Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase Context Sensitive Links 1 of 2 Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F71009396%3A_____%2F22%3AN0000010" target="_blank" >RIV/71009396:_____/22:N0000010 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0928098722001373?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0928098722001373?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejps.2022.106252" target="_blank" >10.1016/j.ejps.2022.106252</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase Context Sensitive Links 1 of 2 Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase

Popis výsledku v původním jazyce

Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 mu M. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 mu M), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.

Název v anglickém jazyce

Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase Context Sensitive Links 1 of 2 Substituted N-phenylitaconamides as inhibitors of mycobacteria and mycobacterial isocitrate lyase

Popis výsledku anglicky

Novel antimycobacterial drugs are needed, especially those with dual activity against both actively growing and non-replicating subpopulations of mycobacteria. Isocitrate lyase (ICL) is one of proposed targets and this enzyme is inhibited by itaconic acid. That is why we have designed and prepared sixteen amides of itaconic acid and various anilines and amine antimicrobial drugs to evaluate them as potential inhibitors of ICL and antimycobacterial agents. N-Phenylitaconamides were prepared from itaconic anhydride and substituted anilines (yields 57-99%). They were characterized and evaluated against mycobacterial ICL and against actively growing mycobacteria (M. tuberculosis H37Rv, M. avium, two strains of M. kansasii). All derivatives showed antimycobacterial efficacy with minimum inhibitory concentrations starting from 125 mu M. M. kansasii was the most susceptible species. Itaconamides derived from sulfonamides or p-aminosalicylic acid were optimal for activity against extracellular mycobacteria. ICL1 was significantly inhibited by two compounds, with 2-methylene-4-[(4nitrophenyl)amino]-4-oxobutanoic acid 1k being the most potent (36% inhibition at 10 mu M), which was also more efficient than two comparators. Molecular docking revealed its mode of binding to the enzyme. Using in silico tools, physicochemical properties and structural features for drug-likeness and gastrointestinal absorption were evaluated.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GJ20-19638Y" target="_blank" >GJ20-19638Y: Design a studium nových antimikrobních látek účinných na rezistentní a biofilm-produkující gram-pozitivní bakterie</a><br>

Návaznosti

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

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

European Journal of Pharmaceutical Sciences

ISSN

0928-0987

e-ISSN

1879-0720

Svazek periodika

176

Číslo periodika v rámci svazku

106252

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

8

Strana od-do

1-8

Kód UT WoS článku

000839196000010

EID výsledku v databázi Scopus

2-s2.0-85134358236