非核苷类HIV-1逆转录酶抑制剂：第一部分。作为HEPT类似物的1-烷氧基甲基-5-烷基-6-萘甲基尿嘧啶的合成及构效关系。

Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues.

作者信息

Meng Ge, Chen Fen-Er, De Clercq Erik, Balzarini Jan, Pannecouque Christophe

机构信息

Department of Chemistry, Fudan University, Shanghai, PR China.

出版信息

Chem Pharm Bull (Tokyo). 2003 Jul;51(7):779-89. doi: 10.1248/cpb.51.779.

DOI:10.1248/cpb.51.779

PMID:12843582

Abstract

1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.

摘要

1-烷氧基甲基-5-烷基-6-萘甲基尿嘧啶是新型的1-[(2-羟乙氧基)甲基]-6-(苯硫基)胸腺嘧啶（HEPT）类似物，被合成用于评估其作为选择性强效非核苷类人类免疫缺陷病毒（HIV）-1逆转录酶抑制剂的活性。使用HIV-1感染的MT-4和CEM生物测定法在体外测定这些化合物的抗HIV-1活性。记录并计算EC50、CC50和SI。合适的位置，特别是萘环的1位，在MT-4和CEM细胞测定中均导致活性显著增加。该系列中最重要的化合物，1-乙氧基甲基-5-异丙基-6-(1-萘甲基)胸腺嘧啶8l（IC50 = 17 nM，CC50 = 38332 nM，SI = 2229）和1-苄氧基甲基-5-乙基-6-(1-萘甲基)胸腺嘧啶8n（IC50 = 17 nM，CC50 = 32560 nM，SI = 1889）在体外抗HIV-1细胞测定中比HEPT（EC50 = 7.0 microM，CD50 = 740 microM）的活性显著更高。