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 C-C 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.
different genes coding for cytochrome P450s. CYP121A1 catalyzes a C-C 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.
Original language | English |
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Article number | doi: 10.1016/j.bmc.2019.02.051 |
Pages (from-to) | 1546-1561 |
Number of pages | 16 |
Journal | Bioorganic & Medicinal Chemistry |
Volume | 27 |
Issue number | 8 |
Early online date | 27 Feb 2019 |
DOIs | |
Publication status | Published - 2019 |
Keywords
- cytochrome P450
- Mycobacterium tuberculosis
- CYP121A1
- 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives
- binding affinity assays
- Molecular modeling
- Structural biology
Research Beacons, Institutes and Platforms
- Biotechnology