Braendvang Morten, Gundersen Lise-Lotte
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway.
Bioorg Med Chem. 2007 Nov 15;15(22):7144-65. doi: 10.1016/j.bmc.2007.07.034. Epub 2007 Aug 22.
A number of 6-(2-furyl)-9-(p-methoxybenzyl)purines carrying a variety of substituents in the 2- or 8-position have been synthesized and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. It is demonstrated that sterical hindrance in the purine 8-position reduces activity and that C-8 should be unsubstituted. In the purine 2-position small, hydrophobic substituents are beneficial. The electronic properties of the 2-substituents appear to have only a minor influence on bioactivity. The compounds studied exhibit low toxicity toward mammalian cells (VERO cells) and are essentially inactive toward Staphylococcus aureus and Escherichia coli. The most active and selective antimycobacterial in the series detected to date is the novel 2-methyl-6-furyl-9-(p-methoxybenzyl)purine with MIC=0.20 microg/mL against M. tuberculosis and IC(50) against VERO cells >62.5 microg/mL. Also the novel 2-fluoro analog and the previously known 2-chloro compound, both with MIC=0.39 microg/mL, are highly interesting drug candidates.
已合成了一系列在2-或8-位带有各种取代基的6-(2-呋喃基)-9-(对甲氧基苄基)嘌呤，并测定了它们在体外抑制结核分枝杆菌生长的能力。结果表明，嘌呤8-位的空间位阻会降低活性，且C-8应无取代基。在嘌呤2-位，小的疏水取代基是有益的。2-取代基的电子性质似乎对生物活性只有轻微影响。所研究的化合物对哺乳动物细胞（VERO细胞）毒性低，对金黄色葡萄球菌和大肠杆菌基本无活性。该系列中迄今为止检测到的最具活性和选择性的抗分枝杆菌药物是新型的2-甲基-6-呋喃基-9-(对甲氧基苄基)嘌呤，对结核分枝杆菌的MIC = 0.20μg/mL，对VERO细胞的IC(50)>62.5μg/mL。同样，新型的2-氟类似物和先前已知的2-氯化合物，MIC均为0.39μg/mL，都是非常有吸引力的候选药物。
