Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1

• Published in: Archiv der Pharmazie (Weinheim) 2009-11, Vol.342 (11), p.663-670
• Main Authors: El-Brollosy, Nasser R., Al-Deeb, Omar. A., El-Emam, Ali A., Pedersen, Erik B., La Colla, Paolo, Collu, Gabriella, Sanna, Giuseppina, Loddo, Roberta
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Drug research; Emivirine analogues; HIV-1; HIV-1 - drug effects; Human immunodeficiency virus 1; Non-nucleoside reverse transcriptase inhibitors; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; TNK-651 analogues; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - pharmacology
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200900139

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.