Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 Praha 6 CZ 16610 Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branišovská 31 České Budějovice CZ 37005 Czech Republic

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane QLD 4072 Australia

The Centre for Microscopy and Microanalysis The University of Queensland Brisbane 4072 Australia

University of Chemical Technology Prague Technická 5 Prague 6 CZ 166 28 Czech Republic

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