5-Substituted Pyrimidines with a 1,5-Anhydro-2,3-dideoxy-d-arabino-hexitol Moiety at N-1:  Synthesis, Antiviral Activity, Conformational Analysis, and Interaction with Viral Thymidine Kinase

• Published in: Journal of medicinal chemistry 1998-10, Vol.41 (22), p.4343-4353
• Main Authors: Ostrowski, Tomasz, Wroblowski, Berthold, Busson, Roger, Rozenski, Jozef, De Clercq, Erik, Bennett, Matthew S, Champness, John N, Summers, William C, Sanderson, Mark R, Herdewijn, Piet
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Arabinonucleosides - chemical synthesis; Arabinonucleosides - chemistry; Arabinonucleosides - pharmacology; Biological and medical sciences; Cell Line; Crystallography, X-Ray; Cytomegalovirus - drug effects; Herpes simplex virus 1; Herpes simplex virus 2; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - enzymology; Herpesvirus 2, Human - drug effects; Herpesvirus 3, Human - drug effects; Medical sciences; Models, Molecular; Molecular Conformation; nucleosides; Pharmacology. Drug treatments; pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Thymidine Kinase - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980287z

A new series of anhydrohexitol nucleosides are described. These compounds have a pyrimidine base moiety substituted in the 5-position with a chloro (1b), trifluoromethyl (1c), vinyl (1d), 2-thienyl (1e), ethynyl (1f) or propynyl (1g) substituent. The vinyl, propynyl, and, in particular, the 5-trifluoromethyl analogue showed potent activity against herpes simplex virus (HSV), 1c with a selectivity index of >16000 against HSV-1 and >1000 against HSV-2. Conformational analysis of anhydrohexitol nucleosides using computational methods indicates that these nucleosides occur in an equilibrium between the C1 and 1C form with a ΔE of 5.9 kJ/mol. When the anhydrohexitol nucleoside is cocrystallized with the HSV-1 thymidine kinase it adopts a 1C conformation, which is opposite to the conformation found for the small molecule alone. The enzyme, apparently, induces a conformational change, and conformational flexibility of an anhydrohexitol nucleoside may be advantageous for recognition by viral enzymes.