Novel adenosine-derived inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase

J Antibiot (Tokyo). 2019 Dec;72(12):934-942. doi: 10.1038/s41429-019-0199-3. Epub 2019 Jul 12.

Abstract

We have found cyclophane-type adenosine derivatives having p-quinone amide moieties (1 and 2) as weak inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) from the Hokkaido University Chemical Library via the luciferase-based high-throughput screening. To obtain more potent inhibitors, we synthesized four new derivatives free from cyclophane rings (3-6). The N-H derivatives 3 and 5 showed more potent activities (24.4 and 11.1 μM, respectively) in the presence of dithiothreitol (DTT), whereas the N-methyl derivative 4 indicated more potent activity (2.1 μM) without DTT. Conformational analysis of compounds 3 and 4 suggested that N-H amide 3 binds to IMP-binding site in the DTT mediated manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / pharmacology
  • Binding Sites
  • Cryptosporidium parvum / enzymology*
  • Dithiothreitol / chemistry
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors*
  • IMP Dehydrogenase / genetics
  • IMP Dehydrogenase / metabolism
  • Structure-Activity Relationship

Substances

  • Antiparasitic Agents
  • Enzyme Inhibitors
  • IMP Dehydrogenase
  • Dithiothreitol