Antileishmanial activity of 2-amino-thiophene derivative SB-200

Abstract

Leishmaniasis, presenting the highest number of cases worldwide is one of the most serious Neglected Tropical Diseases (NTDs). Clinical manifestations are intrinsically related to the host's immune response making immunomodulatory substances the target of numerous studies on antileishmanial activity. The currently available drugs used for treatment present various problems including high toxicity, low efficacy, and associated drug resistance. The search for therapeutic alternatives is urgent, and in this context, thiophene derivatives appear to be a promising therapeutic alternative (many have shown promising anti-leishmanial activity). The objective of this study was to investigate the antileishmanial activity of the 2-amino-thiophenic derivative SB-200. The thiophenic derivative was effective in inhibiting the growth of Leishmania braziliensis, Leishmania major, and Leishmania infantum promastigotes, obtaining respective IC₅₀ values of 4.25 μM, 4.65 μM, and 3.96 μM. For L. infantum, it was demonstrated that the antipromastigote effect of SB-200 is associated with cell membrane integrity losses, and with morphological changes observed during scanning and transmission electron microscopy. Cytotoxicity was performed for J774.A1 macrophages and VERO cells, to obtain a CC₅₀ of 42.52 μM and a SI of 10.74 for macrophages and a CC₅₀ of 39.2 μM and an SI of 9.89 for VERO cells. The anti-amastigote activity of SB-200 revealed an IC₅₀ of 2.85 μM and an SI of 14.97 against macrophages and SI of 13.8 for VERO cells. The anti-amastigote activity of SB-200 is associated with in vitro immunomodulation. For acute toxicity, SB-200 against Zophobas morio larvae permitted 100% survival. We conclude that the 2-amino-thiophenic derivative SB-200 is a promising candidate for in vivo anti-leishmania drug tests to evaluate its activity, efficacy, and safety.

Keywords: 2-Amino-thiophene derivative; Immunomodulation; Leishmaniasis; Visceral leishmaniasis.