Natural Product-Based Phenols as Novel Probes for Mycobacterial and Fungal Carbonic Anhydrases

被引：87

作者：

Davis, Rohan A. ^{[2
]}

Hofmann, Andreas ^{[2
]}

Osman, Asiah ^{[2
]}

Hall, Rebecca A. ^{[3
]}

Muehlschlegel, Fritz A. ^{[3
,4
]}

Vullo, Daniela ^{[1
]}

Innocenti, Alessio ^{[1
]}

Supuran, Claudiu T. ^{[1
]}

Poulsen, Sally-Ann ^{[2
]}

机构：

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

[2] Griffith Univ, Eskitis Inst, Nathan, Qld 4111, Australia

[3] Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England

[4] E Kent Hosp Univ NHS Fdn Trust, Clin Microbiol Serv, Ashford TN24 0LZ, Kent, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 06期

基金：

澳大利亚研究理事会;

关键词：

PATHOGENS CANDIDA-ALBICANS; BETA-CLASS ENZYMES; CRYPTOCOCCUS-NEOFORMANS; SACCHAROMYCES-CEREVISIAE; INHIBITORS; INHIBITION; STRUCTURE ELUCIDATION; HELICOBACTER-PYLORI; SERIES; CO2; CRYSTALLOGRAPHY;

D O I：

10.1021/jm1013242

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen beta-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as alpha-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal beta-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first example of non-sulfonamide inhibitors that display beta over alpha CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.

引用

页码：1682 / 1692

页数：11

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