SYNTHESIS AND ANTIVIRAL ACTIVITY OF 6-BENZYL ANALOGS OF 1-[(2-HYDROXYETHOXY)METHYL]-6-(PHENYLTHIO)THYMINE (HEPT) AS POTENT AND SELECTIVE ANTI-HIV-1 AGENTS

Several 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (1; HEPT) were synthesized and evaluated for their anti-HIV-1 activity. LDA (lithium diisopropylamide) lithiation of 5-ethyluracil d erivatives 7 and 8 and subsequent reaction with an aryl aldehyde gave 6-(arylhydroxymethyl)-5-ethyluracil derivatives 9-12. 6-(Arylhydroxyme thyl)-5-isopropyluracil derivatives 15-18 were prepared from the 5-iso propyl-2-thiouracil derivatives 13 and 14 by the above procedure follo wing oxidative hydrolysis of the thione. Preparation of the target 5-a lkyl-1-(alkoxymethyl)-6-benzyluracil derivatives 27-34 was carried out by acetylation of 9-14 followed by Pd-catalyzed hydrogenolysis. The 1 -butyl- (37 and 39) and 1-(2-methoxyethyl)- (38 and 40) 5-alkyl-6-benz yluracils were synthesized by 1-alkylation of the 3-phenacyl derivativ es 35 and 36 with alkyl halides followed by deprotection of the 3-phen acyl group. Compounds synthesized in this study inhibited HIV-1 replic ation in MT-4 cells in the submicromolar to namomolar concentration ra nge. From this series of compounds, 6-benzyl-1-(ethoxymethyl)-5-isopro pyluracil (33) was selected for clinical evaluation.