Carbonic anhydrase inhibitors. Inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with aliphatic and aromatic carboxylates.
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.
Innocenti
Alessio
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Hall
Rebecca A
RA
Schlicker
Christine
C
Mühlschlegel
Fritz A
FA
Supuran
Claudiu T
CT
D019342:Acetic Acid / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000201:enzymology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D003455:Cryptococcus neoformans / Q000201:enzymology*; D008298:Maleates / Q000737:chemistry / Q000494:pharmacology; D008314:Malonates / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D001565:Benzoates; D002087:Butyrates; D002257:Carbonic Anhydrase Inhibitors; D002264:Carboxylic Acids; D008298:Maleates; D008314:Malonates; C030272:maleic acid; C030290:malonic acid; D002256:Carbonic Anhydrases; D015032:Zinc; D019342:Acetic Acid