Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity.

Angie M Jarrad,Kyra Woods,Chee Wei Ang,Vicky M Avery,Ruby Pelingon,Mark S Butler,Mark A T Blaskovich,Lendl Tan,Amy J Jones,Hye Jee Hahn,Tomislav Karoli,Melissa L Sykes,Matthew A Cooper,Nicholas P West,Anjan Debnath

doi:10.1021/acs.jmedchem.8b01578

Abstract

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed and synthesized, and structure–activity relationships were generated. Selected derivatives had potent antiparasitic and antitubercular activity while maintaining drug-like properties such as low cytotoxicity, good metabolic stability in liver microsomes and high apparent permeability across Caco-2 cells. The kinetic solubility of the new bicyclic derivatives varied and was found to be a key parameter for future optimization. Taken together, these results suggest that promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development.

Highlights

Infectious diseases are an enormous global health burden
The Drugs for Neglected Diseases initiative (DNDi) is currently investigating fexinidazole (4, Figure 1) as a candidate for oral treatment of human African trypanosomiasis (HAT), a parasitic infection caused by Trypanosoma brucei spp. that is a public health threat to ∼70 million people in Africa.[5]
In November 2018 the European Medicines Agency recommended approval of fexinidazole as the first all-oral treatment for sleeping sickness. Bicyclic nitroimidazoles, such as delamanid (5, Figure 1) and pretomanid (6, PA-824), are promising new antimicrobials being developed for the treatment of tuberculosis (TB),[6] the number one cause of death from infectious diseases and the Received: October 10, 2018

Summary

Introduction

Infectious diseases are an enormous global health burden. The nitroimidazole class of antibiotics, exemplified by metronidazole (1, Figure 1), has a long history of use to treat bacterial and parasitic infections.[1]. Secnidazole (2, Figure 1) was recently approved in the USA for the treatment of bacterial vaginosis, despite being available earlier as a generic in many jurisdictions.[2,3] A pediatric formulation of benznidazole 3 (Figure 1), a 2-nitroimidazole used for the treatment of Chagas disease caused by the parasite Trypanosoma cruzi, gained FDA approval in 2017 for use in children.[4] The Drugs for Neglected Diseases initiative (DNDi) is currently investigating fexinidazole (4, Figure 1) as a candidate for oral treatment of human African trypanosomiasis (HAT), a parasitic infection caused by Trypanosoma brucei spp. that is a public health threat to ∼70 million people in Africa.[5] In November 2018 the European Medicines Agency recommended approval of fexinidazole as the first all-oral treatment for sleeping sickness Bicyclic nitroimidazoles, such as delamanid (5, Figure 1) and pretomanid (6, PA-824), are promising new antimicrobials being developed for the treatment of tuberculosis (TB),[6] the number one cause of death from infectious diseases and the Received: October 10, 2018 Published: November 23, 2018

Methods

Results

Conclusion