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Volume 25, Issue 6
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

Sulfonamide derivatives are well-reported hCA IX inhibitors; however, they inhibit all types of hCA without any selectivity, leading to severe adverse effects. Hence, developing a novel non-sulfonamide class of tumor-associated hCA IX inhibitors through non-classical inhibition may provide greater selectivity and better pharmacokinetics.

Objective

The objective of this study was to develop non-sulfonamide derivatives as potential human carbonic anhydrase (hCA) inhibitors and develop a new series of chromene-linked bis-indole derivatives.

Methods

We synthesized and characterized the chromene-linked bis-indole derivatives and further evaluated them against four hCA isoforms, ., hCA I, hCA II, hCA IX, and hCA XII, and determined the ADMET parameters by the method.

Results

Most of the compounds showed significantly greater affinity and selectivity towards the tumor-associated hCA IX over other hCA isoforms within the lower micromolar to submicromolar range. In particular, the bromo-substituted bis-indole derivative showed an excellent inhibition of hCA IX isoform with an affinity () of 2.61 µM. In contrast, the cyano group substituted bis-indole derivative and also displayed a strong inhibition of hCA IX isoform with an affinity () of 2.73 µM. Many other potential candidates, including showed higher affinity at tumor-associated hCA IX with lower than 10 µM compared to other hCA isoforms.

Conclusion

Therefore, the chromene-linked bis-indole derivatives can serve as a novel non-sulfonamide class of tumor-associated hCA IX inhibitors.

© 2025 Bentham Science Publishers
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2024-11-04
2025-04-06

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Synthesis of Chromene-linked Bis-indole Derivatives as Selective Tumor-associated Carbonic Anhydrase IX Inhibitors
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 25, 399 (2025); https://doi.org/10.2174/0118715206341087241029064945
/content/journals/acamc/10.2174/0118715206341087241029064945
/content/journals/acamc/10.2174/0118715206341087241029064945
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  • Article Type:     Research Article
Keyword(s): anticancer agents; bis-indole; Chromene; hCA IX; human carbonic anhydrase; non-sulfonamide class

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