Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability-Reference-Cited by-同舟云学术

Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability

Published:2023-11-06 Issue:24 Volume:18 Page:
ISSN:1860-7179
Container-title:ChemMedChem
language:en
Short-container-title:ChemMedChem

Author:

Campaniço André¹^ORCID,Harjivan Shrika G.¹^ORCID,Freitas Elisabete¹,Serafini Marco¹^ORCID,Gaspar M. Manuela¹^ORCID,Capela Rita¹^ORCID,Gomes Pedro¹,Jordaan Audrey²,Madureira Ana M.¹^ORCID,André Vânia³⁴^ORCID,Silva Andreia B.⁵^ORCID,Duarte M. Teresa³^ORCID,Portugal Isabel¹^ORCID,Perdigão João¹^ORCID,Moreira Rui¹^ORCID,Warner Digby F.²⁶^ORCID,Lopes Francisca¹^ORCID

Affiliation:

1. Instituto de Investigação do Medicamento (iMed.ULisboa) Faculdade de Farmácia Universidade de Lisboa Av. Prof. Gama Pinto 1649–003 Lisboa Portugal

2. Molecular Mycobacteriology Research Unit Department of Pathology and Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town Rondebosch 7701 South Africa

3. Centro de Química Estrutural Institute of Molecular Sciences Instituto Superior Técnico Universidade de Lisboa Av. Rovisco Pais 1 1049–001 Lisboa Portugal

4. Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID) Avenida António José de Almeida, n.° 12 1000–043 Lisboa Portugal

5. Faculdade de Farmácia Universidade de Lisboa Av. Prof. Gama Pinto 1649–003 Lisboa Portugal

6. Wellcome Centre for Infectious Diseases Research in Africa University of Cape Town Cape Town Rondebosch 7701 South Africa

Abstract

AbstractWhile N‐acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N‐acetyl moiety for a N‐carbamoyl group led to analogues with sub‐ and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug‐susceptible and drug‐resistant M. tuberculosis isolates. The new N‐carbamoyl azaaurones exhibited improved microsomal stability, compared to their N‐acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10−8, a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

Funder

South African Medical Research Council

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

Reference64 articles.

1. Global Tuberculosis Report 2022 World Health Organization.2022 Geneva.

2. Challenges in tuberculosis drug research and development

3. Epidemiology of Tuberculosis U.S. Department of Health and Human Services Centers for Disease Control and Prevention.2019 Atlanta.

5. The Epistatic Landscape of Antibiotic Resistance of Different Clades of Mycobacterium tuberculosis

Cited by 4 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Alternative Reactions to Friedel-crafts Acylation on Highly Activated Substrates;Current Organic Chemistry;2024-07

2. Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues;Molecules;2024-06-13

3. Metal-Free Synthesis of 2-Benzylideneindolin-3-ones via a Nucleophilic/Rearrangement/Azide–Alkene Cascade Reaction;Synlett;2024-06-10

4. New azaaurone derivatives as potential multitarget agents in HIV‐TB coinfection;Archiv der Pharmazie;2023-11-30