Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F23%3A10471879" target="_blank" >RIV/00216208:11160/23:10471879 - isvavai.cz</a>

Alternative codes found

RIV/60162694:G33__/23:N0000016 RIV/00179906:_____/23:10471879

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=8o7IC7uOPL" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=8o7IC7uOPL</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsinfecdis.2c00433" target="_blank" >10.1021/acsinfecdis.2c00433</a>

Result language

angličtina

Original language name

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

Original language description

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The delta-lactone form of compound 11 (11&apos;) had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11&apos; opens in human plasma to its parent compound 11 (t(1/2) = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t(1/2) = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t(1/2) of compound 11 overcomes the main drawback of PAS (short t(1/2) necessitating frequent administration of high doses of PAS).

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

2023

Confidentiality

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

Name of the periodical

ACS Infectious Diseases

ISSN

2373-8227

e-ISSN

—

Volume of the periodical

9

Issue of the periodical within the volume

1

Country of publishing house

US - UNITED STATES

Number of pages

18

Pages from-to

79-96

UT code for WoS article

000907013500001

EID of the result in the Scopus database

2-s2.0-85145568803