Bioorganic & Medicinal Chemistry Letters 2009-05-15

Carbonic anhydrase inhibitors. Inhibition of the fungal beta-carbonic anhydrases from Candida albicans and Cryptococcus neoformans with boronic acids.

Alessio Innocenti, Jean-Yves Winum, Rebecca A Hall, Fritz A Mühlschlegel, Andrea Scozzafava, Claudiu T Supuran

Index: Bioorg. Med. Chem. Lett. 19 , 2642-5, (2009)

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Abstract

Inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic fungi Cryptococcus neoformans (Can2) and Candida albicans (Nce103) with a series of aromatic, arylalkenyl- and arylalkylboronic acids was investigated. Aromatic, 4-phenylsubstituted- and 2-naphthylboronic acids were the best Can2 inhibitors, with inhibition constants in the range of 8.5-11.5microM, whereas arylalkenyl and aryalkylboronic acids showed K(I)s in the range of 428-3040microM. Nce103 showed a similar inhibition profile, with the 4-phenylsubstituted- and 2-naphthylboronic acids possessing K(I)s in the range of 7.8-42.3microM, whereas the arylalkenyl and aryalkylboronic acids were weaker inhibitors (K(I)s of 412-5210microM). The host human enzymes CA I and II were also effectively inhibited by these boronic acids. The B(OH)(2) moiety is thus a new zinc-binding group for designing effective inhibitors of the alpha- and beta-CAs.