Tail-approach based design and synthesis of Arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide as human carbonic anhydrase I, II, IV and IX inhibitors

• Published in: Bioorganic chemistry 2022-06, Vol.123, p.105764-105764, Article 105764
• Main Authors: Kumar, Amit, Siwach, Kiran, Rom, Tanmay, Kumar, Rajiv, Angeli, Andrea, Kumar Paul, Avijit, Supuran, Claudiu T., Sharma, Pawan K.
• Format: Article
• Language: English
• Subjects: 1,2,3-triazole; Antigens, Neoplasm; Benzenesulfonamide; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II; Carbonic anhydrase inhibitors; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase IV; Carbonic Anhydrase IX; hCA isoforms; Humans; Molecular Structure; SLC-0111; Structure-Activity Relationship; Sulfanilamide; Sulfonamides - chemistry; Tail-approach; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105764

[Display omitted] •Tail-approach based design, synthesis and characterization of a library of twenty-two arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide moieties are disclosed.•All newly synthesized compounds were screened in vitro for their inhibition efficacy against hCA I, II, IV and IX isoforms.•Some compounds showed either comparable or better inhibition potential than clinically used reference drug AAZ against the targeted isoforms.•In broader sense, sulfanilamide analogues (4a-4k) were found to be better inhibitors of cytosolic hCA I and II isoforms than metanilamide analogues (5a-5k), whereas exactly opposite trend was observed in case of inhibition of membrane bound hCA IV and tumor associated transmembrane hCA IX. A library of twenty-two arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide moieties have been synthesized by utilizing tail-approach and characterized by their IR, 1H NMR, 13C NMR, HRMS and single crystal studies. Further, these newly synthesized compounds were screened in-vitro for their inhibition efficacy against physiologically relevant hCA I, II, IV and IX isoforms. Inhibition data revealed that, in broader sense, sulfanilamide analogues (4a-4k) were comparatively better inhibitors of cytosolic hCA I and II isoforms than metanilamide analogues (5a-5k), whereas exactly opposite trend was observed in case of inhibition of membrane bound hCA IV and transmembrane hCA IX. For hCA I, more than half of the synthesized compounds were found to be moderate inhibitors and three compounds 4b, 5b and 5e (Ki of 40.6, 224.7 and 74.4 nM, respectively) appeared as better inhibitors than reference drug AAZ (Ki = 250 nM). hCA II was potently inhibited by 4e-4g and 5e with Ki of 18.1, 14.1, 14.9 and 17.8 nM, respectively. Interestingly, 4e-4g selectively inhibited hCA II with selectivity of > 15-fold over hCA I, IV and IX isoforms. All the compounds presented moderate to weak inhibition profiles against glaucoma associated hCA IV with Ki of 88 nM-8.87 μM and except 4f, 5k, significant inhibition profiles against tumor associated hCA IX isoform with Ki spanning in range of 0.113 μM-0.318 μM. Moreover, 5e was the only compound among the whole series which effectively inhibited all the tested isoforms.