Expanding the chemical space of aryloxy-naphthoquinones as potential anti-Chagasic agents: synthesis and trypanosomicidal activity

Nohemí A Becerra,Uziel Castillo-Velazquez,Mario Aranda,Gildardo Rivera,Jorge Cantero,Adriana Moreno-Rodríguez,Sofía Toledo,Ana F Elizondo Rodríguez,Margot Paulino,Benjamín Nogueda,Fabiola Chacón-Vargas,Cristian O Salas,Christian Espinosa-Bustos,Karina Vázquez

doi:10.1007/s00044-021-02809-3

Abstract

In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.

Highlights

Chagas disease or American trypanosomiasis is one of the 20 “Neglected Tropical Diseases” (NTD) (WHO, 2020)
In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential antiChagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi)
Considering the aforementioned, in this work, we carried out the synthesis of new naphthoquinones (Fig. 1), which was functionalized according to four criteria, to evaluate the effect of these modifications on the trypanosomicidal effect on epimastigote and tripomastigote forms from Mexican strains of T. cruzi

Summary

Introduction

Chagas disease or American trypanosomiasis is one of the 20 “Neglected Tropical Diseases” (NTD) (WHO, 2020). In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential antiChagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC50 < 1.0 μM) compared to the reference drug benznidazole (Bzn).

Results

Conclusion