Antimycobacterial pyridine carboxamides: From design to in vivo activity
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
37423128
DOI
10.1016/j.ejmech.2023.115617
PII: S0223-5234(23)00583-4
Knihovny.cz E-zdroje
- Klíčová slova
- 4-Aminosalicylic acid, Isoniazid, Multidrug-resistance, Pyrazinamide, Pyridine, Tuberculosis,
- MeSH
- antituberkulotika chemie MeSH
- isoniazid farmakologie MeSH
- kyselina aminosalicylová * farmakologie MeSH
- lidé MeSH
- methionin MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- myši MeSH
- tuberkulóza * farmakoterapie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antituberkulotika MeSH
- isoniazid MeSH
- kyselina aminosalicylová * MeSH
- methionin 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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