Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F21%3A10434655" target="_blank" >RIV/00216208:11160/21:10434655 - isvavai.cz</a>
Alternative codes found
RIV/71009396:_____/21:N0000034
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=xju0Ln2qbL" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=xju0Ln2qbL</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2021.113668" target="_blank" >10.1016/j.ejmech.2021.113668</a>
Alternative languages
Result language
angličtina
Original language name
Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity
Original language description
Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H(37)Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from <= 0.03 mu M), but also against M. kansasii (MIC >= 2 mu M). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 mu M. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better anti-microbial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
—
Volume of the periodical
223
Issue of the periodical within the volume
November
Country of publishing house
FR - FRANCE
Number of pages
11
Pages from-to
113668
UT code for WoS article
000695696100047
EID of the result in the Scopus database
2-s2.0-85108820516