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
A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 μmol L(-1)) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125-0.250 μmol L(-1)), high value of selectivity index (SI) and IC(50) between 0.0218 and 0.326 mmol L(-1). Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- antituberkulotika chemie farmakologie MeSH
- atypické mykobakteriální infekce farmakoterapie MeSH
- buňky Hep G2 MeSH
- hydrazony chemie farmakologie MeSH
- intracelulární infekce bakterií Mycobacterium avium farmakoterapie MeSH
- isoniazid chemie farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium komplex účinky léků MeSH
- Mycobacterium kansasii účinky léků MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- tuberkulóza farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Several new fluorine-containing hydrazones were synthesized and screened for their in vitro antimycobacterial activity. Nine of these derivatives have shown a remarkable activity against MDR-TB strain with MIC 0.5 μg/mL and high value of selectivity index (SI). Compound 3h with the highest SI (1268.58) was used for stability evaluation with putative metabolites (ciprofloxacin and formylciprofloxacin) detection. Compound 3h was stable at pH 7.4 of aqueous buffer and rat plasma, in acidic buffers (at pH 3 and 5) slow decomposition was observed. Interestingly, no formylciprofloxacin was detected in the solution, and only slightly increased concentration of ciprofloxacin was observed instead. Trifluoromethyl hydrazones 3f and 3g exhibited the best activity also against two strains of Mycobacterium kansasii (MIC 1-4 μmol/L). All evaluated compounds were found to be non-cytotoxic.
- MeSH
- antituberkulotika chemie metabolismus farmakologie MeSH
- buněčné linie MeSH
- fluor chemie metabolismus farmakologie MeSH
- hydrazony chemie metabolismus farmakologie MeSH
- krevní plazma metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- multirezistentní tuberkulóza farmakoterapie MeSH
- Mycobacterium kansasii účinky léků MeSH
- Mycobacterium účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata 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