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

TL;DR

This study explores new compounds that inhibit a key enzyme in tuberculosis bacteria and show effectiveness against drug-resistant strains.

Contribution

The paper introduces new chromanone and tetralone derivatives with strong antimycobacterial activity against drug-resistant TB strains.

Findings

Chromanone derivatives with 7-O-(CH2)3-phenyl substitution showed strong CYP121A1 binding affinity.

Tetralone derivatives with O-(CH2)3-phenyl substitution were effective against drug-resistant Mtb strains.

Both compound types retained activity against mono-resistant and multidrug-resistant TB 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 (KD 0.3 to 3.6 μM) compared with the natural substrate (dicyclotyrosine, KD 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.

Chromanone derivatives displayed strong CYP121A1 binding affinity while the tetralone derivatives were very effective antimycobacterial activity against multidrug resistant Mtb.

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