Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds : Structure-activity relationships and antiherpetic activity in vivo
In: Journal of medicinal chemistry (Print), Jg. 48 (2005), Heft 11, S. 3919-3929
academicJournal
- print, 19 ref
Zugriff:
Derivatives of the herpes simplex thymidine kinase inhibitor HBPG [2-phenylamino-9-(4-hydroxybutyl)-6-oxopurine] have been synthesized and tested for inhibitory activity against recombinant enzymes (TK) from herpes simplex types 1 and 2 (HSV-1, HSV-2). The compounds inhibited phosphorylation of [3H]thymidine by both enzymes, but potencies differed quantitatively from those of HBPG and were generally greater for HSV-2 than HSV-1 TKs. Changes in inhibitory potency were generally consistent with the inhibitor/substrate binding site structure based on published X-ray structures of HSV-1 TK. In particular, several 9-(4-aminobutyl) analogues with bulky tertiary amino substituents were among the most potent inhibitors. Variable substrate assays showed that the most potent compound; 2-phenylamino-9-[4-(1-decahydroquinolyl)butyl]-6-oxopurine, was a competitive inhibitor, with Ki values of 0.03 and 0.005 μM against HSV-1 and HSV-2 TKs, respectively. The parent compound HBPG was uniquely active in viral infection models in mice, both against ocular HSV-2 reactivation and against HSV-1 and HSV-2 encephalitis. In assays lacking [3H]thymidine, HBPG was found to be an efficient substrate for the enzymes. The ability of the TKs to phosphorylate HBPG may relate to its antiherpetic activity in vivo.
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Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds : Structure-activity relationships and antiherpetic activity in vivo
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Autor/in / Beteiligte Person: | MANIKOWSKI, Andrzej ; VERRI, Annalisa ; LOSSANI, Andrea ; GEBHARDT, Bryan M ; GAMBINO, Joseph ; FOCHER, Federico ; SPADARI, Silvio ; WRIGHT, George E |
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Zeitschrift: | Journal of medicinal chemistry (Print), Jg. 48 (2005), Heft 11, S. 3919-3929 |
Veröffentlichung: | Washington, DC: American Chemical Society, 2005 |
Medientyp: | academicJournal |
Umfang: | print, 19 ref |
ISSN: | 0022-2623 (print) |
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