2. Academic Validation
  3. Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines

Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines

  • Bioorg Med Chem Lett. 2026 May:134:130541. doi: 10.1016/j.bmcl.2026.130541.
Otília Höeller Guarnieri 1,  Mariza Gabriela Faleiro de Moura Lodi Cruz 2,  Daniela de Melo Resende 2,  Carime L M Pontes 1,  Igor Vivan Roberto 1,  Luiza Schmidt D'Agostini 3,  Bertha Chithambo 4,  Niklas Ehlenz 5,  Xavier Siwe-Noundou 6,  Rui W M Krause 4,  Maique W Biavatti 7,  Jaya R Lakkakula 8,  Nilesh Shirish Wagh 8,  Mario Steindel 3,  Till Opatz 5,  Silvane M Fonseca Murta 2,  Louis P Sandjo 9
Affiliations

Affiliations

  • 1 Department of Chemistry, CFM, Campus Universitário Trindade, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Santa Catarina, Brazil.
  • 2 Group of Parasite Functional Genomics, Instituto René Rachou, Fundação Oswaldo Cruz FIOCRUZ Minas, Belo Horizonte, MG 30190-002, Brazil.
  • 3 Department of Microbiology, Immunology and Parasitology, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
  • 4 Center of Chemico- and Bio-Medical Research (CCBR), Department of Chemistry at Rhodes University in Grahamstown/Makhanda, South Africa.
  • 5 Department of Chemistry, Johannes-Gutenberg University of Mainz, Duesbergweg, 10-14, D-55128 Mainz, Germany.
  • 6 Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria 0204, South Africa.
  • 7 Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Campus Universitário-Trindade, Florianópolis CEP 88040-970, SC, Brazil.
  • 8 Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Mumbai, Maharashtra 410206, India.
  • 9 Department of Chemistry, CFM, Campus Universitário Trindade, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Santa Catarina, Brazil. Electronic address: [email protected].
PMID: 41539588 DOI: 10.1016/j.bmcl.2026.130541
Abstract

Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared N1,N4-bisbenzylbutane-1,4-diamines against recombinant T. cruzi and L. infantum as well as their inhibitory effects against the T. cruzi recombinant trypanothione reductase (TcTR). N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC50 of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC50 of 14.6). It moderately inhibited TcTR with an IC50 of 55.6 ± 18.6 μM. N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited L. infantum with an IC50 of 19.3 ± 1.2 μM (SI of 3.4). N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against T. cruzi (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC50 of 3.9 ± 1.9 μM. Alongside the two diamines, nine Other synthesized derivatives displayed antitrypanosomal activity with IC50 ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during in silico studies of the active compounds using TcTR (PDB ID 4NEW), N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.

Keywords

Antileishmanial activity; Antitrypanosomal activity; N(1),N(4)-bisbenzylbutane-1,4-diamines; Trypanothione reductase.

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