Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives.

Autor: Mohammed AF; School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Andrei G; Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1030, Leuven 3000, Belgium., Hayallah AM; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Abdel-Moty SG; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Snoeck R; Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1030, Leuven 3000, Belgium., Simons C; School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: simonsc@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Mar 15; Vol. 27 (6), pp. 1023-1033. Date of Electronic Publication: 2019 Feb 02.
DOI: 10.1016/j.bmc.2019.02.005
Abstrakt: A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C 6 H 4 ) displayed good inhibitory activity (HSV-1 EC 50 1.5 μM, HSV-2 EC 50 0.8 μM) and retained inhibitory activity in HSV-1 TK - cells (EC 50 0.8 μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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