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

Safaa M. Kishk, Kirsty J. McLean, Sakshi Sood, Mohamed A. Helal, Mohamed S. Gomaa, Ismail Salama, Samia M. Mostafa, Luiz Pedro S. de Carvalho, Andrew W. Munro, Claire Simons

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 ( i Pr K D = 1.6 μM; t Bu K D = 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
Pages (from-to)1546-1561
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number8
Early online date27 Feb 2019
DOIs
Publication statusPublished - 15 Apr 2019
Externally publishedYes

Fingerprint Dive into the research topics of 'Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1'. Together they form a unique fingerprint.

  • Cite this

    Kishk, S. M., McLean, K. J., Sood, S., Helal, M. A., Gomaa, M. S., Salama, I., Mostafa, S. M., de Carvalho, L. P. S., Munro, A. W., & Simons, C. (2019). Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1. Bioorganic and Medicinal Chemistry, 27(8), 1546-1561. https://doi.org/10.1016/j.bmc.2019.02.051