Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium

被引:71
作者
Forsch, RA
Queener, SF
Rosowsky, A [1 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[3] Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA
关键词
D O I
10.1016/j.bmcl.2003.12.103
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
2,4-Diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (6) and 2,4-diamino-5-[3',4'-dimethoxy-5'(4-carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 Of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization. (C) 2004 Elsevier Ltd. All rights reserved.
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收藏
页码:1811 / 1815
页数:5
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