Synthesis of 1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils as Potent Nonnucleoside HIV‐1 RT Inhibitors

Abstract

1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyl uracils (1) and (2) are analogs of MKC‐442, which is a very potent inhibitor of HIV‐1 reverse transcriptase. The target compound 1 was synthesized by the first approach, from the corresponding 1,3‐dibenzyl‐5‐(dimethylamino)‐6‐phenethylpyrimidine‐2,4(1H,3H)‐dione (7), which was synthesized in four steps from 6‐methyluracil (3) by nitration, benzylation, reduction, and methylation of the amino group. Compound 7 was then debenzylated to give the complete deprotected compound 8 with very low yield. To improve the yield, another pathway was developed for introducing the ethoxymethyl group at N‐1 of the uracil ring first. The result of adjusting reaction sequences increased the overall yield dramatically. All synthesized compounds were tested for their inhibition of HIV‐1 reverse transcriptase, and moderate activity was found for target compound 1.

Keywords:

• 5‐dimethylamino‐6‐phenethyluracils
• HIV‐1 reverse transcriptase
• nonnucleoside reverse transcriptase inhibitors

Acknowledgments

We thank the National Science Foundation of China and the 985 Program of the Ministry of Education of China for financial support.