Design, synthesis and biological evaluation of coumarin-3-carboxamides as selective carbonic anhydrase IX and XII inhibitors

• Published in: Bioorganic chemistry Vol. 86; pp. 386 - 392
• Main Authors: Thacker, Pavitra S., Alvala, Mallika, Arifuddin, Mohammed, Angeli, Andrea, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.05.2019; Elsevier
• Subjects: 7-Hydroxycoumarin-3-carboxamides; Antigens, Neoplasm - metabolism; Biochemistry & Molecular Biology; Cancer; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Carbonic Anhydrases - metabolism; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Humans; Hypoxic tumors; Isoforms IX and XII; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Physical Sciences; Science & Technology; Structure-Activity Relationship; Umbelliferones - chemical synthesis; Umbelliferones - chemistry; Umbelliferones - pharmacology; Isoforms IX and XII; Hypoxic tumors; Carbonic anhydrase; 7-Hydroxycoumarin-3-carboxamides; Cancer; PROTEIN; DOCKING; THIOUREA DERIVATIVES; MOIETIES; COUMARINS; ISOFORMS IX; HYDRAZONE; FLUORESCENT-PROBES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.02.004

[Display omitted] •A series of novel 7-hydroxycoumarin-3-carboxamides was synthesized.•The compounds were investigated for inhibition against hCA I, II, IX and XII.•The compounds are inhibiting hCA IX, in 0.2–9.2 µM and hCA XII in 0.2–9.7 µM range.•The compounds showed exclusive selectivity for hCA IX and XII over hCA I and II. A series of novel 7-hydroxycoumarin-3-carboxamides was synthesized by the reaction of 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid with various substituted aromatic amines. The newly synthesized compounds were evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results show that the newly synthesized 7-hydroxycoumarin-3-carboxamides (4a-n) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. The inhibition constants ranged from sub micromolar to low micromolar. Amongst all the compounds tested, compound 4m was the most effective inhibitor exhibiting sub micromolar potency against both hCA IX and hCA XII, with a Ki of 0.2 µM. Therefore, it can be anticipated that compound 4m can serve as a lead for development of anticancer therapy by exhibiting a novel mechanism of action. The binding modes of the most potent compounds within hCA IX and XII catalytic clefts were investigated by docking studies.