Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/71009396:_____/21:N0000034

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity

Popis výsledku v původním jazyce

Based on successful antitubercular isoniazid scaffold we have designed its &quot;mee-too&quot; 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 &lt;= 0.03 mu M), but also against M. kansasii (MIC &gt;= 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.

Název v anglickém jazyce

Design and synthesis of 2-(2-isonicotinoylhydrazineylidene) propanamides as InhA inhibitors with high antitubercular activity

Popis výsledku anglicky

Based on successful antitubercular isoniazid scaffold we have designed its &quot;mee-too&quot; 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 &lt;= 0.03 mu M), but also against M. kansasii (MIC &gt;= 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Svazek periodika

223

Číslo periodika v rámci svazku

November

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

11

Strana od-do

113668

Kód UT WoS článku

000695696100047

EID výsledku v databázi Scopus

2-s2.0-85108820516