New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
29679902
DOI
10.1016/j.ejmech.2018.04.017
PII: S0223-5234(18)30350-7
Knihovny.cz E-zdroje
- Klíčová slova
- 1,3,4-oxadiazole, 2-isonicotinoylhydrazine-1-carboxamide, Antimycobacterial activity, Isoniazid, Mycobacterium tuberculosis, Tuberculosis,
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- bakteriální léková rezistence MeSH
- buňky Hep G2 MeSH
- isoniazid analogy a deriváty chemická syntéza farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- oxadiazoly chemická syntéza chemie farmakologie MeSH
- tuberkulóza farmakoterapie mikrobiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1,3,4-oxadiazole MeSH Prohlížeč
- antituberkulotika MeSH
- isoniazid MeSH
- oxadiazoly MeSH
The development of novel drugs is essential for the treatment of tuberculosis and other mycobacterial infections in future. A series of N-alkyl-2-isonicotinoylhydrazine-1-carboxamides was synthesized from isoniazid (INH) and then cyclized to N-alkyl-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-amines. All derivatives were characterised spectroscopically. The compounds were screened for their in vitro antimycobacterial activity against susceptible and multidrug-resistant Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM; M. avium, M. kansasii). The most active carboxamides were substituted by a short n-alkyl, their activity was comparable to INH with minimum inhibitory concentrations (MICs) against Mtb. of 0.5-2 μM. Moreover, they are non-toxic for HepG2, and some of them are highly active against INH-resistant NTM (MICs ≥4 μM). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-1-carboxamides consists of the inhibition of enoyl-ACP reductase (InhA) in a way similar to INH, which is blocking the biosynthesis of mycolic acids. N-Dodecyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine as the most efficacious oxadiazole inhibits growth of both susceptible and drug-resistant Mtb. strains with uniform MIC values of 4-8 μM with no cross-resistance to antitubercular drugs including INH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation.
Citace poskytuje Crossref.org
Synthesis and Antimycobacterial Activity of Isoniazid Derivatives Tethered with Aliphatic Amines
