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Synthesis of sulfonamide-containing N-hydroxyindole-2-carboxylates as inhibitors of human lactate dehydrogenase-isoform 5

2011; Elsevier BV; Volume: 21; Issue: 24 Linguagem: Inglês

10.1016/j.bmcl.2011.10.031

1464-3405

Carlotta Granchi, Sarabindu Roy, Marco Mottinelli, Elisa Nardini, Fabio Campinoti, Tiziano Tuccinardi, M Lanza, Laura Betti, Gino Giannaccini, Antonio Lucacchini, Adriano Martinelli, Marco Macchia, Filippo Minutolo,

Pharmacogenetics and Drug Metabolism

N-Hydroxyindole-2-carboxylates possessing sulfonamide-substituents at either position 5 or 6 were designed and synthesized. The inhibitory activities of these compounds against isoforms 1 and 5 of human lactate dehydrogenase were analysed, and Ki values of the most efficient inhibitors were determined by standard enzyme kinetic studies. Some of these compounds displayed state-of-the-art inhibitory potencies against isoform 5 (Ki values as low as 5.6 μM) and behaved as competitive inhibitors versus both the substrate and the cofactor.