3-(Pyridine-3-ylmethylene)chroman-4-one and tetralone derivatives: synthesis, <i>Mycobacterium tuberculosis</i> CYP121A1 enzyme inhibition and antimycobacterial activity <i>vs</i> drug-sensitive and drug-resistant strains

Abstract

CYP121A1 is a promising cytochrome P450 (CYP) drug target in <i>Mycobacterium tuberculosis (Mtb)</i> owing to its physiological importance in bacterial cell viability. The continuing rise of multidrug resistant (MDR) and extremely drug resistant (XDR) tuberculosis (TB), offers potential therapeutics with a new mechanism of action to add to the multidrug TB regime. A series of 3-(pyridine-3-ylmethylene)chromanone derivatives (5) with 7-O-alkyl/aryl substitutions were explored for CYP121A1 binding and antimycobacterial activity in susceptible and resistant <i>Mtb</i> strains. The 3-(pyridine-3-ylmethylene)chroman-4-one derivatives (5) with the 7-O-(CH₂)₃-phenyl substitution displayed the strongest CYP121A1 binding affinity (<i.>K</i>_D 0.3 to 3.6 μM) compared with the natural substrate (dicyclotyrosine, <i>K</i>_D 16.8 ± 1.0 μM). Improvements observed in binding affinity from 7-O-benzyl to (CH₂)₂-phenyl to (CH₂)₃-phenyl substitutions are supported by computational studies. Minimum inhibitor concentration (MIC) of the alkyoxyaryl substituted chromanones ranged from 1.5–50 μM (0.5–22.5 μg mL⁻¹) against the <i>H37Rv</i> wild type strain (c.f. isoniazid 1.8 μM (0.2 μg mL⁻¹), rifampicin 0.3 μM (0.2 μg mL⁻¹), kanamycin 16.1 μM (7.8 μg mL⁻¹)) with antimycobacterial activity retained against mono-resistant (isoniazid or rifampicin) and MDR (isoniazid and rifampicin) <i>Mtb</i> strains. In contrast, the tetralone derivatives (8) with either the O-(CH₂)₂-phenyl or O-(CH₂)₃-phenyl substitutions showed no binding affinity with CYP121A1, possibly owing to binding further away from the haem and failing to displace the 6th axial water ligand, but the O-(CH₂)₃-phenyl substituted tetralones were the most consistently effective against <i>H37Rv</i> strain with MIC of 3 μM (1.1–1.2 μg mL⁻¹) and retained activity against the mono-resistant and MDR <i>Mtb</i> strains.