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

Autor: Samia M. Mostafa, Ismail Salama, Mohamed Gomaa, Kirsty J. McLean, Mohamed A. Helal, Safaa M. Kishk, Claire Simons, Luiz Pedro S. de Carvalho, Sakshi Sood, Andrew W. Munro
Rok vydání: 2019
Předmět:
Cytochrome
Molecular model
cytochrome P450
medicine.drug_class
Stereochemistry
Clinical Biochemistry
Antitubercular Agents
Molecular modeling
Pharmaceutical Science
1
4-Dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives
Antimycobacterial
01 natural sciences
Biochemistry
Peptides
Cyclic
Piperazines
Article
Mycobacterium tuberculosis
Cytochrome P-450 Enzyme System
Drug Discovery
medicine
CYP121A1
Cytochrome P-450 Enzyme Inhibitors
Humans
Tuberculosis
Molecular Biology
Gene
1
4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives
binding affinity assays
ComputingMethodologies_COMPUTERGRAPHICS
biology
010405 organic chemistry
Chemistry
Organic Chemistry
Cytochrome P450
Active site
Dipeptides
biology.organism_classification
0104 chemical sciences
3. Good health
Multiple drug resistance
Molecular Docking Simulation
Binding affinity assays
010404 medicinal & biomolecular chemistry
Drug Design
biology.protein
Molecular Medicine
Molecular modelling
Structural biology
Zdroj: Bioorganic & Medicinal Chemistry
Kishk, S, Mclean, K, Sood, S, Helal, M, Gomaa, M, Salama, I, Mostafa, S, de Carvalho, L P, Munro, A & Simons, C 2019, ' Synthesis and Biological Evaluation of Novel cYY Analogues targeting Mycobacterium tuberculosis CYP121A1 ', Bioorganic & Medicinal Chemistry, vol. 27, no. 8, doi: 10.1016/j.bmc.2019.02.051, pp. 1546-1561 . https://doi.org/10.1016/j.bmc.2019.02.051
ISSN: 1464-3391
0968-0896
DOI: 10.1016/j.bmc.2019.02.051
Popis: Graphical 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.
Databáze: OpenAIRE
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