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Design and synthesis of imidazole and triazole pyrazoles as mycobacterium tuberculosis CYP121A1 inhibitors

Kishk, Safaa M., McLean, Kirsty J., Sood, Sakshi, Smith, Darren, Evans, Jack W.D., Helal, Mohamed A., Gomaa, Mohamed S., Salama, Ismail, Mostafa, Samia M., de Carvalho, Luiz Pedro S., Levy, Colin W., Munro, Andrew W. and Simons, Claire 2019. Design and synthesis of imidazole and triazole pyrazoles as mycobacterium tuberculosis CYP121A1 inhibitors. ChemistryOpen 8 (7) , pp. 995-1011. 10.1002/open.201900227

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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 Å3, topological polar surface area <40 Å2.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Publisher: Wiley
ISSN: 2191-1363
Date of First Compliant Deposit: 12 August 2019
Date of Acceptance: 19 July 2019
Last Modified: 19 Oct 2019 03:30
URI: http://orca.cardiff.ac.uk/id/eprint/124879

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