Design, synthesis and biological evaluation of coumarin linked 1,2,4-oxadiazoles as selective carbonic anhydrase IX and XII inhibitors

• Published in: Bioorganic chemistry Vol. 98; pp. 103739 - 103745
• Main Authors: Thacker, Pavitra S., Angeli, Andrea, Argulwar, Omkar S., Tiwari, Prerna L., Arifuddin, Mohammed, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.05.2020; Elsevier
• Subjects: 1,2,4-Oxadiazoles; Antigens, Neoplasm - metabolism; Biochemistry & Molecular Biology; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Chemistry; Chemistry, Organic; Coumarins; Coumarins - chemistry; Coumarins - pharmacology; Dose-Response Relationship, Drug; Drug Design; hCA IX; hCA XII; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Non-classical inhibition; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Physical Sciences; Science & Technology; Structure-Activity Relationship; Coumarins; 1,2,4-Oxadiazoles; Carbonic anhydrases; Non-classical inhibition; hCA XII; hCA IX; PROTEIN; SERIES; PERIPHERY; DOCKING; SULFONAMIDES; DISCOVERY; POTENT
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103739

[Display omitted] •A series of coumarin linked 1,2,4-oxadiazoles was synthesized.•The coumarin-1,2,4-oxadiazole hybrids were investigated for inhibition against four isoforms hCA I, II, IX and XII.•The compounds exhibited low nanomolar to moderate nanomolar inhibitory profiles for both the isoforms, particularly for CA XII, with Kis in the range of 23.6–315.6 nM for CA IX and 1.0–752.6 for CA XII.•The compounds showed exclusive selectivity for hCA IX and XII over hCA I and II. A series of coumarin linked 1,2,4-oxadiazoles were synthesized and the synthesized compounds were subjected for evaluation against the four physiologically and pharmacologically relevant hCA isoforms, hCA I, II, IX and XII. Upon evaluation of the results, it was inferred that the coumarin linked 1,2,4-oxadiazoles showed selective hCA IX and XII inhibition (low to medium nanomolar range) over hCA I and II (>10000 nM). The inhibition constants ranged from low nanomolar to moderately nanomolar. Compounds 6o, 6a, 6q and 6c elicited hCA XII inhibition, with Ki values lower than that of the standard, Acetazolamide (AAZ) with compound 6o exhibiting a Ki value of 1 nM., against hCA IX, the compound 6c exhibited the most potent inhibition with a Ki value of 23.6 nM. Hence, compound 6o can be taken as an effective lead compound for the development of hCA XII inhibitors and compound 6c can be taken as a lead compound for the development of dual hCA IX and XII inhibitors. To understand the molecular interactions, the two most potent compounds 6a and 6o were docked within the hCA XII catalytic cleft in order to study their binding modes with that isoform.