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Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with aliphatic and aromatic carboxylates

Innocenti, Alessio, Hall, Rebecca A., Schlicker, Christine, Mühlschlegel, Fritz A., Supuran, Claudiu T. (2009) Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with aliphatic and aromatic carboxylates. Bioorganic & Medicinal Chemistry, 17 (7). pp. 2654-2657. ISSN 0968-0896. (doi:10.1016/j.bmc.2009.02.058) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:91845)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided.
Official URL
https://doi.org/10.1016/j.bmc.2009.02.058

Abstract

The inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic fungi Cryptococcus neoformans (Can2) and Candida albicans (Nce103) with carboxylates such as the C1-C5 aliphatic carboxylates, oxalate, malonate, maleate, malate, pyruvate, lactate, citrate and some benzoates has been investigated. The best Can2 inhibitors were acetate and maleate (K(I)s of 7.3-8.7 microM), whereas formate, acetate, valerate, oxalate, maleate, citrate and 2,3,5,6-tetrafluorobenzoate showed less effective inhibition, with K(I)s in the range of 42.8-88.6 microM. Propionate, butyrate, malonate, L-malate, pyruvate, L-lactate and benzoate, were weak Can2 inhibitors, with inhibition constants in the range of 225-1267 microM. Nce103 was more susceptible to inhibition with carboxylates compared to Can2, with the best inhibitors (maleate, benzoate, butyrate and malonate) showing K(I)s in the range of 8.6-26.9 microM. L-Malate and pyruvate together with valerate were the less efficient Nce103 inhibitors (K(I)s of 87.7-94.0 microM), while the remaining carboxylates showed a compact behavior of efficient inhibitors (K(I)s in the range of 35.1-61.6 microM). Notably the inhibition profiles of the two fungal beta-CAs was very different from that of the ubiquitous host enzyme hCA II (belonging to the alpha-CA family), with maleate showing selectivity ratios of 113.6 and 115 for Can2 and Nce103, respectively, over hCA II inhibition. Therefore, maleate is a promising starting lead molecule for the development of better, low nanomolar, selective beta-CA inhibitors.

Item Type: Article
DOI/Identification number: 10.1016/j.bmc.2009.02.058
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Becky Hall
Date Deposited: 01 Dec 2021 09:36 UTC
Last Modified: 01 Dec 2021 17:23 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/91845 (The current URI for this page, for reference purposes)
Hall, Rebecca A.: https://orcid.org/0000-0002-4908-8168
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