Avaliação da atividade biológica de compostos sintéticos sobre Leishmania infantum

Abstract

Visceral leishmaniasis (VL), also known as kala-azar, is the most severe form of leishmaniasis and represents a major public health problem in several regions worldwide. The disease is caused by protozoa of the genus Leishmania, with Leishmania infantum being the main species in the Americas. Therefore, the search for new synthetic compounds for the treatment of this parasitic disease is justified. This study aimed to evaluate the in vitro biological activity of new synthetic compounds against L. infantum, the etiological agent of visceral leishmaniasis. A total of 65 compounds from two different classes (quinoline derivatives and Morita-Baylis-Hillman [MBH] adducts) were tested against promastigote and axenic amastigote forms, as well as for their cytotoxicity in erythrocytes and peripheral blood mononuclear cells (PBMCs) from healthy donors. Initially, two synthetic compounds obtained from the MBH reaction (AIM52 and AIC52) were selected for showing inhibition of promastigote viability (IC50 = 38.45 μM and 16.97 μM, respectively). Against amastigote forms, these compounds demonstrated stronger activity (EC50 = 4.02 μM for AIM52 and 4.24 μM for AIC52). Both compounds showed no hemolytic activity at the highest concentration tested (HC50 ≥ 400 μM); however, in PBMCs, they exhibited high cytotoxicity (CC50 = 4.24 μM and 10.34 μM), with Selectivity Indexes (SI ≥ 10.40 and 2.57; SI ≥ 23.57 and 0.76, respectively). Considering these compounds as promising candidates, structural modifications were performed to improve selectivity, resulting in eight modified MBH adducts. Among them, the most active and selective compound against L. infantum was AIN41 (IC50 = 8.16 μM; EC50 = 0.85 μM), with a Selectivity Index of SI ≥ 49.01. These adducts share an isatin-based scaffold, which was also tested alone but did not show anti-Leishmania or cytotoxic activity. In conclusion, Morita-Baylis-Hillman adducts, particularly the modified compound AIN41, demonstrated potent anti-Leishmania activity, high selectivity, and low hemolytic toxicity. Thus, AIN41 emerges as a promising lead compound for the development of new therapies against visceral leishmaniasis, contributing to therapeutic advancements.