Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1.
Antitubercular Agents
/ chemical synthesis
Cytochrome P-450 Enzyme Inhibitors
/ chemical synthesis
Cytochrome P-450 Enzyme System
/ chemistry
Dipeptides
/ chemical synthesis
Drug Design
Humans
Molecular Docking Simulation
Mycobacterium tuberculosis
/ drug effects
Peptides, Cyclic
/ chemical synthesis
Piperazines
/ chemical synthesis
Tuberculosis
/ drug therapy
1,4-Dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives
Binding affinity assays
CYP121A1
Molecular modelling
Mycobacterium tuberculosis
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 04 2019
15 04 2019
Historique:
received:
04
01
2019
revised:
20
02
2019
accepted:
25
02
2019
pubmed:
7
3
2019
medline:
18
2
2020
entrez:
7
3
2019
Statut:
ppublish
Résumé
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 (
Identifiants
pubmed: 30837169
pii: S0968-0896(19)30024-0
doi: 10.1016/j.bmc.2019.02.051
pmc: PMC7049898
pii:
doi:
Substances chimiques
Antitubercular Agents
0
Cytochrome P-450 Enzyme Inhibitors
0
Dipeptides
0
Peptides, Cyclic
0
Piperazines
0
cytochrome P-450 CYP12A1 (house fly)
0
cyclo(tyrosyl-tyrosyl)
5625-40-1
Cytochrome P-450 Enzyme System
9035-51-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1546-1561Subventions
Organisme : Arthritis Research UK
ID : FC001060
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R009961/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 104785/B/14/Z
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001060
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001060
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I019227/1
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
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