Synthesis, Molecular Docking and Anti-Proliferative Activity of New Series of 1-Methylsulphonyl-3-Indolyl Heterocycles

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>

Recent Developments in the Synthesis of Indole‐Pyrazole Hybrids

“…Abo‐Salem and co‐workers reported the synthesis and antiproliferative activities of novel 1‐methylsulphonyl‐3‐indolyl pyrazoles ( 207 , 208 , 209 & 210 ) as shown in Scheme 35 [81] . The target compound 207 was synthesized by the reaction of 1‐methylsulphonyl‐3‐acetylindole ( 205 ) with substituted hydrazines followed by Vilsmeier–Haack formylation reaction.…”

Synthesis, Anti-Proliferative Activity and SAR studies of Novel 5-(3-Indolyl)-5H-Thiazolo[4,3-b][1,3,4]Thiadiazoles tethered with Steroid Moieties

“…Progesterone, dehydroisoandrosterone, epiandrosterone, and 3hydroxy-5a-androstan-17-one are some of the steroids that are widely used as a pharmaceutical prototype for constructing various biologically active compounds [19][20][21][22][23]. Furthermore, indole is a well-known natural compound attracts massive interest of researchers in the field of organic and medicinal chemistry, having a broad spectrum of pharmaceutical activities comprise antitumor, antimicrobial, antiinflammatory, antiviral [24][25][26]. Scientific research studies revealed that a combination of two different bioactive molecules is of great medicinal interest [27].…”

“…These bioactive molecules can efficiently overcome most of the pharmacokinetic disadvantage of classical drugs where they can launch two or more mode of action in parallel to restrain tumor growth [27]. Based on the information provided and as our work continues to synthesize new anticancer agents [25,26,[28][29][30], our efforts in this work have directed to synthesize a new series of thiazolo [4,3-b]-1,3,4-thiadiazoles united to steroid moieties to be exploited for further diversification and screened for anti-proliferative activity.…”

Green Cyclocondensation of β-Ethylthio-β-indolyl-α, β-unsaturated Ketones with Semicarbazide Hydrochloride as Hydrazine Equivalent in Water: Aqueous Synthesis of 3-Pyrazolyl Indoles

“…3-Pyrazolyl indoles as an important subset of 2 indole derivatives had exhibited their versatile synthetic values [3][4][5][6][7] and a broad spectrum of biological activities [8][9][10] such as antimicrobial 11 , anti-inflammatory 12 and antioxidant 13,14 . As a result, much effort has focused on the synthesis of 3-pyrazolyl indoles, mainly including the cyclocondensation of 1, 3-diketones and related derivatives with hydrazines [15][16][17][18][19][20][21][22] , the direct coupling of indole derivatives and pyrazole derivatives 23,24 , acid-catalyzed intramolecular cyclization reaction of N-propargylation of N-acetyl-N-tosyl-hydrazine 25 , and other procedures [26][27][28] . However, all the reported reactions are performed in organic medium and extremely toxic hydrazines appear as a main nitrogen source for most of reactions, which can lead to serious environmental and safety problems.…”