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

Kishk, Safaa M., McLean, Kirsty J., Sood, Sakshi, Helal, Mohamed A., Gomaa, Mohamed S., Salama, Ismail, Mostafa, Samia M., de Carvalho, Luiz Pedro S., Munro, Andrew W. and Simons, Claire 2019. Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1. Bioorganic and Medicinal Chemistry 27 (8) , -. 10.1016/j.bmc.2019.02.051

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Advanced Research Computing @ Cardiff (ARCCA)
Publisher: Elsevier
ISSN: 0968-0896
Date of First Compliant Deposit: 27 February 2019
Date of Acceptance: 27 February 2019
Last Modified: 13 Mar 2020 06:27

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