Evaluation of SB-83, a 2-amino-thiophene derivative, against Leishmania species that cause visceral leishmaniasis

Raiza Raianne Luz Rodrigues; Julyanne Maria Saraiva de Sousa; Airton Lucas Sousa Dos Santos; Vanessa Maria Rodrigues de Souza; Yasmim Alves Aires Machado; Thaís Amanda de Lima Nunes; Marcos Vinícius da Silva; Alyne Rodrigues de Araújo-Nobre; Rodrigo Santos Aquino de Araújo; Francisco Jaime Bezerra Mendonça Junior; Leiz Maria da Costa Veras; Klinger Antonio da Franca Rodrigues

doi:10.1016/j.intimp.2025.114106

Evaluation of SB-83, a 2-amino-thiophene derivative, against Leishmania species that cause visceral leishmaniasis

Int Immunopharmacol. 2025 Jan 24:148:114106. doi: 10.1016/j.intimp.2025.114106. Online ahead of print.

Authors

Affiliations

¹ Infectious Diseases Laboratory, Campus Ministro Reis Velloso, Federal University of Parnaíba Delta, 64202-020 Parnaíba, PI, Brazil.
² Laboratory of Immunology and Parasitology, Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro, 38025-180 Uberaba, MG, Brazil.
³ Biodiversity and Biotechnology Research Center, Campus Ministro Reis Velloso, Federal University of Parnaíba Delta, 64202-020 Parnaíba, PI, Brazil.
⁴ Laboratory of Synthesis and Drug Delivery, Department of Biological Sciences, State University of Paraíba, 58071-160 João Pessoa, PB, Brazil.
⁵ Infectious Diseases Laboratory, Campus Ministro Reis Velloso, Federal University of Parnaíba Delta, 64202-020 Parnaíba, PI, Brazil. Electronic address: klinger@ufdpar.edu.br.

PMID: 39862638
DOI: 10.1016/j.intimp.2025.114106

Abstract

Visceral leishmaniasis is a systemic disease that affects various internal organs and represents the most severe and fatal form of leishmaniasis. Conventional treatment presents significant challenges, such as prolonged management in hospital settings, high toxicity, and an increasing growing number of cases of resistance. In previous studies, our research group demonstrated the effective and selective activity of the 2-amino-thiophene derivative SB-83 in preclinical models of cutaneous leishmaniasis. Given the urgent need for new therapeutic alternatives for visceral leishmaniasis, and considering our previous promising results for SB-83, this study investigated the antileishmanial activity of the compound on the etiological agents of visceral leishmaniasis. SB-83 demonstrated efficacy in inhibiting the growth of promastigote forms of Leishmania (Leishmania) infantum (IC₅₀ = 7.46 µM) and Leishmania (Leishmania) donovani (IC₅₀ = 9.84 µM). In the cytotoxicity evaluation, in RAW 264.7 macrophages, the compound revealed a CC₅₀ = 52.27 µM, being more toxic to the parasite, and respective selectivity indices (SI) of 7 and 5.31 against the previously mentioned species. Atomic force microscopy analysis showed that the compound causes alterations in surface roughness, formation of englobulations, and accumulation of lipids, all of which are indicative of cell death by apoptosis. This was confirmed by flow cytometry, which showed an increase in the number of cells labeled with Annexin V-FITC+/IP-, indicating apoptosis. SB-83 showed even greater efficacy against intramacrophagic amastigote forms (EC₅₀ = 2.91 µM), which was associated with structural changes, such as increased lysosomal volume, and cellular mechanisms, including elevated levels of cytokines TNF-α and IL-12, reactive oxygen and nitrogen species, and reduced levels of cytokines IL-10 and IL-6, as well as decreased arginase activity. The results allow us to conclude that the 2-amino-thiophene derivative SB-83 is a promising compound for development of new treatments against visceral leishmaniasis.

Keywords: 2-Amino-thiophene derivatives; Arginase; SB-83; Visceral leishmaniasis.