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Bioorg Med Chem. 2016 Sep 15;24(18):4100-4107. doi: 10.1016/j.bmc.2016.06.052. Epub 2016 Jun 27.

Synthesis 4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with subnanomolar carbonic anhydrase II and XII inhibitory properties.

Author information

1
Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
2
Department of Chemistry, Kulliyyah of Science, International Islamic University Malaysia, PO Box 141, 25710 Kuantan, Pahang Darul Makmur, Malaysia.
3
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia.
4
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia; Department of Chemistry, College of Science, King Saud University, Riyadh 11362, Saudi Arabia.
5
Department of Chemistry, College of Science, King Saud University, Riyadh 11362, Saudi Arabia.
6
Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (KIs of 28.5-2954nM), being highly effective as hCA II (KIs in the range of 0.62-12.4nM) and XII (KIs of 0.54-7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated.

KEYWORDS:

2-Mercapto-quinazolin-4-one; Carbonic anhydrase; Inhibitor; Sulfonamide; Tail approach

PMID:
27396930
DOI:
10.1016/j.bmc.2016.06.052
[Indexed for MEDLINE]

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