New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10382487" target="_blank" >RIV/00216208:11160/18:10382487 - isvavai.cz</a>

Alternative codes found

RIV/71009396:_____/18:N0000017

Result on the web

<a href="http://www.sciencedirect.com/science/article/pii/S0223523418303507" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0223523418303507</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2018.04.017" target="_blank" >10.1016/j.ejmech.2018.04.017</a>

Result language

angličtina

Original language name

New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action

Original language description

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 non tuberculous 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 mu M. Moreover, they are non-toxic for HepG2, and some of them are highly active against 1NH-resistant NTM (MICs &gt;= 4 mu M). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-l-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-Dodecy1-5-(pyridin-4-y1)-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 mu M with no cross-resistance to antitubercular drugs including 1NH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

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)

Publication year

2018

Confidentiality

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

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Volume of the periodical

151

Issue of the periodical within the volume

May

Country of publishing house

FR - FRANCE

Number of pages

12

Pages from-to

824-835

UT code for WoS article

000432640900056

EID of the result in the Scopus database

2-s2.0-85045741167