Diarylidene-N-Methyl-4-Piperidone and Spirobibenzopyran Curcumin Analogues as Antioxidant and Anti-Inflammatory Pharmacophores

There is a significant need for new small molecule anti-inflammatory compounds. Curcumin, a small molecule natural product from the Turmeric (Curcuma longa) plant, has well-known anti-oxidant properties, resulting from its radical scavenging ability and inhibition of inflammation-associated factors. However, its lack of solubility, instability, and poor bioavailability and biodistribution characteristics are an impediment to its use. To circumvent these issues while retaining curcumin’s biological activity, we synthesized twenty-one diarylidene-N-methyl-4-piperidones (DANMPs), four diheteroarylidene-N-methyl-4-piperidones (DHANMPs), and five spirobibenzopyran (SBP) derivatives. All were screened in terms of anti-oxidant activity via a cell-free 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and for drug-like properties in silico. In the former, some compounds possessed improved radical scavenging behavior versus ascorbic acid, which was used as a benchmark. Conformity to simulated Lipinski’s parameters and Absorption, Distribution, Metabolism, and Excretion (ADME) studies indicated the DANMPs, DHANMPs, and SBPs to be potentially useful compounds. A subset of molecules was investigated in terms of their aqueous solubilities, which were significantly improved compared to that of curcumin. In vitro assessments of the cellular and anti-inflammatory effects of these compounds were conducted using RAW264.7 macrophages. RT-PCR and Griess assays were used to evaluate the presence of inflammatory/activated (M1) markers and production of nitric oxide (NO) species, which are associated with inflammation, respectively. While the compounds did not affect non-stimulated (naïve) macrophages, they did reduce levels of markers and NO to extents similar to or better than curcumin in inflamed cells. Our results indicate that these pharmacophores possess anti-inflammatory properties and can be used as curcumin-substitutes with improved characteristics. Further investigation into their mechanisms of action and potential use in the treatment of inflammatory diseases is merited.