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Issue 5, 2014
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Biological evaluation and molecular modelling of didanosine derivatives

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Five carbonate derivatives of 5′-O-2′,3′-dideoxyinosine (DDI, 1) have been synthesized by combination with aliphatic alcohols, with their in vitro anti-HIV activity and cytotoxicity being evaluated afterward in human peripheral blood mononuclear cells (PBMCs). One particular compound, namely DDI-Penta, exhibited an outstanding performance because it was found to have both a higher inhibitory potency and a lower cytotoxicity than the lead compound, resulting in a 100× enhancement in its selectivity index. In order to further study this phenomenon, the ability of these derivatives to bind to the cytoplasmatic 5′-nucleotidase (ncN-II) was studied by in silico methods. Also, the higher calculated lipophilicity of the synthesized compounds was proposed to improve their permeability through the cell membrane since said lipophilicity would allow a higher concentration of the corresponding prodrug inside the infected cell. Overall, a combination of an optimal lipophilicity and the ability of DDI-Penta to bind to ncN-II is suggested due to the higher potency and lower cytotoxicity observed for this compound. Based on the reported findings, we believe that the combination of certain aliphatic alcohols and DDI through a carbonate linkage could significantly increase the performance of this class of therapeutic compounds; therefore, it merits further evaluations.

Graphical abstract: Biological evaluation and molecular modelling of didanosine derivatives

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The article was received on 03 Jan 2014, accepted on 19 Feb 2014 and first published on 19 Feb 2014

Article type: Concise Article
DOI: 10.1039/C4MD00003J
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Med. Chem. Commun., 2014,5, 622-631

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    Biological evaluation and molecular modelling of didanosine derivatives

    S. Ravetti, C. A. De Candia, M. S. Gualdesi, S. Pampuro, G. Turk, M. A. Quevedo and M. C. Briñón, Med. Chem. Commun., 2014, 5, 622
    DOI: 10.1039/C4MD00003J

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