Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities

Matthias C Witschel, Matthias Rottmann, Anatol Schwab, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Michael Seet, Sandro Tonazzi, Geoffrey Schwertz, Frank Stelzer, Thomas Mietzner, Case McNamara, Frank Thater, Celine Freymond, Aritsara Jaruwat, Chatchadaporn Pinthong, Pinpunya Riangrungroj, Mouhssin Oufir, Matthias Hamburger, Pascal Maser, Laura M Sanz-Alonso & 5 others Susan Charman, Sergio Wittlin, Yongyuth Yuthavong, Pimchai Chaiyen, Francois Diederich

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 Å 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.
Original languageEnglish
Pages (from-to)3117-3130
Number of pages14
JournalJournal of Medicinal Chemistry
Volume58
Issue number7
DOIs
Publication statusPublished - 2015

Cite this

Witschel, Matthias C ; Rottmann, Matthias ; Schwab, Anatol ; Leartsakulpanich, Ubolsree ; Chitnumsub, Penchit ; Seet, Michael ; Tonazzi, Sandro ; Schwertz, Geoffrey ; Stelzer, Frank ; Mietzner, Thomas ; McNamara, Case ; Thater, Frank ; Freymond, Celine ; Jaruwat, Aritsara ; Pinthong, Chatchadaporn ; Riangrungroj, Pinpunya ; Oufir, Mouhssin ; Hamburger, Matthias ; Maser, Pascal ; Sanz-Alonso, Laura M ; Charman, Susan ; Wittlin, Sergio ; Yuthavong, Yongyuth ; Chaiyen, Pimchai ; Diederich, Francois. / Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 7. pp. 3117-3130.
@article{7bfe2e0ca8a94feaa8887f641d1dca0a,
title = "Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities",
abstract = "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 {\AA} 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.",
author = "Witschel, {Matthias C} and Matthias Rottmann and Anatol Schwab and Ubolsree Leartsakulpanich and Penchit Chitnumsub and Michael Seet and Sandro Tonazzi and Geoffrey Schwertz and Frank Stelzer and Thomas Mietzner and Case McNamara and Frank Thater and Celine Freymond and Aritsara Jaruwat and Chatchadaporn Pinthong and Pinpunya Riangrungroj and Mouhssin Oufir and Matthias Hamburger and Pascal Maser and Sanz-Alonso, {Laura M} and Susan Charman and Sergio Wittlin and Yongyuth Yuthavong and Pimchai Chaiyen and Francois Diederich",
year = "2015",
doi = "10.1021/jm501987h",
language = "English",
volume = "58",
pages = "3117--3130",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "7",

}

Witschel, MC, Rottmann, M, Schwab, A, Leartsakulpanich, U, Chitnumsub, P, Seet, M, Tonazzi, S, Schwertz, G, Stelzer, F, Mietzner, T, McNamara, C, Thater, F, Freymond, C, Jaruwat, A, Pinthong, C, Riangrungroj, P, Oufir, M, Hamburger, M, Maser, P, Sanz-Alonso, LM, Charman, S, Wittlin, S, Yuthavong, Y, Chaiyen, P & Diederich, F 2015, 'Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities' Journal of Medicinal Chemistry, vol. 58, no. 7, pp. 3117-3130. https://doi.org/10.1021/jm501987h

Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities. / Witschel, Matthias C; Rottmann, Matthias; Schwab, Anatol; Leartsakulpanich, Ubolsree; Chitnumsub, Penchit; Seet, Michael; Tonazzi, Sandro; Schwertz, Geoffrey; Stelzer, Frank; Mietzner, Thomas; McNamara, Case; Thater, Frank; Freymond, Celine; Jaruwat, Aritsara; Pinthong, Chatchadaporn; Riangrungroj, Pinpunya; Oufir, Mouhssin; Hamburger, Matthias; Maser, Pascal; Sanz-Alonso, Laura M; Charman, Susan; Wittlin, Sergio; Yuthavong, Yongyuth; Chaiyen, Pimchai; Diederich, Francois.

In: Journal of Medicinal Chemistry, Vol. 58, No. 7, 2015, p. 3117-3130.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities

AU - Witschel, Matthias C

AU - Rottmann, Matthias

AU - Schwab, Anatol

AU - Leartsakulpanich, Ubolsree

AU - Chitnumsub, Penchit

AU - Seet, Michael

AU - Tonazzi, Sandro

AU - Schwertz, Geoffrey

AU - Stelzer, Frank

AU - Mietzner, Thomas

AU - McNamara, Case

AU - Thater, Frank

AU - Freymond, Celine

AU - Jaruwat, Aritsara

AU - Pinthong, Chatchadaporn

AU - Riangrungroj, Pinpunya

AU - Oufir, Mouhssin

AU - Hamburger, Matthias

AU - Maser, Pascal

AU - Sanz-Alonso, Laura M

AU - Charman, Susan

AU - Wittlin, Sergio

AU - Yuthavong, Yongyuth

AU - Chaiyen, Pimchai

AU - Diederich, Francois

PY - 2015

Y1 - 2015

N2 - 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 Å 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.

AB - 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 Å 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.

UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/pdf/10.1021/jm501987h

U2 - 10.1021/jm501987h

DO - 10.1021/jm501987h

M3 - Article

VL - 58

SP - 3117

EP - 3130

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -