Transition state analogue inhibitors of protozoan nucleoside hydrolases

Protozoan parasites are unable to synthesize purines de novo and must rely on purine salvage pathways for their requirements. Nucleoside hydrolases, w hich are not found in mammals, function as key enzymes in purine salvage in protozoa. Inhibition of these enzymes may disrupt purine supply and specif ic inhibitors are potential therapeutic agents for the control of protozoan infections. A series of 1,4-dideoxy-1,4-imino-D-ribitols bearing C-bonded aromatic substituents at C-1 have been synthesized, following carbanion add itions to the imine 2, and tested as potential nucleoside hydrolase inhibit ors. Nucleoside analogues 8, 11, 14, 17, 20, 24-26, 28 exhibit K-i values i n the range 0.2-22 mu M against two representative isozymes of protozoan nu cleoside hydrolases. (C) 1999 Elsevier Science Ltd. All rights reserved.