Synthesis and anti-inflammatory evaluation of isoxazole and gamma-hydroxy amide analogs of α-santonin as TNF-α and IL-6 inhibitors

A library of novel isoxazole and ϒ-hydroxy amide analogs of α-Santonin was synthesized involving 1, 3-dipolar cycloaddition and ring opening aminolysis. α-Santonin was first converted into α-desmotroposantonin which was further transformed to isoxazoles using click chemistry. In other scheme aminolysis of α-Santonin resulted in the formation of ϒ-hydroxy amide analogs of α-Santonin. All the synthesised compounds, produced out of these two reaction schemes, were evaluated for anti-inflammatory activity. The results revealed that certain analogs possess moderate anti-inflammatory activity. The tested compounds inhibit the release of NO, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells. Several analogs (SNI-5, SNI-6, SNI-8, SNI-9, SNI-12 and SNM-5, SNM-6, SNM-7, SNM-9, SNM-10, SNM-11) displayed better TNF-α and IL-6 inhibition than the parent molecule. Some analogs (SNI-5, SNI-6, SNI-8, SNI-9, SNI-12 and SNM-5, SNM-6) also exhibit potential suppression of LPS triggered nitric oxide generation. All the active analogs were found nontoxic. Two isoxazoles SNI-5 and SNI-6 showed the best TNF-α and IL-6 inhibition. SNI-6 shows maximum effect against IL-6 with ~ 97% inhibition at 10 µM concentration. SNI-5 and SNI-6 may be considered as promising anti-inflammatory molecules. Among hydroxyl amide analogs SNM-12 is the most potent molecule with ~ 98% TNF-α inhibition at 10 µM.