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ACS Med Chem Lett. 2017 Sep 15;8(10):1105-1109. doi: 10.1021/acsmedchemlett.7b00300. eCollection 2017.

Lucky Switcheroo: Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII.

Author information

  • 1Saint Petersburg State University, Saint Petersburg 199034, Russian Federation.
  • 2Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 3Neurofarba Department, Universita degli Studi di Firenze, 50121 Florence, Italy.

Abstract

A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N1 (as in the earlier reported series) to C2. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitor's lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.

KEYWORDS:

2-imidazolines; N-arylimidazolines; Privileged scaffold; carbonic anhydrase inhibitors; docking simulation; hydrogen bonding; isoform selectivity; molecular dynamics; nonconserved residue; primary sulfonamide; zinc binding group

PMID:
29057059
PMCID:
PMC5642015
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00300
[PubMed]
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