Novel reverse thia-analogs of fosmidomycin: Synthesis and antiplasmodial activity.
Lienau C, Gräwert T, Alves Avelar LA, Illarionov B, Held J, Knaab TC, Lungerich B, van Geelen L, Meier D, Geissler S, Cynis H, Riederer U, Buchholz M, Kalscheuer R, Bacher A, Mordmüller B, Fischer M, Kurz T.
Thia analogs of fosmidomycin are potent inhibitors of the non-mevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC, Dxr) of Plasmodium falciparum. Several new thioethers displayed antiplasmodial in vitro activity in the low nanomolar range, without apparent cytotoxic effects in HeLa cells. The (S)-(+)-enantiomer of a typical representative selectively inhibited IspC and the growth of P. falciparum in continuous culture. The inhibitor was stable at pH 7.6 and room temperature, and no racemization was observed under these conditions during a period of up to two days. Oxidation of selected thioethers to sulfones reduced antiplasmodial activity and the inhibitory activity against Escherichia coli, Mycobacterium tuberculosis and P. falciparum IspC orthologs.