TY - JOUR
T1 - Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
AU - Witschel, Matthias C
AU - Rottmann, Matthias
AU - Schwab, Anatol
AU - Leartsakulpanich, Ubolsree
AU - Chitnumsub, Penchit
AU - Seet, Michael
AU - Tonazzi, Sandro
AU - Schwertz, Geoffrey
AU - Stelzer, Frank
AU - Mietzner, Thomas
AU - McNamara, Case
AU - Thater, Frank
AU - Freymond, Celine
AU - Jaruwat, Aritsara
AU - Pinthong, Chatchadaporn
AU - Riangrungroj, Pinpunya
AU - Oufir, Mouhssin
AU - Hamburger, Matthias
AU - Maser, Pascal
AU - Sanz-Alonso, Laura M
AU - Charman, Susan
AU - Wittlin, Sergio
AU - Yuthavong, Yongyuth
AU - Chaiyen, Pimchai
AU - Diederich, Francois
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/pdf/10.1021/jm501987h
U2 - 10.1021/jm501987h
DO - 10.1021/jm501987h
M3 - Article
VL - 58
SP - 3117
EP - 3130
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 7
ER -
