Potent 4-aminopiperidine based antimalarial agents

被引：14

作者：

Brinner, KM

Powles, MA

Schmatz, DM

Ellman, JA ^{[1
]}

机构：

[1] Univ Calif Berkeley, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USA

[2] Merck & Co Inc, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 02期

关键词：

antimalarial; Plasmodium falciparum; multi-drug resistant; metabolism; log D;

D O I：

10.1016/j.bmcl.2004.10.069

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of compounds with potent activity against a multi-drug-resistant strain of Plasmodium falciparum, the causative agent of the deadliest strain of malaria, is described. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their log D, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of compounds 9e and 10d, which showed good potency (IC50 = 75 nM and <60 nM, respectively, against Dd2), acceptable log D values, and reasonable metabolic stability. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：345 / 348

页数：4

共 7 条

[1] Novel and potent anti-malarial agents [J].

Brinner, KM ;

Kim, JM ;

Habashita, H ;

Gluzman, IY ;

Goldberg, DE ;

Ellman, JA .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (11) :3649-3661

[2] Interference with heme binding to histidine-rich protein-2 as an antimalarial strategy [J].

Choi, CYH ;

Schneider, EL ;

Kim, JM ;

Gluzman, IY ;

Goldberg, DE ;

Ellman, JA ;

Marletta, MA .

CHEMISTRY & BIOLOGY, 2002, 9 (08) :881-889

[3] ORDER AND SPECIFICITY OF THE PLASMODIUM-FALCIPARUM HEMOGLOBIN DEGRADATION PATHWAY [J].

GLUZMAN, IY ;

FRANCIS, SE ;

OKSMAN, A ;

SMITH, CE ;

DUFFIN, KL ;

GOLDBERG, DE .

JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (04) :1602-1608

[4]

KROGSTAD DJ, 1993, MECH MICROBIAL DIS, P597

[5] Isoquine and related amodiaquine analogues: A new generation of improved 4-aminoquinoline antimalarials [J].

O'Neill, PM ;

Mukhtar, A ;

Stocks, PA ;

Randle, LE ;

Hindley, S ;

Ward, SA ;

Storr, RC ;

Bickley, JF ;

O'Neil, IA ;

Maggs, JL ;

Hughes, RH ;

Winstanley, PA ;

Bray, PG ;

Park, BK .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (23) :4933-4945

[6] The structure of malaria pigment β-haematin [J].

Pagola, S ;

Stephens, PW ;

Bohle, DS ;

Kosar, AD ;

Madsen, SK .

NATURE, 2000, 404 (6775) :307-310

[7] Chapter 10. New therapies for parasitic infection [J].

Woster, PM .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 36, 2001, 36 :99-108

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