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.
- 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
This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.
- MeSH
- aminy chemie MeSH
- aniliny chemie MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- atypické mykobakteriální infekce mikrobiologie MeSH
- azoly chemie MeSH
- bakteriální léková rezistence MeSH
- bakteriální proteiny antagonisté a inhibitory chemie MeSH
- cyklizace MeSH
- isoniazid analogy a deriváty chemická syntéza farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium účinky léků enzymologie růst a vývoj MeSH
- Mycobacterium kansasii účinky léků enzymologie růst a vývoj izolace a purifikace MeSH
- Mycobacterium tuberculosis účinky léků enzymologie růst a vývoj MeSH
- oxidoreduktasy antagonisté a inhibitory chemie MeSH
- pyridiny chemie MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The Letter describes the preparation and characterization of a conjugate of isoniazid (INH) with magnetic nanoparticles Fe3O4@SiO2 115±60 nm in size. The INH molecules were attached to the surface of nanoparticles by a covalent pH-sensitive amidine bond. The conjugate was characterized by X-ray diffraction, SEM, dynamic light scattering, IR spectroscopy and microanalysis. The conjugate released isoniazid under in vitro conditions (pH=4; 37 °C; t1/2≈115 s). In addition, the cytotoxicity of the Fe3O4@SiO2-INH conjugate was evaluated in SK-BR-3 cells using the xCELLigence system.
- MeSH
- antibakteriální látky chemická syntéza chemie toxicita MeSH
- difrakce rentgenového záření MeSH
- isoniazid chemická syntéza chemie toxicita MeSH
- koncentrace vodíkových iontů MeSH
- kultivované buňky MeSH
- magnetismus * MeSH
- mikroskopie elektronová rastrovací MeSH
- nanočástice chemie MeSH
- oxid křemičitý chemie MeSH
- proliferace buněk účinky léků MeSH
- železité sloučeniny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The connection of two active molecules across an easily released bridge as a new type of potentially active molecule has been studied. The synthesis is based on derivatives that originate from isonicotinoyl hydrazide, pyrazinamide, p-aminosalicylic acid (PAS), ethambutol, and ciprofloxacin. The lipophilicity, hydrolysis (stability of the compounds), and antituberculotic activity as well as the structure-lipophilicity and structure-activity relationships are discussed.
- MeSH
- antituberkulotika farmakologie chemická syntéza chemie MeSH
- chemické jevy MeSH
- chemie fyzikální MeSH
- financování organizované MeSH
- isoniazid farmakologie chemická syntéza MeSH
- kinetika MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- lipidy chemie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium účinky léků MeSH
- Mycobacterium kansasii účinky léků MeSH
- poločas MeSH
- pyrazinamid farmakologie chemická syntéza MeSH
- vysokoúčinná kapalinová chromatografie MeSH
