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

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

  • J Med Chem. 2017 Jun 22;60(12):4840-4860. doi: 10.1021/acs.jmedchem.7b00008.
Geoffrey Schwertz 1,  Matthias C Witschel 2,  Matthias Rottmann 3 4,  Roger Bonnert 5,  Ubolsree Leartsakulpanich 6,  Penchit Chitnumsub 6,  Aritsara Jaruwat 6,  Wanwipa Ittarat 6,  Anja Schäfer 3 4,  Raphael A Aponte 2,  Susan A Charman 7,  Karen L White 7,  Abhijit Kundu 8,  Surajit Sadhukhan 8,  Mel Lloyd 9,  Gail M Freiberg 10,  Myron Srikumaran 10,  Marc Siggel 1,  Adrian Zwyssig 1,  Pimchai Chaiyen 11,  François Diederich 1
Affiliations

Affiliations

  • 1 Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.
  • 2 BASF SE , Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
  • 3 Swiss Tropical and Public Health Institute (SwissTPH) , Socinstrasse 57, 4051 Basel, Switzerland.
  • 4 Universität Basel , Petersplatz 1, 4003 Basel, Switzerland.
  • 5 Medicines for Malaria Venture , Route de Pré-Bois 20, CH-1215 Geneva, Switzerland.
  • 6 National Center for Genetic Engineering and Biotechnology , 113 Thailand Science Park, Phahonyothin Road, Pathumthni 12120, Thailand.
  • 7 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 8 TCG Lifesciences Private Limited , Block BN, Plot 7, Saltlake Electronics Complex, Sector V, Kolkata 700091, West Bengal India.
  • 9 Covance Laboratories Ltd. , Otley Road, Harrogate HG3 1PY, United Kingdom.
  • 10 Molecular Characterization, Department R4AE, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6217, United States.
  • 11 Department of Biochemistry and Center for Excellence in Protein and Enzyme Technology, Faculty of Science Mahidol University , 272 Rama VI Road, Bangkok 10400, Thailand.
PMID: 28537728 DOI: 10.1021/acs.jmedchem.7b00008
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.

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