Vinylogous amide analogues of diaminopimelic acid (DAP) as inhibitors of enzymes involved in bacterial lysine biosynthesis.
[reaction: see text] Vinylogous amides 5 and 6 have been synthesized from L-propargyl glycine and tested against diaminopimelate (DAP) enzymes involved in bacterial lysine biosynthesis. Both are reversible inhibitors of DAP D-dehydrogenase and DAP epimerase with IC(50) values in the 500 microM range. Compound 5 shows competitive inhibition against the L-dihydrodipicolinate (DHDP) reductase with a K(i) value of 32 microM, which is comparable to the planar dipicolinate 16 (K(i) = 26 microM), the best known inhibitor of the enzyme.
Caplan
J F
JF
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Zheng
R
R
Blanchard
J S
JS
Vederas
J C
JC
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001419:Bacteria / Q000737:chemistry* / Q000378:metabolism; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D050746:Dihydrodipicolinate Reductase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008239:Lysine / Q000096:biosynthesis*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors
D000577:Amides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D003960:Diaminopimelic Acid; D010088:Oxidoreductases; D050746:Dihydrodipicolinate Reductase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000594:Amino Acid Oxidoreductases; C020032:diaminopimelate dehydrogenase; D000591:Amino Acid Isomerases; C042032:diaminopimelate epimerase; D008239:Lysine