Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics.

Ivani Pauli,Brian W Slafer,Mariana L De Souza,Rafaela S Ferreira,Abraham L M Adjanohun,Celso De O Rezende Jr,Adriano D Andricopulo,Fernando B R Da Silva,Luiz C Dias,Ricardo Vaz Del Pintor,Luma G Magalhães,Simone Michelan-Duarte,Leonardo L G Ferreira,Renata Krogh,Fabio C Cruz,Marco A Dessoy

doi:10.3389/fphar.2021.774069

Abstract

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Highlights

Endemic in Latin America, Chagas disease affects 6–7 million people worldwide and has become an emerging public health problem in nonendemic countries1
To further corroborate the formation of a hydrogen bond with Glu208, we evaluated the activities of six compounds against the enzyme rhodesain, a cysteine protease that has a similar active site to that of cruzain, in which Glu208 is replaced with an alanine residue (Lima et al, 2013)
Considering that few molecular targets are validated in neglected tropical disease (NTD) (De Rycker et al, 2018) and the relatively unsuitable compounds regarding toxicity and drug-likeness that have been historically explored in the area, the findings reported address an important gap in Chagas disease drug discovery

Summary

Introduction

Endemic in Latin America, Chagas disease affects 6–7 million people worldwide and has become an emerging public health problem in nonendemic countries. Chemotherapy for Chagas disease consists of benznidazole (BZ) and nifurtimox, two nitro compounds that have limited efficacy and produce serious adverse reactions that lead up to 40% of patients to discontinue treatment (Rodriques Coura and De Castro, 2002). Given these shortcomings, the development of novel, effective and safe drugs for the treatment of Chagas disease is critically needed

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Conclusion