SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF A SERIES OF 1-ALKOXY-5-ALKYL-6-(ARYLTHIO)URACILS

A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and t ested for their ability to inhibit HIV-1 replication. Treatment of 2-a lkyl-3,3-bis(methylthio)acryloyl chlorides (5a-e) with AgOCN in benzen e followed by reaction of the resulting isocyanates 6a-e with an appro priate alkoxyamine gave N-alkoxy-N'-((2-alkyl-3,3-bis(methylthio (10a- z) in good to excellent yields. Cyclization of 10a-z in AcOH containin g st catalytic amount of p-TsOH produced 1-alkaxy-5-alkyl-6-(methylthi o)uracils (11a-z). Oxidation of 11a-z with 3-chloroperoxybenzoic acid in CH2Cl2 resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsulfony l)uracils (12a-x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford 1-alkoxy-5-alkyl-6-(arylthio)urac ils (14-49). Substitution at the 3- and 5-positions of the C-6-(phenyl thio) ring by two methyl groups significantly increased its original a nti-HIV-l activity (EC50: 5-dimethylphenyl)thio)-5-isopropyl-1-propoxy uracil (18), 0.064 mu M; henyl)thio)-1-(3-hydroxypropoxy)-5-isopropylu racil (23), 0.19 mu M). Among the various alkoxy substituents at the N -1, the propoxy group was the most beneficial for improving the anti-H IV-1 activity. The 1-propoxy derivative 18 proved to be the most poten t inhibitor of HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an isopropyl group at C-5 of the uraci l base also remarkably enhanced the activity. When compound 18 was inc ubated with a rat liver homogenate preparation, no metabolite was obse rved, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.