Vinylogous amide analogues of diaminopimelic acid (DAP) as inhibitors of enzymes involved in bacterial lysine biosynthesis

Org Lett. 2000 Nov 30;2(24):3857-60. doi: 10.1021/ol000271e.

Abstract

[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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amino Acid Isomerases / antagonists & inhibitors
  • Amino Acid Oxidoreductases / antagonists & inhibitors
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Bacteria / chemistry*
  • Bacteria / metabolism
  • Diaminopimelic Acid / analogs & derivatives*
  • Diaminopimelic Acid / chemical synthesis*
  • Diaminopimelic Acid / chemistry
  • Dihydrodipicolinate Reductase
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Lysine / biosynthesis*
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors*

Substances

  • Amides
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Diaminopimelic Acid
  • Oxidoreductases
  • Dihydrodipicolinate Reductase
  • Oxidoreductases Acting on CH-CH Group Donors
  • Amino Acid Oxidoreductases
  • diaminopimelate dehydrogenase
  • Amino Acid Isomerases
  • diaminopimelate epimerase
  • Lysine