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

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.