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


IŞIK S., Vullo D., DURDAĞI S., EKİNCİ D., ŞENTÜRK M., ÇETİN A., ...More

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol.25, no.23, pp.5636-5641, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 23
  • Publication Date: 2015
  • Doi Number: 10.1016/j.bmcl.2015.10.021
  • Journal Name: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.5636-5641
  • Keywords: Phenol, Pyridine, Hydrazinecarbothioamide, Carbonic anhydrase, Enzyme inhibition, Molecular docking, SALICYLIC-ACID DERIVATIVES, INHIBITORY PROPERTIES, VITRO INHIBITION, ISOFORMS I, ACTIVATORS, SERIES, VI, BENZENESULFONAMIDES, ERYTHROCYTE, ISOENZYMES
  • Ondokuz Mayıs University Affiliated: Yes

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 (K-I) were calculated. Most compounds investigated here exhibited nanomolar or low micromolar inhibition constants against the three isoenzymes. K-I 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 K-A value of 0.81-12.5 mu M. Compounds 11-16 exhibited moderate inhibition effects on hCA IX in the range of 0.317-1.245 mu M 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. (C) 2015 Elsevier Ltd. All rights reserved.