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Bioorg Med Chem Lett. 2015 Dec 1;25(23):5636-41. doi: 10.1016/j.bmcl.2015.10.021. Epub 2015 Oct 13.

Interaction of carbonic anhydrase isozymes I, II, and IX with some pyridine and phenol hydrazinecarbothioamide derivatives.

Author information

1
Balikesir University, Science & Art Faculty, Department of Chemistry, Balikesir, Turkey.
2
University of Florence, Neurofarba Department, Via Ugo Schiff 6, Polo Scientifico, 50019 Sesto Fiorentino, Firenze, Italy.
3
Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
4
Ondokuz Mayıs University, Department of Agricultural Biotechnology, 55139 Samsun, Turkey.
5
Agri Ibrahim Cecen University, Department of Chemistry, 04100 Agri, Turkey. Electronic address: senturkm36@gmail.com.
6
Bingol University, Faculty of Art & Science, Department of Chemistry, 12000 Bingol, Turkey. Electronic address: acetin74@hotmail.com.
7
Ağrı İbrahim Çeçen University, School of Heatlh Services, 04100 Ağrı, Turkey.
8
University of Florence, Neurofarba Department, Via Ugo Schiff 6, Polo Scientifico, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

A series of hydrazinecarbothioamide derivatives incorporating ethyl, phenyl, tolyl, benzyl, and allyl moieties were prepared and tested as possible inhibitors of three members of the pH regulatory enzyme family, carbonic anhydrase (CA; EC 4.2.1.1). The inhibitory and activatory potencies of the compounds against the cytosolic human isoforms hCA I and hCA II and the transmembrane, tumor-associated hCA IX were analyzed by a hydrase assay with CO2 as substrate, and the inhibition constants (KI) were calculated. Most compounds investigated here exhibited nanomolar or low micromolar inhibition constants against the three isoenzymes. KI values were in the range of 34.1-871 nM for hCA I and compounds 5-10 showed interesting activation of the hCA II with KA value of 0.81-12.5 μM. Compounds 11-16 exhibited moderate inhibition effects on hCA IX in the range of 0.317-1.245 μM but they were less effective for hCA II. Tested compounds were also investigated using in silico applications at the binding pockets of these three targets. The different mechanisms of inhibition by these tested compounds as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest for the design of novel CA inhibitors.

KEYWORDS:

Carbonic anhydrase; Enzyme inhibition; Hydrazinecarbothioamide; Molecular docking; Phenol; Pyridine

PMID:
26520662
DOI:
10.1016/j.bmcl.2015.10.021
[Indexed for MEDLINE]

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