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, which are not found in mammals, function as key enzymes in purine salvage in protozoa. Inhibition of these enzymes may disrupt purine supply and specific 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 additions to the imine 2, and tested as potential nucleoside hydrolase inhibitors. Nucleoside analogues 8, 11, 14, 17, 20, 24-26, 28 exhibit Ki values in the range 0.2-22 microM against two representative isozymes of protozoan nucleoside hydrolases.
Furneaux
R H
RH
Carbohydrate Chemistry, Industrial Research Limited, Lower Hutt, New Zealand.
Schramm
V L
VL
Tyler
P C
PC
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056890:Eukaryota / Q000187:drug effects / Q000201:enzymology; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D009699:N-Glycosyl Hydrolases; C110539:inosine-adenosine-guanosine-preferring nucleoside hydrolase