Novel potential agents for human cytomegalovirus infection: synthesis and antiviral activity evaluation of benzothiadiazine dioxide acyclonucleosides.
The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3. 5-3.7 micrograms/mL, cytotoxicity (CC50) >/= 40 micrograms/mL, MCC = 20 micrograms/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.
Martinez
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A
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Esteban
A I
AI
Castro
A
A
Gil
C
C
Conde
S
S
Andrei
G
G
Snoeck
R
R
Balzarini
J
J
De Clercq
E
E
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014779:Virus Replication
C118870:1-benzyl-3-(benzyloxymethyl)-2,1,3-benzothiadiazin-4-one 2,2-dioxide; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides