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Synthesis, Evaluation of Cytotoxicity and Molecular Docking Studies of the 7-Acetamido Substituted 2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin Polymerization

1
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa
2
Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2018, 11(2), 59; https://doi.org/10.3390/ph11020059
Received: 9 May 2018 / Revised: 22 May 2018 / Accepted: 25 May 2018 / Published: 11 June 2018
(This article belongs to the Special Issue Heterocyclic Chemistry for Cancer and CNS Diseases)
The 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5ah were prepared and evaluated for potential antigrowth effect in vitro against human lung cancer (A549) and cervical cancer (HeLa) cells and for the potential to inhibit tubulin polymerization. The corresponding intermediates, namely, the 3-unsubstituted 7-acetyl-2-aryl-5-bromoindole 2ad and 7-acetamido-2-aryl-5-bromoindole 4ad were included in the assays in order to correlate both structural variations and cytotoxicity. No cytotoxicity was observed for compounds 2ad and their 3-trifluoroacetyl–substituted derivatives 5ad against both cell lines. The 7-acetamido derivatives 4d exhibited modest cytotoxicity against both cell lines. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5eh were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound, 5g, induced programmed cell death (apoptosis) in a caspase-dependent manner for both A549 and HeLa cells. Compounds 5eh were found to significantly inhibit tubulin polymerization against indole-3-carbinol and colchicine as reference standards. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity. View Full-Text
Keywords: 7-acetamido-2-aryl-5-bromoindoles; trifluoroacetylation; cytotoxicity; apoptosis; tubulin polymerization; molecular docking 7-acetamido-2-aryl-5-bromoindoles; trifluoroacetylation; cytotoxicity; apoptosis; tubulin polymerization; molecular docking
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Mphahlele, M.J.; Parbhoo, N. Synthesis, Evaluation of Cytotoxicity and Molecular Docking Studies of the 7-Acetamido Substituted 2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin Polymerization. Pharmaceuticals 2018, 11, 59.

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