Synthesis of 3-chloro-1-substituted aryl pyrrolidine-2,5-dione derivatives: discovery of potent human carbonic anhydrase inhibitors

OKTAY K., KOSE L. P., Sendil K., GÜLTEKİN M. S., GÜLÇİN İ.

MEDICINAL CHEMISTRY RESEARCH, cilt.26, sa.8, ss.1619-1627, 2017 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 26 Sayı: 8
  • Basım Tarihi: 2017
  • Doi Numarası: 10.1007/s00044-017-1865-2
  • Dergi Adı: MEDICINAL CHEMISTRY RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1619-1627
  • Anahtar Kelimeler: Aryl pyrrolidine, Carbonic anhydrase, Isoenzymes, Enzyme inhibition, Enzyme purification, ACETYLCHOLINE ESTERASE INHIBITORS, ISOENZYMES HCA I, PURIFICATION, SULFAMIDES, MALEIMIDES, ACTIVATORS, MOIETIES, ACID, XII, LACTOPEROXIDASE
  • Atatürk Üniversitesi Adresli: Evet

Özet

Carbonic anhydrase isoenzymes are important metalloenzymes that are involved in many physiologic processes, in which they catalyze the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3 (-)) and protons (H+) via a metal hydroxide nucleophilic mechanism. Because of their known biological activities and potential as carbonic anhydrase inhibitors, the present study focused on developing of a convenient route to synthesize 3-chloro-1-aryl pyrrolidine-2,5-diones (2b). This synthetic route started with (Z)-4-oxo-4-(arylamino)but-2-enoic acid (3b) and sulfurous dichloride (SOCl2) and resulted in a ring closing reaction that produced a series of 3-chloro-N-aryl maleimide derivatives (20-29) in good yields. This is the first report of the syntheses of 3-chloro-1-aryl pyyrolidine-2,5-diones 20-23 and 27-29 by ring-closing reactions of (Z)-4-oxo-4-(arylamino)but-2-enoic acid. The structures of all of the products were determined by H-1-NMR, C-13-NMR and infrared spectroscopy. Their biological activities were studied against human carbonic anhydrase I, and II. The 3-chloro-1-aryl pyrrolidine-2,5-diones strongly inhibited the activity of human carbonic anhydrase I and II, with K (i) values in the low nanomolar range of 23.27-36.83 nmol/L against human carbonic anhydrase I and 10.64-31.86 nmol/L against human carbonic anhydrase II.