Abstract
<p><strong>Objective</strong>:<strong> </strong>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 <em>via</em> molecular docking study.</p><p><strong>Methods</strong>:<strong> </strong>Novel series of pyrazole, pyrimidine and triazole derivatives bearing 1-methylsulphonyl-1<em>H</em>-indole were prepared <em>via</em> a series of hetero cyclization reactions utilizing 3-(1-methylsulphonyl-1<em>H</em>-indol-3-yl)-1-(substituted phenyl)-1<em>H</em>-pyrazole-4-carboxaldehydes 3a-d and 3-chloro-3-(1-methylsulphonyl-1<em>H</em>-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.</p><p><strong>Results</strong>:<strong> </strong>Compounds 5c, 7 and 12 revealed potent anti-proliferative effects against A-549 cancer cell line with IC<sub>50</sub> of 44.3, 17.2 and 38.7 µmol/l, respectively compared to the reference drug doxorubicin (IC<sub>50</sub> of 48.8 µmol/l). While compound <strong>5c</strong> was found to be highly active with IC<sub>50</sub> of 5.66 µmol/l against HCT-116 cancer cell line than doxorubicin (IC<sub>50</sub> of 65.00 µmol/l).</p><p><strong>Conclusion</strong>:<strong> </strong>Further work is recommended to confirm the inhibition of CA IX in a specific bioassay.</p>
Highlights
Classical Vilsmeier–Haack reaction is an efficient method for the formylation of an electron rich aromatic and heterocycles compounds [1]
Based on the above observations and in continuous of our work [25,26,27,28,29], the present work aimed to synthesize a new series of 1-methylsulphonyl-3indolyl heterocycles via Vilsmeier Haack reaction of 1methylsulphonyl-3-acetylindole and its hydrazone derivatives and evaluating their anti-proliferative activity
The required starting materials were prepared via the condensation of 1-methylsulphonyl-3-acetylindole (1) with some hydrazines, namely phenylhydrazine, 2,4-dinitrophenylhydrazine, 2,4,6-trichlorophenylhydrazine under heating in acetic acid to give the corresponding hydrazones 2a, 2c, and 2d
Summary
Classical Vilsmeier–Haack reaction is an efficient method for the formylation of an electron rich aromatic and heterocycles compounds [1]. The reaction of compounds containing acetyl group [2] or its hydrazine [3] with Vilsmeier-Haack reagent is highly versatile and leads to imino alkylations followed by cyclization to afford aromatic and/or heterocyclic compounds [4,5,6,7]. The reaction of compounds containing active methylene group with Vilsmeier-Haack reagent under heating gives the corresponding β-haloenecarboxaldehyde derivatives [8, 9], which are useful precursors in the construction of different heterocyclic systems [8,9,10,11,12,13]. We attempted to explore the mode of interaction of anti-proliferative compounds with the active site of carbonic anhydrase IX (PDB ID: 4BCW) theoretically via molecular docking study
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