From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds

Saulo Fehelberg Pinto Braga; Viviane Corrêa Santos; Rafael Pinto Vieira; Elany Barbosa da Silva; Ludovica Monti; Susann H Krake; Pablo D G Martinez; Luiz Carlos Dias; Conor R Caffrey; Jair L Siqueira-Neto; Renata Barbosa de Oliveira; Rafaela Salgado Ferreira

doi:10.1016/j.ejmech.2022.114876

From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds

Eur J Med Chem. 2022 Dec 15:244:114876. doi: 10.1016/j.ejmech.2022.114876. Epub 2022 Oct 27.

Affiliations

¹ Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil; Department of Pharmacy, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, 35400-000, Minas Gerais, Brazil. Electronic address: saulo.braga@ufop.edu.br.
² Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
³ Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0657, USA.
⁴ Institute of Chemistry, Department of Organic Chemistry, Campinas State University, Cidade Universitária Zeferino Vaz, CP 6154, Campinas, 13083-970, São Paulo, Brazil.
⁵ Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, 31270-901, MG, Brazil.
⁶ Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil. Electronic address: rafaelasf@icb.ufmg.br.

PMID: 36343429
DOI: 10.1016/j.ejmech.2022.114876

Abstract

Chagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6-7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC₅₀ 26 μM, K_i 3 μM) and TbrCatL (IC₅₀ 50 μM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later characterized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC₅₀ 13-49.7 μM) and T. cruzi (EC₅₀ 0.027-0.59 μM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.

Keywords: Cruzain; TbrCatL (rhodesain); Thiosemicarbazone; Trypanosoma brucei; Trypanosoma cruzi.

MeSH terms

Chagas Disease* / drug therapy
Cysteine Proteinase Inhibitors / pharmacology
Humans
Structure-Activity Relationship
Thiosemicarbazones* / pharmacology
Trypanocidal Agents* / pharmacology
Trypanosoma brucei brucei*
Trypanosoma cruzi*

Substances

Trypanocidal Agents
Thiosemicarbazones
Cysteine Proteinase Inhibitors