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

Abstract

CYP121A1 is a promising cytochrome P450 (CYP) drug target in Mycobacterium tuberculosis (Mtb) 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 Mtb 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 (K_D 0.3 to 3.6 μM) compared with the natural substrate (dicyclotyrosine, K_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 H37Rv 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) Mtb 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 H37Rv strain with MIC of 3 μM (1.1–1.2 μg mL⁻¹) and retained activity against the mono-resistant and MDR Mtb strains.