Synthesis of Chromene-linked Bis-indole Derivatives as Selective Tumor-associated Carbonic Anhydrase IX Inhibitors.

Autor:	Singh P; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India., Nerella SG; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, MD, 20892, USA., Swain B; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India., Angeli A; Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy., Kausar S; Chemistry Section, School of Sciences, Maulana Azad National Urdu University (MANUU), Hyderabad 500032, Telangana. India., Ullah Q; Chemistry Section, School of Sciences, Maulana Azad National Urdu University (MANUU), Hyderabad 500032, Telangana. India., Supuran CT; Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy., Arifuddin M; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.; Department of Chemistry, Directorate of Distance Education, Maulana Azad National Urdu University, Hyderabad, 500 032, India.
Jazyk:	angličtina
Zdroj:	Anti-cancer agents in medicinal chemistry [Anticancer Agents Med Chem] 2024 Nov 04. Date of Electronic Publication: 2024 Nov 04.
DOI:	10.2174/0118715206341087241029064945
Abstrakt:	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 nonsulfonamide 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, i.e., hCA I, hCA II, hCA IX, and hCA XII, and determined the ADMET parameters by the In-silico method. Results: Most of the compounds showed significantly greater affinity and selectivity towards the tumorassociated hCA IX over other hCA isoforms within the lower micromolar to submicromolar range. In particular, the bromo-substituted bis-indole derivative 6t showed an excellent inhibition of hCA IX isoform with an affinity (Ki) of 2.61 μM. In contrast, the cyano group substituted bis-indole derivative 6s and also displayed a strong inhibition of hCA IX isoform with an affinity (Ki) of 2.73 μM. Many other potential candidates, including 6g, 6i, 6k, 6m, 6o, 6p, and 6r, 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. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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