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

Kód výsledku v 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>

Nalezeny alternativní kódy

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

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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).

Název v anglickém jazyce

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

Popis výsledku anglicky

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).

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

2023

Kód důvěrnosti údajů

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

Název periodika

ACS Infectious Diseases

ISSN

2373-8227

e-ISSN

—

Svazek periodika

9

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

18

Strana od-do

79-96

Kód UT WoS článku

000907013500001

EID výsledku v databázi Scopus

2-s2.0-85145568803