113778-69-1Relevant articles and documents
Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
Witschel, Matthias C.,Rottmann, Matthias,Schwab, Anatol,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Seet, Michael,Tonazzi, Sandro,Schwertz, Geoffrey,Stelzer, Frank,Mietzner, Thomas,McNamara, Case,Thater, Frank,Freymond, Céline,Jaruwat, Aritsara,Pinthong, Chatchadaporn,Riangrungroj, Pinpunya,Oufir, Mouhssin,Hamburger, Matthias,M?ser, Pascal,Sanz-Alonso, Laura M.,Charman, Susan,Wittlin, Sergio,Yuthavong, Yongyuth,Chaiyen, Pimchai,Diederich, Fran?ois
, p. 3117 - 3130 (2015)
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 ? 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.
ISOINDOLINES AS HDAC INHIBITORS
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Paragraph 00290, (2019/11/12)
The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs), having the formula: (I) wherein Z, X1, X2, Y1, Y2, Y3, L, Z, and R are described herein.
Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Bonnert, Roger,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Charman, Susan A.,White, Karen L.,Kundu, Abhijit,Sadhukhan, Surajit,Lloyd, Mel,Freiberg, Gail M.,Srikumaran, Myron,Siggel, Marc,Zwyssig, Adrian,Chaiyen, Pimchai,Diederich, Fran?ois
supporting information, p. 4840 - 4860 (2017/06/28)
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 ? 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.
