New Derivatives of 5-Substituted Uracils: Potential Agents with a Wide Spectrum of Biological Activity

Abstract

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2'-deoxy-5-iodocytidine and 5-bromovinyl-2'-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of the biological activity of new nucleoside analogues, namely, 5'-norcarbocyclic derivatives of substituted 5-arylamino- and 5-aryloxyuracils, against RNA viruses.

Keywords: 5′-norcarbocyclic nucleoside analogues; RNA viruses; chemical synthesis.

Figure 1

5-Substituted pyrimidine analogues with different types of antiviral activity.

Scheme 1

Synthesis of 5-amino derivatives of uracil and their 5′-norcarbocyclic analogues. Reaction conditions: (a) (CH₂OH)₂, quinoline, reflux for 1 h; (b) Pd(PPh₃)₄, THF, DMF.

Scheme 2

Synthesis of 5-phenoxyuracils and their 5′-norcarbocyclic derivatives. Reaction conditions: (a) BrCH₂C(O)OC₂H₅, K₂CO₃, DMF; (b) ethyl formate, NaH, THF; (c) thiourea, NaH, iPrOH; (d) MCA, HCl, H₂O; (e) 6-oxobicyclo[3.1.0]hex-2-ene, Pd(PPh₃)₄, THF, DMF.