Determinação do efeito citotóxico e avaliação do potencial leishmanicida in vitro de novos derivados aminoguanidina hidrazonas e outros compostos relacionados

Abstract

According to data from the World Health Organization (WHO), Neglected Populations Diseases (NPDs) affect more than one billion people worldwide. Among them, leshmaniasis is responsible for to affect more than 12 million people, being expect average two million new cases per year in the five continents, representing a serious public health problem. Until moment, available drug therapy is not ideal, given that drugs have significant adverse effects, long therapeutic regimens, and most of them require parenteral administration. In this sense, the search for new therapeutic alternatives becomes essential. Thus, this work aimed to determine the cytotoxic and leishmanicidal effect of new derivatives aminoguanidine hydrazones and other related compounds. Initially, ninety derivatives were tested, of which sixty-six not showed significant cytotoxicity in the MTT-reduced cell viability assay, up to the maximum concentration tested, 10 μM. These were then submitted to the amastigote assay of Leishmania infantum chagasi, in which it was possible to observe that eight presented leishmanicidal activity above 50% and IC50 less than 10 μM, and could be compared with the standard drug used pentamidine that had a maximum effect of the 67.3% e IC50 of the 4.4 μM. Among the most active compounds are two aminoguanidine hydrazone derivatives: LQM 19 and LQM 55, one aromatic heterocyclic guanylidrazonic derivative: LQM 195 and four thiosemicarbazones derivatives: LQM 08.1, LQM 17.1, LQM 95.1 and LQM 106.1. The LQM 19 derivative showed maximal effect (ME) of 63.8% and 50% inhibitory concentration (IC50) of 4.97 uM and LQM 55 derivative had ME of the 63.5% and IC50 of 7.7 uM. This was also seen for LQM 195 derivative had EM of 55.3% and an IC50 of 0.06 μM. As well as the LQM 08.1 derivative had EM of 56.9% and an IC50 of 8.73 μM, the same can be seen for the LQM 17.1 derivative had ME of 66.38% and an IC50 of 2.2 μM for the LQM 95.1 derivative had ME of 60.2% and an IC50 of the 1.6 μM and also for the LQM 106.1 derivative had ME of 60.4% and an IC50 of 3.2 μM. Given the promising results, it was necessary to select a derivative to perform the structural modifications and as the class of thiosemicarbazones stood out the LQM 17.1 derivative was chosen to perform structural modifications, seeking a more active compound, giving rise to twelve new compounds. However, the modifications made did not result in improvement of the activity. Thus, it is concluded that it is valid to deepen the studies with the seven derivatives that stand out for the leishmanicidal activity against amastigotes of L. infantum chagasi, through the evaluation of the mechanisms of action and also the leishmanicidal activity on other Leishmania species, seeking those that could be future drug prototypes.