1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

Pyrimidine analogs have long found use over a broad chemotherapeutic spectrum. In an effort to further explore the antiviral potential of several uracil derivatives previously synthesized in our laboratories, a series of benzylated pyrimidines were designed and synthesized. Introduction of the benzyl residue onto the 5-phenylaminouracil scaffold was carried out using 2,4-bis(trimethylsilyloxy) pyrimidine with the corresponding benzyl bromides. Similarly, 1-benzyl-5-(benzylamino)- and 1-benzyl-5-(phenethylamino) uracils were obtained via amination of 1-benzyl-5-bromouracils with benzylamine or phenylethylamine. The results of the broad screen antiviral studies revealed that compounds 5 and 11 exhibit promising inhibitory activity against HIV-1 in CEM-SS culture. A 50% protective effect was observed at concentrations of 11.9 and 9.5 mu M, respectively. Moreover, compounds 8 and 3 exhibited good inhibitory effects against EBV in AKATA cell culture with EC50 values of 2.3 and 12 mu M, respectively. The synthesis and biological studies are detailed herein. (C) 2010 Elsevier Ltd. All rights reserved.