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Your search keyword '"Leartsakulpanich U"' showing total 2 results
Start Over Author "Leartsakulpanich U" Publisher american chemical society
2 results on '"Leartsakulpanich U"'

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

Author

Schwertz G, Witschel MC, Rottmann M, Bonnert R, Leartsakulpanich U, Chitnumsub P, Jaruwat A, Ittarat W, Schäfer A, Aponte RA, Charman SA, White KL, Kundu A, Sadhukhan S, Lloyd M, Freiberg GM, Srikumaran M, Siggel M, Zwyssig A, Chaiyen P, and Diederich F

Subjects
Animals, Antimalarials chemistry, Arabidopsis Proteins antagonists & inhibitors, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Cysteine chemistry, Drug Stability, Enzyme Inhibitors metabolism, Glycine Hydroxymethyltransferase metabolism, Half-Life, Ligands, Malaria, Falciparum drug therapy, Mice, SCID, Plasmodium falciparum drug effects, Plasmodium falciparum enzymology, Plasmodium falciparum pathogenicity, Plasmodium vivax enzymology, Protein Conformation, Rats, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes pharmacology, Antimalarials pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycine Hydroxymethyltransferase antagonists & inhibitors
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 (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 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.

Published
2017
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2. Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities.

Author

Witschel MC, Rottmann M, Schwab A, Leartsakulpanich U, Chitnumsub P, Seet M, Tonazzi S, Schwertz G, Stelzer F, Mietzner T, McNamara C, Thater F, Freymond C, Jaruwat A, Pinthong C, Riangrungroj P, Oufir M, Hamburger M, Mäser P, Sanz-Alonso LM, Charman S, Wittlin S, Yuthavong Y, Chaiyen P, and Diederich F

Subjects
Administration, Oral, Animals, Antimalarials administration & dosage, Antimalarials pharmacokinetics, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Drug Evaluation, Preclinical methods, Drug Resistance drug effects, Enzyme Inhibitors chemical synthesis, Female, Glycine Hydroxymethyltransferase chemistry, Glycine Hydroxymethyltransferase metabolism, Hep G2 Cells drug effects, Humans, Liver metabolism, Liver parasitology, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Mice, Inbred Strains, Mice, SCID, Microsomes, Liver drug effects, Organisms, Genetically Modified, Plasmodium berghei drug effects, Plasmodium berghei pathogenicity, Plasmodium falciparum enzymology, Plasmodium falciparum pathogenicity, Plasmodium vivax enzymology, Plasmodium vivax pathogenicity, Pyrazoles chemistry, Rats, Antimalarials chemistry, Antimalarials pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycine Hydroxymethyltransferase antagonists & inhibitors, Plasmodium falciparum drug effects, Plasmodium vivax drug effects
Abstract

Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.

Published
2015
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