Synthesis and antiviral evaluation of 1-[(2-Phenoxyethyl)oxymethyl] and 6-(3,5-Dimethoxybenzyl) analogues of HIV drugs emivirine and TNK-651

Novel emivirine analogues 6a, b were synthesized by reacting chloromethyl ethyl ether with 5-ethyl/isopropyl-6-(3,5-dimethoxybenzyl)uracils 5e, f. On the other hand, A series of new TNK-651 analogues 10a–f substituted at N-1 with phenoxyethoxymethyl moiety was prepared on treatment of the corresponding uracils 5a–f with bis(phenoxyethoxy)methane (9). The newly synthesized non-nucleosides were tested for antiviral activity against wild type HIV-1 IIIB as well as the resistant strains N119 (Y181C), A17 (K103N+Y181C), and the triple mutant EFVR (K103R+V179D+P225H) in MT-4 cells. Most of the tested compounds showed good activities. Among them 6-(3,5-dimethylbenzyl)-5-ethyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10c) and 6-(3,5-dimethylbenzyl)-5-isopropyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10d) that showed inhibitory potency higher than emivirine against both wild type HIV-1 and the tested mutant strains, as well as higher activity than efavirenz against EFV

Synthesis and antiviral evaluation of 6-(trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of HIV drugs Emivirine and GCA-186

The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 wild type and mutants resistant to non-nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV-1. Among them, compound 1-(ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil (9i) showed the largest inhibitory potency (EC(50) = 0.02 microM), resulting equally potent than emivirine against wild type HIV-1. Furthermore, compound 9i showed marginal better activity against resistant mutants than emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate beta-keto ester with thiourea or a cross-coupling reaction of 6-chloro-2,4-dimethoxypyrimidines with benzylic Grignard reagents

Synthesis of novel uracil non-nucleoside derivatives as potential reverse transcriptase inhibitors of HIV-1

Novel emivirine and TNK-651 analogues 5a–d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a–d, 2-phenylethyloxymethyl 9e–h, and 3-phenylprop-1-yloxymethyl 9i–l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a–c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine