Maruenda H, Johnson F
Chemistry Department, State University of New York at Stony Brook 11794-3400, USA.
J Med Chem. 1995 Jun 9;38(12):2145-51. doi: 10.1021/jm00012a014.
A variety of N1-substituted pyrimido[5,4-f]benzo[1,4]thiazepines, 5, designed as conformationally constrained analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymidine HEPT (1), were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The preparation of these compounds was carried out based on a Mannich-type cyclization of 6-[(2-aminophenyl)thio]uracils followed by alkylation at N1 by a one-pot Vorbruggen reaction. The pyrimidobenzothiazepines were developed to give molecules with IC50 values in the micromolar range, as exemplified by [[(2-ethoxyethyl)oxy]methyl]-pyrimido[5,4- f]benzo[1,4]thiazepine, 25, (IC50 = 0.64 microM), the most active compound of this series. The structural and electronic features of this novel class of HIV-1 RT inhibitors are presented and compared with those of HEPT (1), TIBO (2), and nevirapine (3).
设计了多种N1-取代的嘧啶并[5,4-f]苯并[1,4]硫氮杂䓬（5），作为1-[(2-羟基乙氧基)甲基]-6-(苯硫基)胸苷HEPT（1）的构象受限类似物进行合成，并评估其对1型人类免疫缺陷病毒（HIV-1）逆转录酶（RT）的抑制作用。这些化合物的制备基于6-[(2-氨基苯基)硫基]尿嘧啶的曼尼希型环化反应，随后通过一锅法Vorbruggen反应在N1处进行烷基化。开发嘧啶并苯并硫氮杂䓬是为了得到IC50值在微摩尔范围内的分子，例如[[(2-乙氧基乙基)氧基]甲基]-嘧啶并[5,4-f]苯并[1,4]硫氮杂䓬（25）（IC50 = 0.64微摩尔），该系列中活性最高的化合物。本文介绍了这类新型HIV-1 RT抑制剂的结构和电子特征，并与HEPT（1）、TIBO（2）和奈韦拉平（3）的结构和电子特征进行了比较。
