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.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. brollosy@yahoo.com
Nasser R
NR
El-Brollosy
Omar A
OA
Al-Deeb
Ali A
AA
El-Emam
Erik B
EB
Pedersen
Paolo
P
La Colla
Gabriella
G
Collu
Giuseppina
G
Sanna
Roberta
R
Loddo
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C083858:emivirine