SYNTHESIS, MOLECULAR DOCKING AND ANTI-PROLIFERATIVE ACTIVITY OF NEW SERIES OF 1-METHYLSULPHONYL-3-INDOLYL HETEROCYCLES

Objective : The present work aimed to synthesize a new series of 1-methylsulphonyl-3-indolyl heterocycles and study their cytotoxic activity. In addition, we attempted to explore the mode of the interaction of anti-proliferative compounds with the active site of carbonic anhydrase IX (CA IX) theoretically via molecular docking study. Methods : Novel series of pyrazole, pyrimidine and triazole derivatives bearing 1-methylsulphonyl-1 H -indole were prepared via a series of hetero cyclization reactions utilizing 3-(1-methylsulphonyl-1 H -indol-3-yl)-1-(substituted phenyl)-1 H -pyrazole-4-carboxaldehydes 3a-d and 3-chloro-3-(1-methylsulphonyl-1 H -indol-3-yl)propenal (6) and evaluating their anti-proliferative activity. The structures of the newly synthesized compounds were confirmed by elemental analyses, IR, NMR and mass spectral data. In addition, molecular docking study of the most promising antiproliferative compounds against the active site of carbonic anhydrase IX (PDB ID: 4BCW) theoretically is discussed. Results : Compounds 5c, 7 and 12 revealed potent anti-proliferative effects against A-549 cancer cell line with IC 50 of 44.3, 17.2 and 38.7 µmol/l, respectively compared to the reference drug doxorubicin (IC 50 of 48.8 µmol/l). While compound 5c was found to be highly active with IC 50 of 5.66 µmol/l against HCT-116 cancer cell line than doxorubicin (IC 50 of 65.00 µmol/l). Conclusion : Further work is recommended to confirm the inhibition of CA IX in a specific bioassay.