM) were found trough the cross-activity analysis of compounds previously identified as active against any of the parasites.Besides the pharmacologicaly active ingredients licensed for other indications with potential clinical use in the short (furvine) and mid terms (thioridazine), it was possible to identify other series of compounds (2-nitrovynilfuran derivatives, anti-histamine and antidepressive drugs structurally similar to cyproheptadine and thioridazine, and triphenylethylene derivatives) with potential use as anti-trypanosomatids in the long term.Finally, the results demonstrated the efficiency of the combination of chemo-informatics and experimental studies applied to drug repositioning as a strategy to identify potentially efficacious compounds for the treatment of neglected diseases of high impact on public health.