Mona A Abdullaziz, Sana Takada, Boris Illarionov, Lais Pessanha de Carvalho, Yasumitsu Sakamoto, Stefan Höfmann, Talea Knak, Anna-Lene Kiffe-Delf, Flaminia Mazzone, Klaus Pfeffer, Rainer Kalscheuer, Adelbert Bacher, Jana Held, Markus Fischer, Nobutada Tanaka, Thomas Kurz
Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum . Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar Pf DXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N -phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N -terminal domain...
April 22, 2024: ACS Infectious Diseases