Avaliação da citotoxicidade e potencial leishmanicida in vitro de derivados 2-amino- alquil-1,2,3-triazol-1,4-naftoquinonas

Abstract

Parasites of the genus Leishmania are the causative agents of leishmaniasis in humans, a neglected disease that affects millions of people. Leishmanicidal therapy has some limitations such as high toxicity and significant adverse effects, in addition to strains already resistant to these therapies. One of the strategies for improving leishmaniasis therapy is the discovery of new drugs through chemical synthesis. Thus, this work aims to investigate the cytotoxicity and in vitro leishmanicidal activity of 2-amino-alkyl-1,2,3-triazol-1,4-naphthoquinones derivatives. For this, the cytotoxicity of the derivatives was evaluated in J774.A1 macrophages by MTT colorimetric assay and leishmanicidal activity in L. amazonensis and L. chagasi promastigote cultures by direct counting under optical microscope. Statistical analyzes were performed using the GraphPad Prisma® 5 software. In the cytotoxicity assay the derivatives LSCB 84, LSCB 85, LSCB 96, LSCB 97 and LSCB 104 were not toxic to macrophages and this result is believed to be related to the absence of grouping. hydroxyl in the structure of these compounds, while the other derivatives showed toxicity around 50%, besides all the derivatives showed lower toxicity than the standard pentamidine drug. The toxicity of the derivatives was also evaluated in silico using the OSIRIS® Program where it was observed through the parameters that the triazole-amino-quinone derivatives showed values close to the standard pentamidine drug. When investigating a possible leishmanicidal activity, only LSCB 97 and LSCB 100 were not active against L. chagasi. Derivatives LSCB 84, LSCB 85, LSCB 87, LSCB 88, LSCB 93, LSCB 99, LSCB 107, LSCB 109 were quite active with efficacy ranging from 99.1 ± 1.5% to 80.9 ± 9, 2% and IC50 from 0.3 ± 0.1 μM to 8.4 ± 0.8 μM. Regarding the effect against L. amazonensis forms, derivatives LSCB 97, LSCB 104 and LSCB 101 did not show significant leishmanicidal activity, however derivatives LSCB84, LSCB 85 and LSCB 93 showed activity of 83.13 ± 6.22%. (with IC50 of 32.04 ± 18.25 μM), 77.10 ± 8.23% (with IC50 of 62.4 ± 11.95 μM) and 93.97 ± 6.06% respectively. Most of the derivatives were more active and more selective for the L. chagasi promastigote forms, and showed to be promising molecules regarding their leishmanicidal activity for both species.