Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1

Bioorg Med Chem. 2019 Apr 15;27(8):1546-1561. doi: 10.1016/j.bmc.2019.02.051. Epub 2019 Feb 27.

Abstract

The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a CC crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25 μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KD = 1.6 μM; tBu KD = 1.2 μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.

Keywords: 1,4-Dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives; Binding affinity assays; CYP121A1; Molecular modelling; Mycobacterium tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology*
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Dipeptides
  • Peptides, Cyclic
  • Piperazines
  • cytochrome P-450 CYP12A1 (house fly)
  • cyclo(tyrosyl-tyrosyl)
  • Cytochrome P-450 Enzyme System