Synthesis and antimycobacterial activity of highly functionalized tetrahydro-4(1H)-pyridinones

A series of 35 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones, 2e,3e,5e,6e-tetraaryltetrahydro-4(1H)-pyridinones and their N-nitroso and N-cyano analogs have been prepared. All these 35 compounds obtained were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among them, the N-nitrosopyridinones are found to be more active against MTB than the corresponding N-CN analogs, which, in turn, were slightly more active than NH analogs. In particular, the N-nitroso compounds, 3d, 4b and 4e with halogen-bearing phenyl rings at 2,6-positions showed maximum activity with MIC values of 3.97, 3.11 and 3.11 μM, being more efficacious than the first line anti-TB drugs, ciprofloxacin, ethambutol and pyrazinamide. A general trend has also been discerned in all the three classes of NH, N-CN and N-NO compounds, in each of which those bearing four aryl rings display higher activity than that having three analogously substituted aryl rings disclosing that lipophilicity could be an important factor underlying antimycobacterial activity.