2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling

Autor(es):Mostrar menos -

Alves Ferreira, Rafael Augusto ^[1] ; Rezende Junior, Celso de Oliveira ^[1] ; Grigol Martinez, Pablo David ^[1] ; Koovits, Paul John ^[1] ; Soares, Bruna Miranda ^[1] ; Ferreira, Leonardo L. G. ^[2] ; Michelan-Duarte, Simone ^[2] ; Chelucci, Rafael Consolin ^[2] ; Andricopulo, Adriano D. ^[2] ; Galuppo, Mariana K. ^[3] ; Uliana, Silvia R. B. ^[3] ; Matheeussen, An ^[4] ; Caljon, Guy ^[4] ; Maes, Louis ^[4] ; Campbell, Simon ^[5] ; Kratz, Jadel M. ^[5] ; Mowbray, Charles E. ^[5] ; Dias, Luiz Carlos ^[1]

Afiliação do(s) autor(es)

^[1] Univ Campinas UNICAMP, Inst Chem, Campinas, SP - Brazil

^[2] Univ Sao Paulo, Lab Med & Computat Chem, Phys Inst Sao Carlos, Sao Carlos, SP - Brazil

^[3] Univ Sao Paulo, Biomed Sci Inst, Dept Parasitol, Sao Paulo, SP - Brazil

^[4] Lab Microbiol Parasitol & Hyg LMPH, Antwerp - Belgium

^[5] Drugs Neglected Dis Initiat DNDi, Geneva - Switzerland

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 15, n. 2 FEB 2021.
• Citações Web of Science: 0

Resumo

Author summary Leishmaniasis is a neglected tropical disease affecting millions of people worldwide and, in the case of visceral leishmaniasis (VL), is potentially fatal if untreated. Protozoan parasites of the genus Leishmania spp. are the causative agents of leishmaniasis, which has different clinical manifestations, including the visceral form and a cutaneous form that causes disfiguring skin lesions. The current treatment options are limited either by the length of treatment or toxic side effects. Starting from a promising hit in an in vitro phenotypic screen, hundreds of analogues were synthesized with the aim of finding a molecule capable of killing the parasite whilst causing little or no harm to the patient. The program led to several active compounds with good in vitro activity against L. infantum intracellular amastigotes, however, in vivo data showed low parasiticidal efficacy. Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 mu M) and 39 (L. infantum IC50: 0.5 mu M) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency. (AU)

• Processo FAPESP: 15/09080-2 - Avaliação de candidatos a fármacos para o tratamento de leishmaniose no Brasil
• Beneficiário: Silvia Reni Bortolin Uliana
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/50655-9 - Consórcio FAPESP/MMV/DNDI/UNICAMP/USP para descobrir novos medicamentos para o tratamento de doenças parasitárias tropicais
• Beneficiário: Luiz Carlos Dias
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs