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Synthesis, Structure-Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity.

Authors
  • Akester, Jessica N1
  • Njaria, Paul2
  • Nchinda, Aloysius1
  • Le Manach, Claire1
  • Myrick, Alissa1, 3
  • Singh, Vinayak1, 3, 4
  • Lawrence, Nina5
  • Njoroge, Mathew5
  • Taylor, Dale5
  • Moosa, Atica6
  • Smith, Anthony J7
  • Brooks, Elizabeth J7
  • Lenaerts, Anne J7
  • Robertson, Gregory T7
  • Ioerger, Thomas R8
  • Mueller, Rudolf1
  • Chibale, Kelly1, 2, 3, 4
  • 1 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. , (South Africa)
  • 2 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. , (South Africa)
  • 3 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. , (South Africa)
  • 4 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. , (South Africa)
  • 5 H3D, Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa. , (South Africa)
  • 6 MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa. , (South Africa)
  • 7 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, 200 West Lake Street, Fort Collins, Colorado 80523, United States. , (United States)
  • 8 Department of Computer Science, Texas A&M University, College Station, Texas 77843-3112, United States. , (United States)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Jul 10, 2020
Volume
6
Issue
7
Pages
1951–1964
Identifiers
DOI: 10.1021/acsinfecdis.0c00252
PMID: 32470286
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Phenotypic whole-cell screening against Mycobacterium tuberculosis (Mtb) in glycerol-alanine-salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing the sulfone moiety with a sulfoxide 2. The synthesis and structure-activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound 2 displayed favorable in vitro properties and was therefore selected for in vivo pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone 1. Both derivatives exhibited promising PK parameters; however, when 2 was evaluated for in vivo efficacy in an acute TB infection mouse model, it was found to be inactive. In order to understand the in vitro and in vivo discrepancy, compound 2 was subsequently retested in vitro using different Mtb strains cultured in different media. This revealed that activity was only observed in media containing glycerol and led to the hypothesis that glycerol was not used as a primary carbon source by Mtb in the mouse lungs, as has previously been observed. Support for this hypothesis was provided by spontaneous-resistant mutant generation and whole genome sequencing studies, which revealed mutations mapping to glycerol metabolizing genes indicating that the 2-aminoquinazolinones kill Mtb in vitro via a glycerol-dependent mechanism of action.

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