Aly Youssef L, Pedersen Erik B, La Colla Paolo, Loddo Roberta
Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark.
Arch Pharm (Weinheim). 2007 May;340(5):225-35. doi: 10.1002/ardp.200600163.
Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding analogues 10a-d with a 3-trimethylsilylalkynylbenzyl substituent and their desilylated analogues 11a-d. However, they all showed activity against HIV-1 wild type in the range of more than 10fold lower than the one of MKC-442. Moderate activity against Y181C and Y181C + K103N mutated strains was also observed and, in some cases, they were marginally better than those found for MKC-442. A few amino-DABO and S-DABO analogues were also synthesized but they were found to be inactive against HIV.
报道了一系列6-(3-炔基苄基)取代的MKC-442（6-苄基-1-(乙氧基甲基)-5-异丙基尿嘧啶）类似物的合成及其抗病毒活性，MKC-442是一种高效抗HIV药物。假定3-炔基能使取代苄基更好地与逆转录酶（RT）堆积，据信这会提高对HIV-1的抗病毒活性。溴代衍生物，即5-烷基-6-(3-溴苄基)-1-乙氧基甲基衍生物7a、b和5-烷基-6-(3-溴苄基)-1-烯丙氧基甲基衍生物9a、b，对HIV的活性与其相应的具有3-三甲基硅基炔基苄基取代基的类似物10a-d及其去硅基类似物11a-d处于同一水平。然而，它们对HIV-1野生型的活性均比MKC-442低10倍以上。还观察到它们对Y181C和Y181C + K103N突变株有中等活性，在某些情况下，它们略优于MKC-442。还合成了一些氨基-DABO和S-DABO类似物，但发现它们对HIV无活性。
