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Antimalarial inhibitors rargeting serine hydroxymethyltransferase (SHMT) with in vivo efficacy and analysis of their binding mode based on X-ray cocrystal structures

Schwertz, Geoffrey and Witschel, Matthias C. and Rottmann, Matthias and Bonnert, Roger and Leartsakulpanich, Ubolsree and Chitnumsub, Penchit and Jaruwat, Aritsara and Ittarat, Wanwipa and Schäfer, Anja and Aponte, Raphael A. and Charman, Susan A. and White, Karen L. and Kundu, Abhijit and Sadhukhan, Surajit and Lloyd, Mel and Freiberg, Gail M. and Srikumaran, Myron and Siggel, Marc and Zwyssig, Adrian and Chaiyen, Pimchai and Diederich, François. (2017) Antimalarial inhibitors rargeting serine hydroxymethyltransferase (SHMT) with in vivo efficacy and analysis of their binding mode based on X-ray cocrystal structures. Journal of Medicinal Chemistry, 60 (12). pp. 4840-4860.

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Official URL: http://edoc.unibas.ch/55622/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
e-ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 06:58
Deposited On:20 Oct 2017 06:30

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