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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 15, n. 2 FEB 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 15/09080-2 - Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil
• Grantee: Silvia Reni Bortolin Uliana
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/50655-9 - FAPESP/MMV/DNDi/UNICAMP/USP Consortium to discover new drugs for the treatment of tropical parasitic diseases
• Grantee: Luiz Carlos Dias
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC