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5‐[2‐(N‐(Substituted phenyl)acetamide)]amino‐1,3,4‐thiadiazole‐2‐sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects
Author(s) -
Jiang Caibao,
Shi Jinguo,
Liao Liping,
Zhang Liantao,
Liu Jiayong,
Wang Yang,
Lao Yaoqiang,
Zhang Jingxia
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900703
Subject(s) - carbonic anhydrase , acetamide , acetazolamide , chemistry , neuroprotection , carbonic anhydrase ii , carbonic anhydrase i , cytotoxicity , stereochemistry , carbonic anhydrase inhibitor , efflux , medicinal chemistry , biochemistry , pharmacology , enzyme , organic chemistry , in vitro , biology , physiology
In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a – 5 k were monosubstituted compounds, and 6 a – 6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a – 5 k and 6 a – 6 k . The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)‐induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC 50 =16.7 nM, CAI/CAII=54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC 50 =12.0 nM, CAI/CAII=20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.