期刊
BIOORGANIC CHEMISTRY
卷 123, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105764
关键词
Carbonic anhydrase inhibitors; hCA isoforms; 1,2,3-triazole; Benzenesulfonamide; Tail-approach; SLC-0111
资金
- Council of Scientific and Industrial Research, New Delhi, India
- DST-FIST [SR/FST/CS-I/2017/12 (C)]
A library of 22 arylthiazolylhydrazono-1,2,3-triazoles was synthesized using a tail-approach method, characterized through various spectroscopic techniques, and screened in-vitro, revealing varying inhibition efficacy against different isoforms of hCA.
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, H-1 NMR, C-13 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 (K-i of 40.6, 224.7 and 74.4 nM, respectively) appeared as better inhibitors than reference drug AAZ (K-i = 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 K-i of 88 nM-8.87 mu M and except 4f, 5k, significant inhibition profiles against tumor associated hCA IX isoform with K-i spanning in range of 0.113 mu M-0.318 mu M. Moreover, 5e was the only compound among the whole series which effectively inhibited all the tested isoforms.
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