Antimycobacterial pyridine carboxamides: From design to in vivo activity
Language English Country France Media print-electronic
Document type Journal Article
PubMed
37423128
DOI
10.1016/j.ejmech.2023.115617
PII: S0223-5234(23)00583-4
Knihovny.cz E-resources
- Keywords
- 4-Aminosalicylic acid, Isoniazid, Multidrug-resistance, Pyrazinamide, Pyridine, Tuberculosis,
- MeSH
- Antitubercular Agents chemistry MeSH
- Isoniazid pharmacology MeSH
- Aminosalicylic Acid * pharmacology MeSH
- Humans MeSH
- Methionine MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis * MeSH
- Mice MeSH
- Tuberculosis * drug therapy microbiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Isoniazid MeSH
- Aminosalicylic Acid * MeSH
- Methionine MeSH
Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).
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