The design, synthesis, and anti-inflammatory evaluation of a drug-like library based on the natural product valerenic acid

  • Bioorg Med Chem Lett. 2017 Jul 15;27(14):3185-3189. doi: 10.1016/j.bmcl.2017.05.021.
Folake A Egbewande  1 ,  Niclas Nilsson  2 ,  Jonathan M White  3 ,  Mark J Coster  1 ,  Rohan A Davis  4
Affiliations
  • 1. Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
  • 2. LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
  • 3. School of Chemistry and Bio21 Institute, The University of Melbourne, VIC 3010, Australia.
  • 4. Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia. Electronic address: [email protected].
PMID: 28558967 DOI: 10.1016/j.bmcl.2017.05.021
Abstract

The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8-8.3μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release.

Keywords
Anti-inflammatory; Drug design; Library; Parallel synthesis; Scaffold; Valerenic acid.