In vitro activities of methylenecyclopropane analogues of nucleosides and their phosphoralaninate prodrugs against cytomegalovirus and other herpesvirus infections

Human cytomegalovirus (HCMV) infection does not generally cause problems in the immunocompetent adult but can result in severe clinical disease in the fetus, neonate, and immunocompromised host. Ganciclovir (GCV), the agent c urrently used to treat most HCMV infections, has resulted in much therapeut ic success; however, efficacy remains suboptimal. Therefore, there is still a need to develop new compounds for use against HCMV infections. In the pr esent study, several Z- and E-series methylenecyclopropane analogues and th eir phosphoroalaninate prodrugs were tested initially for activity against HCMV, strain AD169, and murine cytomegalovirus (MCMV) in vitro. Many mere f ound to exhibit efficacy comparable to that of GCV against HCMV in plaque a ssays and were active against MCMV as well. The compounds were also tested for efficacy against herpes simplex virus types 1 and 2, varicella-zoster v irus, and Epstein-Barr virus, and some had levels of activity that mere com parable to that of acyclovir. In addition, the compounds synguanol (QYL-438 ) and 2-amino-6-cyclopropylamino analogue (QYL-769) were chosen for further evaluation and were found to be effective against additional laboratory an d clinical isolates of HCMV and GCV-resistant isolates. QYL-438 and QYL-769 were found to be nontoxic in human and mouse fibroblasts and were consider ably less toxic than GCV in granulocyte macrophage CFUs and erythroid burst -forming units. These results provide evidence for the high activity of som e of these methylenecyclopropane analogues against various herpesviruses, p articularly HCMV: in tissue culture and suggest that further evaluation is warranted to determine their potential for use in future clinical studies.