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

作者：Schwertz Geoffrey; Witschel Matthias C; Rottmann Matthias; Bonnert Roger; Leartsakulpanich Ubolsree; Chitnumsub Penchit; Jaruwat Aritsara; Ittarat Wanwipa; Schaefer Anja; Aponte Raphael A; Charman Susan A; White Karen L; Kundu Abhijit; Sadhulchan Surajit; Lloyd Mel; Freiberg Gail M; Srikumaran Myron; Siggel Marc; Zwyssig Adrian; Chaiyen Pirnchai; Diederich Francois

来源：Journal of Medicinal Chemistry, 2017, 60(12): 4840-4860.

DOI：10.1021/acs.jmedchem.7b00008

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 (t(1/2) > 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 angstrom 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.

• 出版日期2017-6-22