Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F21%3A10442616" target="_blank" >RIV/00216208:11160/21:10442616 - isvavai.cz</a>

Alternative codes found

RIV/71009396:_____/21:N0000033

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=2V5EnCnB22" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=2V5EnCnB22</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ph14121302" target="_blank" >10.3390/ph14121302</a>

Result language

angličtina

Original language name

Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

Original language description

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H(37)Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from &lt;= 0.125 mu M), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 mu M, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

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

2021

Confidentiality

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

Name of the periodical

Pharmaceuticals

ISSN

1424-8247

e-ISSN

—

Volume of the periodical

14

Issue of the periodical within the volume

12

Country of publishing house

CH - SWITZERLAND

Number of pages

18

Pages from-to

1302

UT code for WoS article

000737064400001

EID of the result in the Scopus database

2-s2.0-85121303910