Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.

Chee Wei Ang,Anjan Debnath,Janet C Reid,Vicky M Avery,Neda Abugharbiyeh,Nicholas P West,Matthew A Cooper,Lendl Tan,Mark A T Blaskovich,Melissa L Sykes

doi:10.1021/acs.jmedchem.0c01372

Abstract

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

Highlights

Diseases caused by protozoans and bacteria remain a major global health threat, especially in low- and medium-income countries where they affect millions of lives
Following the potential of nitroimidazopyrazinones shown against T. b. brucei from our earlier investigation,[26] we have expanded our study to another pathogenic kinetoplastid, Trypanosoma cruzi, which causes Chagas disease
Modification of the methylene chain of 16 with polar linkers was not favorable for activity against M. tuberculosis, though some of them were active against the trypanosome species tested

Summary

Introduction

Diseases caused by protozoans and bacteria remain a major global health threat, especially in low- and medium-income countries where they affect millions of lives. Nitroimidazoles were discovered in the early 1950s.3 They have broad-spectrum activity across parasites, mycobacteria, and both Gram-positive and Gramnegative bacteria.[3] Recently, there has been a great interest in developing nitroimidazoles based on new bicyclic core scaffolds, resulting in the success of a nitroimidazooxazole, delamanid 1 and a nitroimidazooxazine, pretomanid 2 (Figure 1) as approved drugs for treatment of tuberculosis (TB).[4,5] Both 1 and 2 are pro-drugs that share an interesting dual mode of action. Nitroimidazole 2 was recently approved by the FDA in August 2019 as part of an all-oral combination regimen to treat drug-resistant TB, alongside bedaquiline and linezolid.[10]

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