5-(1-Substituted) alkyl pyrimidine nucleosides as antiviral (herpes) agents

The treatment of viral diseases remains one of the major challenges to modern medicine. During the past two decades there has been increased recognition of the consequences of serious viral illnesses that are not controlled by vaccination. These illnesses include human immunodeficiency virus, human herpes viruses, and viruses that cause hepatitis. There are now eight pathogens recognized in the herpes virus family that cause infections in humans. Infections by the herpes viruses are opportunistic and often life-threatening, leading to significant morbidity and mortality in the increasing number of chronically immune compromised individuals such as AIDS patients, cancer patients and transplant recipients on immunosuppressive therapy. Nearly all individuals with AIDS are infected with one or more of the herpes viruses. Antiviral therapy with guanosine nucleoside analogs acyclovir and ganciclovir has had a major impact on diseases caused by herpes simplex virus type-1 and type-2 (HSV-1, HSV-2), Varicella zoster virus (VZV), and human cytomegalovirus (HCMV) but development of resistant virus strains and the absence of any effective treatment for other members of the herpes family provide a stimulus for increased search of new agents effective against various herpes viruses. Pyrimidine nucleosides have taken up an important role in the therapy of virus infection. Significant progress in the study of anti-herpes nucleosides has been made by the advent of 5-substituted pyrimidine nucleosides such as 5-iodo-, 5-ethyl-, 5-(2-chloroethyl)-, and (E)-5-(2-bromovinyl)- derivatives of 2'-deoxyuridine. These are highly specific inhibitors of HSV-1, HSV-2, and/or VZV infections. However, Epstein Barr virus (EBV) and HCMV are much less sensitive to these agents. In 5-substituted pyrimidine nucleosides the nature of substituents, particularly at the C-5 position, has been found to be an important determinant of anti-herpes activity. Structural requirements at the C-2 carbon of the 5-substituent of pyrimidine nucleosides have been well established for anti-herpes activity. However, there is little qualitative or mechanistic knowledge of the derivatives with substitution at the C-1 carbon of the 5-substituent of pyrimidine nucleosides. During the last few years of our research, we have investigated a variety of C-1 functionalized substituents at the 5-position of the pyrimidine nucleosides to determine their usefulness as antiviral (herpes) agents. In the 5-(1-substituted) group of pyrimidine nucleosides, we demonstrated that novel substituents present at the C-1 carbon of the 5-side chain of the pyrimidine nucleosides are important determinants of potent and broad spectrum antiviral (herpes) activity including EBV and HCMV. In this article the work on design, synthesis and structure activity relationships of several 5-[(1-substituted) alkyl (or vinyl)] pyrimidine nucleoside derivatives as potential inhibitors of herpes viruses is reviewed.