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 journalArticlepeer-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 languageEnglish
    Article numberdoi: 10.1016/j.bmc.2019.02.051
    Pages (from-to)1546-1561
    Number of pages16
    JournalBioorganic & Medicinal Chemistry
    Volume27
    Issue number8
    Early online date27 Feb 2019
    DOIs
    Publication statusPublished - 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

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