Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitorsCitation formats

  • External authors:
  • Safaa Kishk
  • Kirsty Mclean
  • Sakshi Sood
  • Darren Smith
  • Jack Evans
  • Mohamed Helal
  • Mohamed Gomaa
  • Ismail Salama
  • Samia Mostafa
  • Luiz Pedro de Carvalho
  • Claire Simons

Standard

Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors. / Kishk, Safaa; Mclean, Kirsty; Sood, Sakshi; Smith, Darren; Evans, Jack; Helal, Mohamed; Gomaa, Mohamed; Salama, Ismail; Mostafa, Samia; de Carvalho, Luiz Pedro; Levy, Colin; Munro, Andrew; Simons, Claire.

In: ChemistryOpen, Vol. 8, No. 7, doi: 10.1002/open.201900227, 2019, p. 995-1011.

Research output: Contribution to journalArticle

Harvard

Kishk, S, Mclean, K, Sood, S, Smith, D, Evans, J, Helal, M, Gomaa, M, Salama, I, Mostafa, S, de Carvalho, LP, Levy, C, Munro, A & Simons, C 2019, 'Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors', ChemistryOpen, vol. 8, no. 7, doi: 10.1002/open.201900227, pp. 995-1011. https://doi.org/10.1002/open.201900227

APA

Kishk, S., Mclean, K., Sood, S., Smith, D., Evans, J., Helal, M., Gomaa, M., Salama, I., Mostafa, S., de Carvalho, L. P., Levy, C., Munro, A., & Simons, C. (2019). Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors. ChemistryOpen, 8(7), 995-1011. [doi: 10.1002/open.201900227]. https://doi.org/10.1002/open.201900227

Vancouver

Kishk S, Mclean K, Sood S, Smith D, Evans J, Helal M et al. Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors. ChemistryOpen. 2019;8(7):995-1011. doi: 10.1002/open.201900227. https://doi.org/10.1002/open.201900227

Author

Kishk, Safaa ; Mclean, Kirsty ; Sood, Sakshi ; Smith, Darren ; Evans, Jack ; Helal, Mohamed ; Gomaa, Mohamed ; Salama, Ismail ; Mostafa, Samia ; de Carvalho, Luiz Pedro ; Levy, Colin ; Munro, Andrew ; Simons, Claire. / Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors. In: ChemistryOpen. 2019 ; Vol. 8, No. 7. pp. 995-1011.

Bibtex

@article{e2ca0ae233ba4f59baf36feced74c342,
title = "Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors",
abstract = "The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 {\AA}3, topological polar surface area <40 {\AA}2.",
keywords = "cytochrome P450, CYP121A1, Mycobacterium tuberculosis, enzyme inhibitors, heme protein, enzyme assays",
author = "Safaa Kishk and Kirsty Mclean and Sakshi Sood and Darren Smith and Jack Evans and Mohamed Helal and Mohamed Gomaa and Ismail Salama and Samia Mostafa and {de Carvalho}, {Luiz Pedro} and Colin Levy and Andrew Munro and Claire Simons",
year = "2019",
doi = "10.1002/open.201900227",
language = "English",
volume = "8",
pages = "995--1011",
journal = "ChemistryOpen",
issn = "2191-1363",
publisher = "John Wiley & Sons Ltd",
number = "7",

}

RIS

TY - JOUR

T1 - Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors

AU - Kishk, Safaa

AU - Mclean, Kirsty

AU - Sood, Sakshi

AU - Smith, Darren

AU - Evans, Jack

AU - Helal, Mohamed

AU - Gomaa, Mohamed

AU - Salama, Ismail

AU - Mostafa, Samia

AU - de Carvalho, Luiz Pedro

AU - Levy, Colin

AU - Munro, Andrew

AU - Simons, Claire

PY - 2019

Y1 - 2019

N2 - The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 Å3, topological polar surface area <40 Å2.

AB - The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 Å3, topological polar surface area <40 Å2.

KW - cytochrome P450

KW - CYP121A1

KW - Mycobacterium tuberculosis

KW - enzyme inhibitors

KW - heme protein

KW - enzyme assays

U2 - 10.1002/open.201900227

DO - 10.1002/open.201900227

M3 - Article

VL - 8

SP - 995

EP - 1011

JO - ChemistryOpen

JF - ChemistryOpen

SN - 2191-1363

IS - 7

M1 - doi: 10.1002/open.201900227

ER -