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2000
Volume 25, Issue 18
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

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’-oxycoumarin)-[1,2,4]triazolo[1,5-]pyrimidine scaffold.

Methods

The chemical structures of novel coumarin-based triazolopyrimidines - 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 and with hCA IX and XII isoforms. Selected derivatives and were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally, compounds and were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells.

Results

kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (-) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII), with K values ranging from 0.75 to 10.5 μM, while hCA I, II, IV isoforms were not significantly inhibited (Ks > 100 μM). Compound emerged as the most potent and selective inhibitor, with K of 0.92 and 0.75 μM 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 as a selective inhibitor of the isoforms hCA IX and XII, showing minimal inhibition over hCA I, II, and IV isoenzymes (selectivity indices > 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 as a promising candidate for further therapeutic development, especially in combination with clinically used chemotherapeutic agents.

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2025-09-14

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/content/journals/acamc/10.2174/0118715206373602250318062414
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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
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 25, 1429 (2025); https://doi.org/10.2174/0118715206373602250318062414
/content/journals/acamc/10.2174/0118715206373602250318062414
/content/journals/acamc/10.2174/0118715206373602250318062414
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The following supporting information can be downloaded: 1H-NMR and 13C-NMR spectra of compounds -. Preparation and purification CA isoforms. Supplementary material is available on the publisher's website along with the published article.

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  • Article Type:     Research Article
Keyword(s): [1,2,4]triazolo[1,5-a]pyrimidine; antiproliferative activity; Carbonic anhydrase inhibitors; coumarin; isoform selectivity; structure–activity relationship

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