Structure−Activity Relationships of (S,Z)-2-Aminopurine Methylenecyclopropane Analogues of Nucleosides. Variation of Purine-6 Substituents and Activity against Herpesviruses and Hepatitis B Virus

Abstract

A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N(6)-alkyl compounds 2a, 2b, 2c, 2d, 2e,2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K(2)CO(3) afforded O(6)-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S(6)-alkyl compounds 4h and 4i. The N(6)-alkyl derivatives 2a, 2b, O(6) analogues 3a, 3c, 3h, 3i, and S(6) compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.

Stereoselective Phosphorylation of Cyclopropavir by pUL97 and Competitive Inhibition by Maribavir

“…We also hypothesize that formation of the (ϩ)-enantiomer of CPV triphosphate results in viral DNA synthesis inhibition, whereas formation of the (Ϫ)-enantiomer does not. Consistent with this hypothesis, the (S)-(ϩ)-enantiomer of synguanol (a guanosine methylenecyclopropane homolog with only one hydroxymethyl group on the cyclopropane ring) is active against HCMV, whereas the (R)-(Ϫ)-enantiomer is not (12,42,43,51).…”

In Vitro Activity and Mechanism of Action of Methylenecyclopropane Analogs of Nucleosides against Herpesvirus Replication

“…ACV was used as a positive control. To determine antiviral efficacy, 10 6 Daudi cells were incubated for 1 h with sufficient EBV strain P3HR-1 to infect 10% of the cells. After infection, appropriate dilutions of drug were added, and cells were incubated for 3 days at 37°C.…”

“…After infection, appropriate dilutions of drug were added, and cells were incubated for 3 days at 37°C. Negative controls were prepared by incubating 10 6 Daudi cells in drug-free medium for 3 days at 37°C. Virus controls were prepared by incubating 10 6 Daudi cells as described above in drug-free medium for 3 days at 37°C.…”

“…In both cases, the Z-and E-isomeric series of analogs were generated. We have reported previously that Z isomers of the first generation of methylenecyclopropane analogs are potent agents against some members of the herpesvirus family (6,10,(16)(17)(18)(19)(20)(21). These analogs had strong antiviral activity against HCMV, murine CMV (MCMV), human herpesvirus 6 (HHV-6), (10,20,24), rat CMV, rhesus monkey CMV, guinea pig CMV (20), and HHV-8 (10).…”

Human Cytomegalovirus UL97 Kinase Is Involved in the Mechanism of Action of Methylenecyclopropane Analogs with 6-Ether and -Thioether Substitutions

“…This dihydroxymethyl MCPN analog also exhibited good in vitro antiviral activity against Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8 (9). Recently, we described monohydroxymethyl MCPN analogs that retain good activity against HCMV, EBV, HHV-6, and HHV-8; unlike CPV, however, the monohydroxymethyl analogs are also active against HSV-1, HSV-2, and varicella-zoster virus (VZV) (11)(12)(13). The new MCPN analogs show promise as broad-spectrum antiherpes agents.…”