Publications by authors named "Robert Selwyne Arul Christopher"

2 Publications

  • Page 1 of 1

Discovery of in vitro antitubercular agents through in silico ligand-based approaches.

Eur J Med Chem 2016 Oct 20;121:169-180. Epub 2016 May 20.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53019 Siena, Italy; Sbarro Institute for Cancer Research & Molecular Medicine, Center for Biotechnology, College of Science & Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address:

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 μg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.032DOI Listing
October 2016

A combination strategy to inhibit Pim-1: synergism between noncompetitive and ATP-competitive inhibitors.

ChemMedChem 2013 Mar;8(3):484-96

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.

Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure-activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP-competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance.
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http://dx.doi.org/10.1002/cmdc.201200480DOI Listing
March 2013
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