Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures

Geoffrey Schwertz, Matthias C Witschel, Matthias Rottmann, Roger Bonnert, Ubolsree Leartsakulpanich, Penchit Chitnumsub, Aritsara Jaruwat, Wanwipa Ittarat, Anja Schäfer, Raphael A. Aponte, Susan A Charman, Karen L White, Abhijit Kundu, Surajit Sadhukhan, Mel Lloyd, Gail M. Freiberg, Myron Srikumaran, Marc Siggel, Adrian Zwyssig, Pimchai Chaiyen & 1 others François Diederich

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

Original languageEnglish
Pages (from-to)4840-4860
Number of pages21
JournalJournal of Medicinal Chemistry
Volume60
Issue number12
DOIs
Publication statusPublished - 22 Jun 2017

Cite this

Schwertz, Geoffrey ; Witschel, Matthias C ; Rottmann, Matthias ; Bonnert, Roger ; Leartsakulpanich, Ubolsree ; Chitnumsub, Penchit ; Jaruwat, Aritsara ; Ittarat, Wanwipa ; Schäfer, Anja ; Aponte, Raphael A. ; Charman, Susan A ; White, Karen L ; Kundu, Abhijit ; Sadhukhan, Surajit ; Lloyd, Mel ; Freiberg, Gail M. ; Srikumaran, Myron ; Siggel, Marc ; Zwyssig, Adrian ; Chaiyen, Pimchai ; Diederich, François. / Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 12. pp. 4840-4860.
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title = "Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures",
abstract = "Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73{\%} of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 {\AA} resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.",
author = "Geoffrey Schwertz and Witschel, {Matthias C} and Matthias Rottmann and Roger Bonnert and Ubolsree Leartsakulpanich and Penchit Chitnumsub and Aritsara Jaruwat and Wanwipa Ittarat and Anja Sch{\"a}fer and Aponte, {Raphael A.} and Charman, {Susan A} and White, {Karen L} and Abhijit Kundu and Surajit Sadhukhan and Mel Lloyd and Freiberg, {Gail M.} and Myron Srikumaran and Marc Siggel and Adrian Zwyssig and Pimchai Chaiyen and Fran{\cc}ois Diederich",
year = "2017",
month = "6",
day = "22",
doi = "10.1021/acs.jmedchem.7b00008",
language = "English",
volume = "60",
pages = "4840--4860",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
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Schwertz, G, Witschel, MC, Rottmann, M, Bonnert, R, Leartsakulpanich, U, Chitnumsub, P, Jaruwat, A, Ittarat, W, Schäfer, A, Aponte, RA, Charman, SA, White, KL, Kundu, A, Sadhukhan, S, Lloyd, M, Freiberg, GM, Srikumaran, M, Siggel, M, Zwyssig, A, Chaiyen, P & Diederich, F 2017, 'Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures' Journal of Medicinal Chemistry, vol. 60, no. 12, pp. 4840-4860. https://doi.org/10.1021/acs.jmedchem.7b00008

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; Schäfer, Anja; Aponte, Raphael A.; Charman, Susan A; White, Karen L; Kundu, Abhijit; Sadhukhan, Surajit; Lloyd, Mel; Freiberg, Gail M.; Srikumaran, Myron; Siggel, Marc; Zwyssig, Adrian; Chaiyen, Pimchai; Diederich, François.

In: Journal of Medicinal Chemistry, Vol. 60, No. 12, 22.06.2017, p. 4840-4860.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures

AU - Schwertz, Geoffrey

AU - Witschel, Matthias C

AU - Rottmann, Matthias

AU - Bonnert, Roger

AU - Leartsakulpanich, Ubolsree

AU - Chitnumsub, Penchit

AU - Jaruwat, Aritsara

AU - Ittarat, Wanwipa

AU - Schäfer, Anja

AU - Aponte, Raphael A.

AU - Charman, Susan A

AU - White, Karen L

AU - Kundu, Abhijit

AU - Sadhukhan, Surajit

AU - Lloyd, Mel

AU - Freiberg, Gail M.

AU - Srikumaran, Myron

AU - Siggel, Marc

AU - Zwyssig, Adrian

AU - Chaiyen, Pimchai

AU - Diederich, François

PY - 2017/6/22

Y1 - 2017/6/22

N2 - Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-Aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

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