Modifications of flexible nonyl chain and nucleobase head group of (+)-erythro-9-(2's-hydroxy-3's-nonyl)adenine [(+)-EHNA] as adenosine deaminase inhibitors

Bioorg Med Chem. 2017 Oct 15;25(20):5799-5819. doi: 10.1016/j.bmc.2017.09.015. Epub 2017 Sep 14.

Abstract

A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5'C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds 7a (Ki: 1.1nM) 7b (Ki: 5.2nM) and 26a (Ki: 5.9nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.

Keywords: ADA; Constrained analogues; Docking; EHNA; Nonyl chain modification; Pharmacokinetics.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacokinetics
  • Adenine / pharmacology
  • Adenosine Deaminase Inhibitors / chemical synthesis
  • Adenosine Deaminase Inhibitors / chemistry*
  • Adenosine Deaminase Inhibitors / pharmacokinetics
  • Adenosine Deaminase Inhibitors / pharmacology
  • Catalytic Domain
  • Enzyme Activation / drug effects
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Adenosine Deaminase Inhibitors
  • 9-(2-hydroxy-3-nonyl)adenine
  • Adenine