Thiazolo[4,5-d]pyrimidines. Part II. Synthesis and anti-human cytomegalovirus activity in vitro of certain acyclonucleosides and acyclonucleotides derived from the guanine analogue 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione.
The synthesis and in vitro antiviral activity of certain hydroxyalkoxymethyl, hydroxyalkyl, hydroxyalkenyl and phosphonoalkenyl derivatives of the guanine congener 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione are reported. The compounds of this study were selected for their structural similarity to acyclonucleosides with known anti-herpesvirus activity. 5-Amino-3-[(Z)-4-hydroxy-2-buten-1-yl]thiazolo[4,5-d]pyrimidine-2, 7(3H,6H)- dione was the only member of the series to display significant in vitro activity against human cytomegalovirus (HCMV); however, this compound did not inhibit other herpesviruses, human immunodeficiency virus type 1 or murine cytomegalovirus. It was found to have a cytotoxicity profile similar to that of ganciclovir (DHPG). The antiviral effect was found to be sensitive to the initial viral input and the time of addition during the virus replication cycle. Significantly, the compound was found to have equal anti-HCMV activity, against standard virus strains, to DHPG, but also showed potent activity against DHPG-resistant virus strains, except for a strain mutated in the UL97 (phosphotransferase) gene.
Revankar
G R
GR
Aronex Pharmaceuticals, Woodlands, TX 77381-4223, USA.
Ojwang
J O
JO
Mustain
S D
SD
Rando
R F
RF
De Clercq
E
E
Huffman
J H
JH
Drach
J C
JC
Sommadossi
J P
JP
Lewis
A F
AF
D000998:Antiviral Agents / Q000737:chemistry*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013844:Thiazoles / Q000737:chemistry*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
C117006:5-amino-3-(4-hydroxy-2-buten-1-yl)thiazolo(4,5-d)pyrimidine-2,7(3H,6H)-dione; D000998:Antiviral Agents; D009705:Nucleosides; D009711:Nucleotides; D011743:Pyrimidines; D011744:Pyrimidinones; D013844:Thiazoles