|
|
Acyclic nucleoside bisphosphonates as inhibitors of 6-oxopurine phosphoribosyltransferases: Potential antimalarial and antibacterial agents
Hocková, Dana ; Keough, D. T. ; Špaček, Petr ; Janeba, Zlatko ; Edstein, M. D. ; Chavchich, M. ; Wang, T. H. ; Eng, W. S. ; West, N. P. ; de Jersey, J. ; Guddat, L. W.
Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human, Plasmodium falciparum, P. vivax, Escherichia coli and Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferases (PRTases), key enzymes of the purine salvage pathway. Chemical modifications based on the crystal structures of several inhibitors in complex with human HGPRTase have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaff old. The crystal structures of these inhibitors in complex with human HGPRTase show that they can fill three critical locations in the active site: the binding sites of the purine base, the 5’-phosphate group and pyrophosphate. Prodrugs have been synthesized and have been shown to arrest the growth of P. falciparum in erythrocyte culture. Prodrugs of selected ANPs also inhibit the growth of Mycobacterium tuberculosis in cell-based assays.
|
host ::
RSS.