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(Hetero)aroyl esters of 2-(N-phthalimido)ethanol and analogues: parallel synthesis, anti-HIV-1 activity and cytotoxicity

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Abstract

The structural simplification of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) O-(2-phthalimidoethyl)-N-(hetero)aroyl-N-arylthiocarbamates led us to design (hetero)aroyl esters of 2-(N-phthalimido)ethanol as a potential new class of anti-HIV-1 agents. The setup of a solution-phase parallel synthesis method allowed the rapid preparation of a high number of analogues. In cell-based assays, 20 of 34 esters showed anti-HIV-1 activity ranging from nanomolar to micromolar concentrations. The most potent esters had only a minor effect or were ineffective in enzyme assay against HIV-1 reverse transcriptase. Variations on the O-(2-phthalimidoethyl) moiety led to compounds devoid of antiretroviral activity, but cytotoxic, in particular those bearing the 4-chloro-3-nitrobenzoyl moiety. The most cytotoxic compound displayed a CC50 value of 1.6 μM.

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Acknowledgements

This work was supported by MURST (Cofinanziamento Nazionale), CNR (Rome) and Ministero Italiano della Salute - Istituto Superiore di Sanità (grant no. 40D.46). Fondazione Carige is gratefully acknowledged for financially supporting S.C. The authors thank Mr. O. Gagliardo for the microanalyses, Mr. F. Tuberoni, Dr. M. Anzaldi, Dr. R. Raggio, and Dr. C. Rossi, for the IR and NMR spectra.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132, Genova, Italy

    Sara Cesarini, Andrea Spallarossa, Angelo Ranise & Silvia Schenone

  2. Dipartimento di Scienze e Tecnologie Biomediche, Università di Cagliari, Cittadella Universitaria, S.S. 554, Km 4,500, 09042, Monserrato (Cagliari), Italy

    Paolo La Colla, Gabriella Collu, Giuseppina Sanna & Roberta Loddo

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  1. Sara Cesarini
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  2. Andrea Spallarossa
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  3. Angelo Ranise
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  5. Paolo La Colla
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Correspondence to Sara Cesarini or Paolo La Colla.

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Cesarini, S., Spallarossa, A., Ranise, A. et al. (Hetero)aroyl esters of 2-(N-phthalimido)ethanol and analogues: parallel synthesis, anti-HIV-1 activity and cytotoxicity. Med Chem Res 19, 311–336 (2010). https://doi.org/10.1007/s00044-009-9192-x

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