Design and Synthesis of 2-substituted [1,2,4]Triazolo[1,5-a]pyrimidines Tethered with Umbelliferone as Selective Carbonic Anhydrase IX and XII Inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F25%3A43932947" target="_blank" >RIV/60461373:22310/25:43932947 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.eurekaselect.com/article/147405" target="_blank" >https://www.eurekaselect.com/article/147405</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2174/0118715206373602250318062414" target="_blank" >10.2174/0118715206373602250318062414</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design and Synthesis of 2-substituted [1,2,4]Triazolo[1,5-a]pyrimidines Tethered with Umbelliferone as Selective Carbonic Anhydrase IX and XII Inhibitors

Popis výsledku v původním jazyce

Objective: This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7&apos;-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold. Methods: The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells. Results: In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with K-I values ranging from 0.75 to 10.5 mu M, while hCA I, II, IV isoforms were not significantly inhibited (K(I)s &gt; 100 mu M). Compound 3d emerged as the most potent and selective inhibitor, with K-Is of 0.92 and 0.75 mu M for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin. Conclusion: In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices &gt; 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

Název v anglickém jazyce

Design and Synthesis of 2-substituted [1,2,4]Triazolo[1,5-a]pyrimidines Tethered with Umbelliferone as Selective Carbonic Anhydrase IX and XII Inhibitors

Popis výsledku anglicky

Objective: This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7&apos;-oxycoumarin)-[1,2,4]triazolo[1,5-a]pyrimidine scaffold. Methods: The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells. Results: In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with K-I values ranging from 0.75 to 10.5 mu M, while hCA I, II, IV isoforms were not significantly inhibited (K(I)s &gt; 100 mu M). Compound 3d emerged as the most potent and selective inhibitor, with K-Is of 0.92 and 0.75 mu M for hCA IX and XII, respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines, particularly HD-MB03, when it was studied for its adjuvant effects in combination with cisplatin. Conclusion: In this study, we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices &gt; 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Anti-Cancer Agents in Medicinal Chemistry

ISSN

1871-5206

e-ISSN

1875-5992

Svazek periodika

25

Číslo periodika v rámci svazku

18

Stát vydavatele periodika

AE - Spojené arabské emiráty

Počet stran výsledku

18

Strana od-do

1429-1446

Kód UT WoS článku

001471000900001

EID výsledku v databázi Scopus

2-s2.0-105007933890