A Simple and Direct Synthesis of Pentasubstituted Pyrroles via [3+4] Annulation and Their In Vitro Evaluation as Thrombolytic Agents and Cytotoxicity Studies on L929 Cells

Abstract

AbstractWe have developed two different methods for synthesis of two distinct polysubstituted pyrroles. The first method proceeds by the reaction of N,S‐acetal, arylglyoxals and malononitrile in the presence of H2O / PEG400 to the synthesis of 2‐(2‐argio‐1‐methyl‐5‐(methylthio)‐4‐nitro‐1H‐pyrrol‐3‐yl)‐2‐cyanoacetamide (4a‐4p). The second method for the synthesis of other divergent pyrroles 2‐(2‐argio‐1‐methyl‐5‐(methylthio)‐4‐nitro‐1H‐pyrrol‐3‐yl)acetonitrile (6a‐6f) under solvent free at thermal condition using methylcyanoacetate instead of malononitrile by decarboxylative elimination. Among the pyrroles 2‐(4‐methoxyphenyl) (4c), 2‐(4‐fluorophenyl) (4d) 2‐(4‐chlorophenyl) (4e), 2‐(2,4‐dichlorophenyl) (4f), 2‐(3‐chloro‐4‐fluorophenyl) (4g), 2‐(2‐bromo‐4‐chlorophenyl) (4h), (2‐(3‐bromophenyl) (4i), 2‐(4‐bromophenyl) (4j), (2‐(4‐hydroxyphenyl) (4l), and 2‐(3‐nitrophenyl) (4m) displayed moderate to good clot lysis. The cytotoxicity studies were also carried out on L929 cells for selected compounds. The test derivatives 4 c, 4 d, 4 g and 4 h showed good cell viability at lower concentration. The compound 4 f showed mild to non‐toxicity at higher and lower concentration. The density functional theory calculations (DFT) were carried out for the possible configurations of 6a‐argio‐2‐imino‐6‐methyl‐5‐(methylthio)‐4‐nitro‐3,3a,6,6a‐tetrahydro‐2H‐furo[2,3‐b] pyrrole‐3‐carbonitrile (D), 2‐amino‐6a‐argio‐6‐methyl‐5‐(methylthio)‐4‐nitro‐3a,6a‐dihydro‐6H‐furo[2,3‐b]pyrrole‐3‐carbonitrile (E) and 4c.