Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1 |
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| Authors: | Nasser R. El-Brollosy Omar. A. Al-Deeb Ali A. El-Emam Erik B. Pedersen Paolo La Colla Gabriella Collu Giuseppina Sanna Roberta Loddo |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Fax: +966-1-467-6220;2. Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark;3. Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia e Virologia Generale e Biotecnologie Microbiche, Università di Cagliari, Monserrato, Italy |
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| Abstract: | 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. |
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