Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities

被引：51

作者：

Witschel, Matthias C. ^{[1
]}

Rottmann, Matthias ^{[2
,3
]}

Schwab, Anatol ^{[4
]}

Leartsakulpanich, Ubolsree ^{[5
]}

Chitnumsub, Penchit ^{[5
]}

Seet, Michael ^{[4
]}

Tonazzi, Sandro ^{[4
]}

Schwertz, Geoffrey ^{[4
]}

Stelzer, Frank ^{[1
]}

Mietzner, Thomas ^{[1
]}

McNamara, Case ^{[6
]}

Thater, Frank ^{[1
]}

Freymond, Celine ^{[2
,3
]}

Jaruwat, Aritsara ^{[5
]}

Pinthong, Chatchadaporn ^{[7
,8
]}

Riangrungroj, Pinpunya ^{[5
]}

Oufir, Mouhssin ^{[9
]}

Hamburger, Matthias ^{[9
]}

Maeser, Pascal ^{[2
,3
]}

Sanz-Alonso, Laura M. ^{[10
]}

Charman, Susan ^{[11
]}

Wittlin, Sergio ^{[2
,3
]}

Yuthavong, Yongyuth ^{[5
]}

Chaiyen, Pimchai ^{[7
,8
]}

Diederich, Francois ^{[4
]}

机构：

[1] BASF SE, D-67056 Ludwigshafen, Germany

[2] Swiss Trop & Publ Hlth Inst Swiss TPH, CH-4051 Basel, Switzerland

[3] Univ Basel, CH-4003 Basel, Switzerland

[4] ETH, Organ Chem Lab, CH-8093 Zurich, Switzerland

[5] Natl Ctr Genet Engn & Biotechnol, Khlong Luang 12120, Pathum Thani, Thailand

[6] Calif Inst Biomed Res Calibr, La Jolla, CA 92037 USA

[7] Mahidol Univ, Fac Sci, Dept Biochem, Bangkok 10400, Thailand

[8] Mahidol Univ, Fac Sci, Ctr Excellence Prot Struct & Funct, Bangkok 10400, Thailand

[9] Univ Basel, Dept Pharmaceut Sci, Pharmaceut Biol, CH-4056 Basel, Switzerland

[10] GlaxoSmithKline, DDW, Tres Cantos 28760, Spain

[11] Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 07期

关键词：

ARTEMISININ-RESISTANT MALARIA; IDENTIFICATION; SPECIFICITY; PARASITES; PATHWAY; VIVAX;

D O I：

10.1021/jm501987h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 angstrom resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.

引用

页码：3117 / 3130

页数：14

共 2 条

[1] Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
Schwertz, Geoffrey
Witschel, Matthias C.
Rottmann, Matthias
Leartsakulpanich, Ubolsree
Chitnumsub, Penchit
Jaruwat, Aritsara
Amornwatcharapong, Watcharee
Ittarat, Wanwipa
Schafer, Anja
Aponte, Raphael A.
Trapp, Nils
Chaiyen, Pimchai
Diederich, Francois
CHEMMEDCHEM, 2018, 13 (09) : 931 - 943
[2] Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
Schwertz, Geoffrey
Witschel, Matthias C.
Rottmann, Matthias
Bonnert, Roger
Leartsakulpanich, Ubolsree
Chitnumsub, Penchit
Jaruwat, Aritsara
Ittarat, Wanwipa
Schaefer, Anja
Aponte, Raphael A.
Charman, Susan A.
White, Karen L.
Kundu, Abhijit
Sadhulchan, Surajit
Lloyd, Mel
Freiberg, Gail M.
Srikumaran, Myron
Siggel, Marc
Zwyssig, Adrian
Chaiyen, Pirnchai
Diederich, Francois
JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (12) : 4840 - 4860

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