Thiazolopyrimidine inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) from Mycobacterium tuberculosis and Plasmodium falciparum.
A library of 40,000 compounds was screened for inhibitors of 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) protein from Arabidopsis thaliana using a photometric assay. A thiazolopyrimidine derivative resulting from the high-throughput screen was found to inhibit the IspF proteins of Mycobacterium tuberculosis, Plasmodium falciparum, and A. thaliana with IC(50) values in the micromolar range. Synthetic efforts afforded derivatives that inhibit IspF protein from M. tuberculosis and P. falciparum with IC(50) values in the low micromolar range. Several compounds act as weak inhibitors in the P. falciparum red blood cell assay.
Geist
Julie G
JG
Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich, Switzerland.
Lauw
Susan
S
Illarionova
Victoria
V
Illarionov
Boris
B
Fischer
Markus
M
Gräwert
Tobias
T
Rohdich
Felix
F
Eisenreich
Wolfgang
W
Kaiser
Johannes
J
Groll
Michael
M
Scheurer
Christian
C
Wittlin
Sergio
S
Alonso-Gómez
José L
JL
Schweizer
W Bernd
WB
Bacher
Adelbert
A
Diederich
François
F
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017360:Arabidopsis / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011743:Pyrimidines; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D019761:Phosphorus-Oxygen Lyases; C512265:IspF protein, Arabidopsis