A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7-14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58-6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 166 10 Prague 6 Czech Republic

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

Institute of Parasitology Biology Centre Czech Academy of Sciences Branišovská 31 České Budějovice 37005 Czech Republic; Faculty of Science University of South Bohemia Branišovská 31 České Budějovice 37005 Czech Republic

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