Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido [2,3-d]pyrimidines as dihydrofolate reductase inhibitors

被引：51

作者：

Gangjee, A ^{[1
]}

Adair, O

Queener, SF

机构：

[1] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA

[2] Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2001年 / 9卷 / 11期

关键词：

D O I：

10.1016/S0968-0896(01)00223-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Six 2,4-diaminopyrido[2,3-d]pyrimidines with a 6-methylthio bridge to an aryl group were synthesized and biologically evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). The syntheses of analogues 3-8 were achieved by nucleophilic displacement of 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine 14 with various arylthiols. The alpha -naphthyl analogue 4 showed the highest selectivity ratios of 3.6 and 8.7 against pcDHFR and tgDHFR, respectively, versus rat liver (rl) DHFR. The beta -naphthyl analogue 5 exhibited the. highest potency within the series with an IC50 value against pcDHFR and tgDHFR of 0.17 and 0.09 muM, respectively. Analogue 4 was evaluated for in vitro antimycobacterium activity and was shown to inhibit the growth of Mycobacterium tuberculosis H(37)Rv cells by 58% at a concentration of 6.25 mug/mL. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：2929 / 2935

页数：7

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