key: cord-0956407-sfl5nrc4
authors: Paramonova, Maria P.; Khandazhinskaya, Anastasia L.; Seley-Radtke, Katherine L.; Novikov, Mikhail S.
title: Novel 1-[5-(4-bromophenoxy)pentyl]-3-(2-arylamino- 2-oxoethyl)uracils and their antiviral properties
date: 2017-02-28
journal: Mendeleev Communications
DOI: 10.1016/j.mencom.2017.01.027
sha: 703f5c2ded7f6d49679f062b771ea7b54eacff5d
doc_id: 956407
cord_uid: sfl5nrc4

The title compounds were prepared from 1-[5-(4-bromophenoxy) pentyl]uracil by the introduction of N-arylacetamide moiety at the 3-position, the better approach involving the use of N-aryl-2-chloroacetamides as the reactants. Antiviral activity of the obtained compounds was estimated.

Betaherpesvirinae; it is prevalent in nearly 90% of the adult population worldwide. 1 HCMV infection is associated with viral persistence in a latent form similar to other herpesviruses and reactivation of HCMV is a serious issue for patients with impaired immune systems. For example, there is a high probability of serious coinfections such as pneumonia and gastrointestinal diseases, among others, in recipients of donor organs and bone marrow transplants or HIV-infected patients. 2 Because of the high prevalence of the virus throughout the human population, HCMV is the most common cause of congenital viral infections in newborns. 3 HCMV is able to penetrate the placenta and subsequently infect the fetus, leading to stillbirths 4 and innate deformities. 5 The current treatment for HCMV infections is focused on five FDA-approved drugs: ganciclovir, 6 its oral prodrug form valg anciclovir, 7 foscarnet, 8 cidofovir and its prodrug brincidofovir. 9 Unfortunately, these drugs also cause some serious side effects, which significantly limit their clinical utility. 10 Aside from low bioavailability these drugs also exhibit significant toxicity. In particular, foscarnet and cidofovir lead to nephrotoxicity, 11 while ganciclovir inhibits the functions of bone marrow, thereby leading to thrombocytopenia and granulocytopenia. 12 Further, it has been found that long-term treatment of HCMV infections leads to the generation of resistant HCMV variants. 13 As a result, there is an urgent need to find safer compounds that exhibit potent anti-HCMV activity, which is not accompanied by such serious side effects.

Previously we have synthesized a series of 1-[w-(aryloxy)alkyl] uracil derivatives containing an N-(4-phenoxyphenyl)acetamide fragment at the N 3 atom of the pyrimidine ring. These compounds exhibited potent inhibitory activity against HCMV in HEL cell cultures. 14 The most active was uracil derivative 1 bearing five methylene groups. 14 Initially target N-arylamides 2-5 were prepared by conversion of 1-[5-(4-bromophenoxy)pentyl]uracil 6 to uracil-3-acetic acid derivative 7 (Scheme 1, Method A), whose synthesis was described previously. 14 Subsequent treatment of acid 7 with thionyl chloride and condensation of the resulting acyl chloride with the appropriate arylamines (aniline, 4-phenylaniline, 2-amino-9H-fluorene or 1-aminopyrene) in the presence of pyridine in 1,2-dichloroethane led to the desired N-arylamides 2-5 in 56-74% yields.

The second route (Scheme 1, Method B) was proposed to poten tially increase the yields of the target compounds. † This approach employed substituted N-aryl-2-chloroacetamides as alkyla ting agents. We have previously described the synthesis of several rela ted compounds by this method. 15 Conversion of the correspon ding anilines into their N-trimethylsilyl derivatives was 16 with the corresponding chloroacetamides 8-11 in DMF in the presence of a 1.5-fold excess of potassium carbonate led to the target compounds 2-5 in 78-90% yields.

O Br N N O O O H N

Compounds 2-5 were then evaluated as potential inhibitors against a broad set of DNA and RNA viruses, including HIV-1, N-Arylacetamides 9-11 (general procedure). A mixture of 8.14 mmol of arylamine, HMDS (15 ml) and NH 4 Cl (0.1 g) was refluxed for 12 h until a homogeneous solution was obtained. Excess HMDS was removed under reduced pressure, and the residual clear oil was dissolved in anhydrous 1,2-dichloroethane (40 ml). A solution of chloroacetyl chloride (0.7 ml, 8.80 mmol) in anhydrous 1,2-dichloroethane (10 ml) was added dropwise with stirring at 0 °C. The mixture was stirred overnight at room temperature and then evaporated under reduced pressure to 1/3 volume. Hexane (20 ml) was added and the mixture was kept overnight in a refri gerator. The resulting precipitate was filtered and recrystallized from a mixture of EtOAc-hexane (1 : 1 or 1 : 2). 13 

A mixture of carboxylic acid derivative 7 (0.7 g, 1.70 mmol) and thionyl chloride (0.15 ml, 2.06 mmol) in anhydrous 1,2-dichloroethane (10 ml) was refluxed with the exclusion of moisture for 6 h. The volatiles were evaporated under reduced pressure and the residue was dissolved in anhydrous 1,2-dichloroethane (10 ml). The resulting solution was added drop wise to a stirred and cooled (0 °C) solution of arylamine (1.72 mmol) and pyridine (2 ml) in anhydrous 1,2-dichloroethane (40 ml), and this was stirred for an additional 3 h at 0 °C and then kept overnight at room temperature. The mixture was then washed with 4% aqueous HCl (2 × 30 ml) and water (2 × 30 ml), the solvents were evaporated under reduced pressure, and the crude product purified by flash chromatography eluting with 1,2-di chloroethane-EtOAc (1 : 2). The product was recrystallized from a mixture of hexane- EtOAc (1 : 1) .

Method B. A mixture of 1-[5-(4-bromophenoxy)pentyl]uracil 6 (0.5 g, 1.42 mmol) and K 2 CO 3 (0.3 g, 2.17 mmol) in DMF (10 ml) was stirred at 80 °C for 1 h. After cooling to room temperature, the corresponding 2-chloro acetamide 8-11 (1.46 mmol) was added and stirring was continued for 24 h. The reaction mixture was filtered, concentrated under reduced pressure, puri fied by flash chromatography eluting with 1,2-dichloroethane-EtOAc (1 : 2) and then recrystallized from a mixture of hexane-EtOAc (1 : 1). 13 16 Disappointingly, none of the com pounds in this series showed any meaningful antiviral activity. However, in further analyzing the screening results it appears that the oxygen atom of the acetanilide fragment of 1 likely makes a critical contribution to the anti-HCMV activity. Thus, the new uracil acetamide derivatives seem to be a promising class of viral rep lication inhibitors and warrant further structure-activity investi gations.

After cooling to room temperature, ethyl bromoacetate (0.17 ml, 1.56 mmol) was added and stirring was continued for 24 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by flash chromatography eluting with 1,2-dichloro ethane. The crude product was then dissolved in EtOH (20 ml), LiOH (0.2 g, 8.35 mmol) and water (10 ml) were added, and the resulting mixture was stirred at room temperature for 12 h. After adjusting the pH to 2 with the addition of 1 m HCl, the resulting precipitate was filtered and recrystallized from a mixture of hexane

12.90 (br. s, 1H, COOH). 13 C NMR (100 MHz

This work was supported by the Russian Foundation for Basic Research (grant no. 15-44-02299). The authors are grateful to Professors C. Pannecouque, G. Andrei and R. Snoeck of the Rega Institute for antiviral evaluation of synthesized compounds.

Supplementary data associated with this article can be found in the online version at doi: 10.1016/j.mencom.2017.01.027.