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Conformational aspects in the design of inhibitors for serine hydroxymethyltransferase (SHMT): biphenyl, aryl sulfonamide, and aryl sulfone motifs

Schwertz, Geoffrey and Frei, Michelle S. and Witschel, Matthias C. and Rottmann, Matthias and Leartsakulpanich, Ubolsree and Chitnumsub, Penchit and Jaruwat, Aritsara and Ittarat, Wanwipa and Schäfer, Anja and Aponte, Raphael A. and Trapp, Nils and Mark, Kerstin and Chaiyen, Pimchai and Diederich, François. (2017) Conformational aspects in the design of inhibitors for serine hydroxymethyltransferase (SHMT): biphenyl, aryl sulfonamide, and aryl sulfone motifs. Chemistry - A European Journal, 23 (57). pp. 14345-14357.

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Official URL: https://edoc.unibas.ch/63202/

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Abstract

Malaria remains a major threat to mankind due to the perpetual emergence of resistance against marketed drugs. Twenty-one pyrazolopyran-based inhibitors bearing terminal biphenyl, aryl sulfonamide, or aryl sulfone motifs were synthesized and tested towards serine hydroxymethyltransferase (SHMT), a key enzyme of the folate cycle. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target, as well as PfNF54 strains in cell-based assays in the low nanomolar range (18-56 nm). Seven co-crystal structures with P. vivax (Pv) SHMT were solved at 2.2-2.6 Å resolution. We observed an unprecedented influence of the torsion angle of ortho-substituted biphenyl moieties on cell-based efficacy. The peculiar lipophilic character of the sulfonyl moiety was highlighted in the complexes with aryl sulfonamide analogues, which bind in their preferred staggered orientation. The results are discussed within the context of conformational preferences in the ligands.
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 and Schäfer, Anja
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:0947-6539
e-ISSN:1521-3765
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Jul 2018 07:36
Deposited On:03 Jul 2018 07:36

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