Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi.

Leonardo S Lara,David R Da Rocha,Mirian C S Pereira,Vitor F Ferreira,Thaís B Santos,Guilherme C Lechuga,Caroline Dos S Moreira

doi:10.3390/molecules26020423

Leonardo S Lara, David R Da Rocha + Show 5 more

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https://doi.org/10.3390/molecules26020423

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Abstract

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a–i and 2a–j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.

Highlights

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery
(1a–f, 1h and 1i) was designed considering the results reported in previous studies of our research group, where we observed that the introduction of chlorine atoms in R1, combined with benzene in R2, promoted good anti-T. cruzi activity [29]
Among the 20 neglected tropical diseases (NTDs) proposed for control or elimination by 2020, Chagas disease (CD), discovered 110 years ago, has made little progress in finding new drugs effective in treating the disease

Summary

Introduction

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile. Chagas disease (CD), a serious parasitic disease caused by T. cruzi, continues to be a neglected disease with a high social and economic impact in Latin America, despite the control strategies of the World Health Organization’s programs launched to combat this disease [1]. Non-endemic countries have faced this silent disease because of the emigration of asymptomatic infected individuals, who are unaware that they harbor T. cruzi, making ms in published maps and institutional affiliations

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