Drug targets in cytomegalovirus infection.

Human cytomegalovirus (HCMV) infections are usually benign and self-limiting in the immunocompetent population; however, HCMV is a well-recognized problem among immunocompromised patients (in particular immunosuppressed patients with stem cell or solid organ transplantation, AIDS, or cancer). In this group of patients, HCMV infections are a significant cause of morbidity and mortality. Additionally, congenital HCMV infections are a leading cause of birth defects and infections in children, occurring in 1 to 2% of all live births. Currently available drugs for the treatment of HCMV diseases in the immunocompromised host include ganciclovir (GCV), its oral prodrug valganciclovir (VGCV), cidofovir (CDV), foscavir (FOS), and fomivirsen. Except for fomivirsen, all these drugs are targeted at the viral DNA polymerase. Even if presently approved anti-HCMV drugs have considerable helped in the management of HCMV disease in the immunocompromised host, their use is limited due to questions of toxicity, poor oral bioavailability, modest efficacy, and development of virus-drug resistance. Furthermore, no drug has been licensed to treat congenital HCMV. For these reasons, there is a real need to develop new compounds active against HCMV. The search for novel inhibitors of HCMV replication has led to the identification of new molecular viral targets such as the protein kinase UL97 and proteins involved in genome replication or in viral maturation and egress. Moreover, a new strategy based on the identification of specific cellular targets required for viral replication has been developed. This review will focus on new compounds that inhibit a specific viral process (viral targets) and on cell-based approaches (cellular targets) that result in selective inhibition of virus replication.

Antiviral activity of 3-(3,5-dimethylbenzyl)uracil derivatives against HIV-1 and HCMV.

Antiviral activity of 1,3-disubstituted uracil derivatives was evaluated against HIV-1 and HCMV. It appears that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residues of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also exhibited good anti-HIV-1 activity; and that of the 2- and 4-picolyl derivatives was particularly excellent.

Synthesis and anti-HIV-1 and anti-HCMV activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil derivatives.

3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated according to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2- and 4-picolyl derivatives was particularly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group.

Synthesis and antiviral activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil against HIV-1.

1,3-disubstituted uracils were obtained from uracil by the stepwise alkylation at N-1 and N-3 position with alkyl halide/alkali or alcohol under Mitsunobu conditions. The antiviral activity against HIV-1 of these compounds was examined to find that 1-cyanomethyl-3-(3,5-dimethylbenzyl)uracil and 1-phenyl-3-(3,5-dimethyl-benzyl)uracil showed powerful inhibition.

Synthesis and antiviral activity of 1,3-disubstituted uracils against HIV-1 and HCMV.

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

Halophenyl furanopyrimidines as potent and selective anti-VZV agents.

Bicyclic furano pyrimidines have been previously reported by us to be highly potent and selective inhibitors of varicella zoster virus (VZV). p-Alkyl phenyl analogues are particularly potent with EC50 values below 1 nM. In this article we report the synthesis and anti-VZV activity of a series of halophenyl analogues, with variation in the nature (F, Cl, Br) and location (o, m, p) of the halogen substituent. The compounds show a range of activities from ca. 10 nM to > 50 microM. In most cases, ortho substitution leads to greatest activity, meta substitution is in general poor, and the effect of p-substitution shows a marked dependence on the halogen atom. The p-fluorophenyl compound is unique amongst compounds of this class in being inactive as an antiviral. The possible origins of these marked SARs are discussed.

Influence of 2-substituent on the activity of imidazo[1,2-a] pyridine derivatives against human cytomegalovirus.

The synthesis of various 2-substituted imidazo[1,2-a]pyridine bearing a thioether side chain in position 3 was reported. The new compounds were characterized by 1H and 13C NMR spectra. A conformational study was obtained by X-ray crystallographic analysis for 2-biphen-4-ylimidazopyridine 7. The antiviral activity against human cytomegalovirus (HCMV) was investigated. It was strongly influenced by the nature of C-2 substituent.