Antimalarial activity of tetrahydro-β-carbolines targeting the ATP binding pocket of the Plasmodium falciparum heat shock 90 protein

被引：13

作者：

Eagon, Scott ^{[1
]}

Hammill, Jared T. ^{[2
]}

Bach, Jordan ^{[1
]}

Everson, Nikalet ^{[3
]}

Sisley, Tyler A. ^{[4
,5
]}

Walls, Michael J. ^{[6
]}

Durham, Sierra ^{[7
]}

Pillai, Dylan R. ^{[8
]}

Falade, Mofolusho O. ^{[2
]}

Rice, Amy L. ^{[2
]}

Kimball, Joshua J. ^{[3
]}

Lazaro, Horacio ^{[3
]}

DiBernardo, Celine ^{[1
]}

Guy, R. Kiplin ^{[2
]}

机构：

[1] Calif Polytech State Univ San Luis Obispo, Dept Chem & Biochem, San Luis Obispo, CA 93407 USA

[2] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY 40508 USA

[3] Promega Biosci, 277 Granada Dr, San Luis Obispo, CA 93401 USA

[4] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[5] Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA

[6] Tauro Univ, Dept Publ Hlth, Vallejo, CA 94592 USA

[7] Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA

[8] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 21期

关键词：

Malaria; Plasmodium falciparum; Tetrahydro-beta-carbolines; Structure activity relationship; Structure based design; DRUG DISCOVERY; RESISTANCE; ACCURACY; HSP90;

D O I：

10.1016/j.bmcl.2020.127502

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of tetrahydro-beta-carboline derivatives of a lead compound known to target the heat shock 90 protein of Plasmodium falciparum were synthesized and assayed for both potency against the parasite and toxicity against a human cell line. Using a rationalized structure based design strategy, a new lead compound with a potency two orders of magnitude greater than the original lead compound was found. Additional modeling of this new lead compound suggests multiple avenues to further increase potency against this target, potentially paving the path for a therapeutic with a mode of action different than any current clinical treatment.

引用

页数：6

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