Synthesis and Biological Evaluation of Novel cYY Analogues targeting Mycobacterium tuberculosis CYP121A1

Safaa Kishk; Kirsty Mclean; Sakshi  Sood; Mohamed Helal; Mohamed Gomaa; Ismail Salama; Samia Mostafa; Luiz Pedro de Carvalho; Andrew Munro; Claire Simons

doi:10.1016/j.bmc.2019.02.051

Synthesis and Biological Evaluation of Novel cYY Analogues targeting Mycobacterium tuberculosis CYP121A1

Safaa Kishk, Kirsty Mclean, Sakshi Sood, Mohamed Helal, Mohamed Gomaa, Ismail Salama, Samia Mostafa, Luiz Pedro de Carvalho, Andrew Munro, Claire Simons

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
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	https://doi.org/10.1016/j.bmc.2019.02.051
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2019.02.051

Cite this

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, 27(8), 1546-1561. Article doi: 10.1016/j.bmc.2019.02.051. Advance online publication. https://doi.org/10.1016/j.bmc.2019.02.051

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title = "Synthesis and Biological Evaluation of Novel cYY Analogues targeting Mycobacterium tuberculosis CYP121A1",

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 twentydifferent 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 theoverproduction 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 halidesor 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). Computationalstudies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.",

keywords = "cytochrome P450, Mycobacterium tuberculosis, CYP121A1, 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives, binding affinity assays, Molecular modeling, Structural biology",

author = "Safaa Kishk and Kirsty Mclean and Sakshi Sood and Mohamed Helal and Mohamed Gomaa and Ismail Salama and Samia Mostafa and {de Carvalho}, {Luiz Pedro} and Andrew Munro and Claire Simons",

year = "2019",

doi = "10.1016/j.bmc.2019.02.051",

language = "English",

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AU - Kishk, Safaa

AU - Mclean, Kirsty

AU - Sood, Sakshi

AU - Helal, Mohamed

AU - Gomaa, Mohamed

AU - Salama, Ismail

AU - Mostafa, Samia

AU - de Carvalho, Luiz Pedro

AU - Munro, Andrew

AU - Simons, Claire

PY - 2019

Y1 - 2019

N2 - 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 twentydifferent 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 theoverproduction 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 halidesor 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). Computationalstudies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.

AB - 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 twentydifferent 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 theoverproduction 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 halidesor 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). Computationalstudies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding.

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KW - Mycobacterium tuberculosis

KW - CYP121A1

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KW - binding affinity assays

KW - Molecular modeling

KW - Structural biology

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DO - 10.1016/j.bmc.2019.02.051

M3 - Article

SN - 0968-0896

VL - 27

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EP - 1561

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 8

M1 - doi: 10.1016/j.bmc.2019.02.051

ER -

Synthesis and Biological Evaluation of Novel cYY Analogues targeting Mycobacterium tuberculosis CYP121A1

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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