2-(2,4-Dioxy-1,2,3,4-Tetrahydropyrimidin-1-yl)-N-(4-Phenoxyphenyl)-Acetamides as a Novel Class of Cytomegalovirus Replication Inhibitors.

A series of novel uracil derivatives, bearing N-(4-phenoxyphenyl)acetamide moiety at N3 of a pyrimidine ring, has been synthesized. Their antiviral activity has been evaluated. It has been found that the novel compounds possess high inhibitory activity against replication of human cytomegalovirus (AD-169 and Davis strains) in HEL cell cultures. In addition, some of the derivatives proved to be inhibitory against varicella zoster virus.

C ytomegalovirus (CMV) is widespread in the human population and has been found in people of all geographical regions as well as in representatives of all socio-economic groups [1]. CMV causes a lifelong latent infection that can reactivate periodically. In healthy individuals, the infection is usually asymptomatic [2]; however in individuals with reduced immune status, particularly in AIDS patients [3] and those receiving immunosuppressive therapy after organ transplantation [4], CMV is associated with significant morbidity and mortality. CMV is considered to be the most dangerous cause of congenital diseases. The virus can be transmitted from the mother to the fetus, resulting in a stillbirth, birth defects, and developmental disorders [5].
Ganciclovir, foscarnet, cidofovir and their prodrugs valganciclovir, and cidofovir are used to treat CMV [6]. However, these drugs cause many adverse side effects [6]. Long-term therapy of a CMV infection can lead to the emergence of resistant variants of CMV [7], therefore the search for new highly effective anti-CMV agents is an urgent task.
We have recently synthesized a number of 1-cinnamyl-3-benzyl-uracil derivatives which effectively blocked the replication of HIV-1 and CMV in cell cultures [8], and we describe the synthesis and properties of 1-[ω-(phenoxy)alkyl]uracil derivative as an anti-CMV agent [9]. In the continuation of the search for new inhibitors of CMV replication, we synthesized uracil derivatives bearing N-(4-phenoxyphenyl)acetamide moiety at N3 of a pyrimidine ring and studied their antiviral properties.
Anti-CMV properties of the uracil derivatives (4)- (11) were studied in HEL cell culture against CMV (AD-169 and Davis strains). It has been found that certain compounds of this series exhibit strong inhibitory activity against CMV, which is comparable with the effect of ganciclovir. The uracil derivatives substituted at position 1 of the pyrimidine ring with benzyl (compound (4)) and 3,5-dimethylbenzyl (compound (6)) were the most active. They inhibited CMV replication with EC 50 = 3.06-8.9 µM. Other modifications of the structure resulted in complete loss of inhibitory activity.
It has also been found that the compounds (4) and (6) exhibit significant activity against VZV. They blocked VZV replication (Oka strain) in a HEL cell culture with EC 50 = 8.18 µM (compound (4)) and 17.0 µM (compound (6)), which is inferior to the protective action of acyclo- vir (EC 50 = 1.33 µM) and brivudine (EC 50 = 0.026 µM), currently used to treat infections caused by this virus [11]. However, the thymidine kinase deficient VZV mutant strain (07-1), which is resistant to acyclovir and brivudine, was susceptible to 1-benzyl-3-acetanilide uracil derivatives with EC 50 = 6.68 µM (compound (4)) and 16.1 µM (compound (6)). Therefore, the uracil derivatives whose synthesis is described in this work represent a new class of inhibitors of CMV reproduction whose effect is comparable to that of ganciclovir. Furthermore, some compounds of this series have pronounced inhibitory effect on VZV, both the wild-type strain (OKA) and the strain (07-1) resistant to the action of acyclovir. The data demonstrate that it is a promising direction for the development of new effective antiviral agents.
This work was supported by RFBR (grant number 13-04-01391_A), the biological part of the work supported by the grant GOA 10/014.