Synthesis and Antiviral Activity of 1,3-Disubstituted Uracils against HIV-1 and HCMV

Abstract

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.

Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives

“…AzBBU and AmBBU were synthesized as previously described (28). The lead compound 1-benzyl-3-(3,5-dimethylbenzyl) uracil (BBF-29), 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442), and the nucleoside analog 2=,3=-didehydro-3=-deoxy-4=-ethynylthymidine (4=-Ed4T) were prepared according as previously described (25,34,52). All compounds were dissolved in dimethyl sulfoxide at 100 mM and stored at Ϫ20°C until use.…”

Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

“…Chloro-5,6-dihydro-5-fluoro-6-methoxyuracil(6) 5-Fluorouracil (5FU, Sigma-Aldrich, Tokyo, Japan; 6.50 g, 50.0 mmol) was dissolved in MeOH (350.0 ml) and N-Chlorosuccinimide (Sigma-Aldrich, 13.30 g, 100.0 mmol) was added to the solution, and then stirred for overnight at 50°C. The mixture was evaporated, and was recrystallized from 50% EtOH in H 2 O to give white crystals of 4 (5.73 g, 29.2 mmol, 58%).Mp 213.5-215.3 °C.…”

Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

“…In an earlier report 11) attempts were made to enhance the antiviral activity by methyl modifications in the N 3 -benzyl-1-cyanomethyluracils. Methyl functions in the ortho (1a) or para position (1c) of this N-3 benzyl group proved undesirable.…”

“…1-Benzyl derivative (2b) is unique since it also showed antiviral activity against HCMV as well as anti-HIV-1 activity. 11) This background prompted us to explore the antiviral activity of the 3-(3,5-dimethyl-benzyl)uracil bearing an alkyl or arylalkyl group at N1. Also reported here is Docking Studies of 1,3-disubstituted uracils with RT nevirapine binding site using the program, Glide ligand docking jobs.…”

“…8) Thereafter, many pyrimidine derivatives emerged as anti-HIV agents. 9,10) Against the background of these reports, we undertook a search for an anti-HIV agent by the structure-activity relationship (SAR) of the 1,3-disubstituted uracil 11) . It is demonstrated that the introduction of a cyanomethyl group onto N1 of uracil is effective for anti-HIV-1 activity.…”