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

Abstract

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 1H-NMR, 13C-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.