Avcc 140206

1 ©2003 International Medical Press 0956-3202/02/$17.00 Human cytomegalovirus (HCMV), a highly prevalent member of herpesvirus family, rarely causes disease in immunocompetent persons. However, reactivation of virus is of significant concern in the immunocompromised individual, most notably transplant recipients and patients with acquired immune deficiency syndrome (AIDS) (Snydman, 2001; Levin et al., 2001). The interest in HCMV has increased with the escalation in the number of patients undergoing immunosuppressive therapy following organ and bone marrow transplantation, as well as the increasing number of AIDS patients. Furthermore, HCMV may have an important role in the development of vascular diseases such as arteriosclerosis, restenosis after coronary angioplasty and transplant vascular sclerosis (chronic rejection) (Levi, 2001; Horvath et al., 2000; Van der Bij & Speich, 2001). Antiviral agents currently licensed for the treatment of HCMV infection include ganciclovir, foscarnet, cidofovir and fomivirsen (Villarreal, 2001; Griffiths, 2002). All of them either directly or indirectly inhibit viral polymerase, or are able to reduce viral replication in patients who deve-lop the clinical symptoms associated with HCMV disease. However, toxicity associated with these drugs, poor oral bioavailability and high relapse rates have made their use less than optimal (Emery, 2001; Chou, 1999). Moreover, with the advent of the virus resistance to current drugs (Limaye, 2002), new drugs that act by a new mechanism of action may be highly desirable for the treatment of HCMV infection (Martinez et al., 2001; Castro & Martinez, 2000). In our search for new antiviral agents (Martinez et al., 1999a, 2000a), we discovered the benzothiadiazine dioxide (BTD)-modified acyclonucleosides, which showed a marked activity against HCMV and varicella-zoster virus (Martinez et al., 1997). The structure of these compounds is unique, not only for the nature of the heterocyclic base but also for the lack of the 5′-OH mimetic group pre-sent in ganciclovir and other current anti-HCMV drugs, which points to a different mechanism of action (Martinez et al., 1999b). These factors were considered in the first optimization step performed on this family of compounds leading to the BTD dibenzylderivatives as potent non-nucleoside HCMV inhibitors, active against some current drugresistant strains (Martinez et al., 1999c). Pharmacological studies revealed that the selective biological action exerted by the BTD derivatives against HCMV is in the early stages of the viral replicative cycle (Martinez et al., 2000b). As the viral target is yet unknown, a CoMFA analysis were performed to obtain further insights into the structural requirements for the biological activity of BTD. It suggested that the steric component is a predominant factor in the antiviral activity of these analogues with electrostatic factors playing a smaller yet significant role. From these results, new series of BTD derivatives were synthesized to Benzothiadiazine dioxide human cytomegalovirus inhibitors: synthesis and antiviral evaluation of main heterocycle modified derivatives