Publication: Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
Issued Date
2017-06-22
Resource Type
ISSN
15204804
00222623
00222623
Other identifier(s)
2-s2.0-85021175260
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.60, No.12 (2017), 4840-4860
Suggested Citation
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, François Diederich 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 (2017), 4840-4860. doi:10.1021/acs.jmedchem.7b00008 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/41854
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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
Author(s)
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
François Diederich
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
François Diederich
Abstract
© 2017 American Chemical Society. 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.