Azole chroman-4-one, tetralone and chromen-4-one derivatives: synthesis, Mycobacterium tuberculosis CYP121A1 enzyme inhibition and antimycobacterial activity

7902 triple auxotrophic drug susceptible strain (MIC 6g 2.6 μM, 1 μg/mL; 6h 2.5 μM. 1 μg/mL) comparable with ethambutol and ethionamide. Importantly, the choman-4-one and tetralone derivatives all retained antimycobacterial activity against isoniazid (INH), rifampicin (RIF) and INH + RIF resistant strains. Tetralone derivative 6h and chromen-4-one 12c displayed mycobacteriostatic properties and both compounds displayed favourable SI values in A459 cells and macrophages with the tetralone 6h showing an improved therapeutic window with SI > 10. Type II direct CYP121A1 binding was generally supported by computational studies with all compounds near the haem. Generally, correlation was observed between binding affinity and antimycobacterial activity. The image compares two chemical compounds, labeled 6h and 12c, with their molecular structures and binding affinities to Mtb CYP121A1 enzyme. Compound 6h has a dissociation constant of 0.22 micromolar, while 12c has 0.52 micromolar. Below each compound, a table lists minimum inhibitory concentrations (MIC) against different Mycobacterium tuberculosis strains. For 6h, MIC values are 6 micromolar for wild type H37Rv, 2.5 micromolar for drug sensitive mc27902, and 2.5 micromolar for multidrug resistant mc8250. For 12c, MIC values are higher: 25 micromolar for wild type H37Rv, 8.5 micromolar for drug sensitive mc27902, and 6.5 micromolar for multidrug resistant mc8250. The data show that compound 6h has lower MIC values across all strains compared to 12c.