Highly potent and selective inhibition of varicella‐zoster virus replication by bicyclic furo[2,3‐d]pyrimidine nucleoside analogues

Abstract

The bicyclic furo[2,3-d]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella-zoster virus (VZV). From extensive structure-activity relationship (SAR) studies, the 6-(p-alkylphenyl)substituted furopyrimidine derivatives Cf 1742 and Cf 1743 emerged as the most potent inhibitors of VZV replication: they were found to inhibit both laboratory VZV strains and clinical VZV isolates at subnanomolar concentrations, while not being toxic to the host cells at 100,000-fold higher concentrations. Although the precise mechanism of action of these compounds remains to be elucidated, it is clear that for their antiviral activity they depend on phosphorylation by the VZV-encoded thymidine kinase. The furo[2,3-d]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone. Also, the latter is not inhibitory to dihydropyrimidine dehydrogenase, an enzyme involved in the degradation of thymine, uracil, and the anticancer agent 5-fluorouracil. Further development of the furo[2,3-d]pyrimidine nucleoside analogues as new therapeutic modalities for the treatment of VZV infections (i.e., varicella and herpes zoster) seems highly justified.

Antiviral drugs in current clinical use

“…Also for the herpesviruses (i.e. HSV), new antivirals have been described that target the helicase/primase complex, terminase complex or UL97 protein kinase (Eizuru, 2003), and, likewise, new inhibitors are on the horizon for CMV (De Clercq, 2003b) and VZV (De Clercq, 2003d).…”

The Unabated Synthesis of New Nucleoside Analogues with Antiviral Potential: A Tribute to Morris J. Robins

“…Unexpectedly, the furopyrimidine derivatives containing a long alkyl (C 8 -C 10 ) side chain ( Figure 2) exhibited a highly potent and selective activity against varicellazoster virus (VZV). [15] This activity was further increased if this aliphatic side chain was interrupted by a phenyl moiety, thus leading to a series of bicyclic furopyrimidine nucleoside analogues (BCNAs) bearing an aryl side chain, [16] the prototype of this class of compounds being Cf 1743 [17] ( Figure 2). …”

“…As reviewed earlier, [17] the antiviral activity of Cf 1743 (Cf standing for Cardiff) (and the other furo[2,3-d]pyrimidine based BCNAs) is confined to VZV, and this antiviral activity depends on a specific phosphorylation by the VZV-encoded thymidine kinase; but, how the compound eventually acts in inhibiting VZV replication (i.e., by suppressing viral DNA synthesis) has so far not been resolved. Unlike BVDU, the furo[2,3-d]pyrimidine nucleoside analogues are not susceptible to degradation by human or bacterial thymidine phosphorylase, which may otherwise release the free aglycone.…”

New Organogermanium Substrates for Palladium-Catalyzed Cross-Coupling Reactions. Application of Organogermanes towards the Synthesis of Carbon-5 Modified Uridine Analogues

“…Similarly, the same enzyme is also in charge of the degradation of 5-fluorouracil. 52 Recently, bicyclic furo [2,3-d]pyrimidine nucleoside analogues (BCNAs) have emerged as a new generation of potent antivirals with activity against varicella zoster virus (VZV). 53,54 Among the BCNAs, Cf 1742 and Cf 1743 ( Figure 8) showed high anti-VZV replication activity at subnanomolar concentrations (EC 50 :0.1-1 nM), which in comparison is about 10-fold lower than for BVDU, and 10,000-fold lower than acyclovir.…”

“…52 Therefore, BCNAs are the therapy of choice for VZV infections in patients under 5-fluorouracil treatment.…”