A Class of Sulfonamides with Strong Inhibitory Action against the alpha-Carbonic Anhydrase from Trypanosoma cruzi

Guzel-Akdemir O., AKDEMİR A., Pan P., Vermelho A. B., Parkkila S., Scozzafava A., ...Daha Fazla

JOURNAL OF MEDICINAL CHEMISTRY, cilt.56, sa.14, ss.5773-5781, 2013 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 56 Sayı: 14
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1021/jm400418p
  • Dergi Adı: JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.5773-5781
  • İstanbul Üniversitesi Adresli: Evet

Özet

Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an alpha-carbonic anhydrase (CA, EC 4.2.1.1) possessing high catalytic activity (TcCA) which was recently characterized (Pan et al. J. Med. Chem. 2013, 56, 1761-1771). A new class of sulfonamides possessing low nanomolar/subnanomolar TcCA inhibitory activity is described here. Aromatic/heterocydic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with K(I)s in the range of 0.5-12.5 nM, being less effective against the human off-target isoforms hCA I and II. A homology model of TcCA helped us to rationalize the excellent inhibition profile of these compounds against the protozoan enzyme, a putative new antitrypanosoma drug target. These compounds were ineffective antitrypanosomal agents in vivo due to penetrability problems of these highly polar molecules that possess sulfonamide moieties.