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Syntéza, charakterizace, studie molekulárního dokování nových alkylových derivátů 5-(2-brom-4-fluorfenyl)-4-ethyl- 4H-1,2,4-triazol-3-thiolu


Authors: Roman Shcherbyna;  Valerü Kalchenko;  Sergii Kulish;  Volodymyr Salionov;  Liubov Morozova;  Natalia Nedorezaniuk;  Olha Mazur
Published in: Čes. slov. Farm., 2023; 72, 190-200
Category: Original Articles

Overview

Hlavním cílem tohoto článku je prezentovat výsledky syntézy nových alkylových derivátů 5-(2-brom-4-fluorfenyl)-4-ethyl-4H-1,2,4-triazol-3-thiolu a molekulárního dokování studie proti COX-1 a COX-2. Předchozí studie prokázaly široký rozsah biologické aktivity 1,2,4-triazolových derivátů. Proto bylo důležité zjistit, jak nová řada 1,2,4-triazolových derivátů poskytne potenciální protizánětlivou aktivitu. K dosažení cíle byly připraveny alkylové deriváty 5-(2-brom-4-fluorfenyl)-4-ethyl-4H-1,2,4-triazol-3-thiolů (2a-2i) z 5-(2Byl získán brom-4-fluorfenyl)-4-ethyl-4H-l,2,4-triazol-3-thiol (1e). Struktura syntetizovaných sloučenin byla potvrzena 1H-NMR elementární analýzou. Totožnost a čistota sloučenin byla potvrzena metodou kapalinové chromatografie-hmotnostní spektrometrie. Tyto sloučeniny mají relativně jednoduché schéma syntézy, což jim dává výhodu v procesu tvorby potenciálního léčiva a výskyt alkylových radikálů v molekule by měl mít pozitivní vliv na farmakokinetické ukazatele, stabilitu, selektivitu a biologickou dostupnost. U syntetizovaných sloučenin byla provedena studie in silico, konkrétně molekulární dokování týkající se interakce s COX-1 a COX-2. Na základě indexů selektivity vazebných režimů pozorovaných pro vybrané sloučeniny (2e, 2g) s aktivními místy COX1 bylo zjištěno, že sloučeniny mohou pravděpodobně uplatňovat svůj protizánětlivý účinek cestou biosyntézy prostaglandinů, inhibicí COX-1 místo COX-2. Rovněž byl prokázán vliv hydrofobních interakcí alkylových skupin 1,2,4-triazolových derivátů na změnu afinity a selektivity k COX-1 nebo COX-2. Proto jsou deriváty 1,2,4 slibnými kandidáty na zlepšení, další studium a budoucí vývoj nových, účinnějších protizánětlivých léčiv pro terapeutické použití.

Klíčová slova:

1,2,4-triazol – syntéza – molekulární dokování – protizánětlivá aktivita – in silico


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