Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action

被引：45

作者：

Bozdag, Murat ^{[1
]}

Carta, Fabrizio ^{[1
]}

Vullo, Daniela ^{[1
]}

Akdemir, Atilla ^{[2
]}

Isik, Semra ^{[1
]}

Lanzi, Cecilia ^{[3
]}

Scozzafava, Andrea ^{[1
]}

Masini, Emanuela ^{[3
]}

Supuran, Claudiu T. ^{[1
,4
]}

机构：

[1] Univ Florence, Lab Chim Bioinorgan, Polo Sci, I-50019 Florence, Italy

[2] Bezmialem Vakif Univ, Fac Pharm, Dept Pharmacol, TR-34093 Istanbul, Turkey

[3] Univ Firenze, NEUROFARBA Dept, Sez Farmacol, I-50139 Florence, Italy

[4] Univ Firenze, NEUROFARBA Dept, Sez Sci Farmaceut, I-50019 Florence, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 10期

关键词：

Carbonic anhydrase; Dithiocarbamate; Antiglaucoma; Intraocular pressure; ISOFORM-SELECTIVE INHIBITORS; TRYPANOSOMA-CRUZI; CAUSATIVE AGENT; ZINC-COMPLEXES; PATENT; IX; SULFONAMIDES; COUMARINS; XII; PHENOLS;

D O I：

10.1016/j.bmc.2015.03.068

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono-and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian alpha-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：2368 / 2376

页数：9

共 82 条

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