10779/crick.11371590.v1
Safaa M Kishk
Safaa M
Kishk
Kirsty J McLean
Kirsty J
McLean
Sakshi Sood
Sakshi
Sood
Mohamed A Helal
Mohamed A
Helal
Mohamed S Gomaa
Mohamed S
Gomaa
Ismail Salama
Ismail
Salama
Samia M Mostafa
Samia M
Mostafa
Luiz Pedro S de Carvalho
Luiz Pedro S
de Carvalho
Andrew W Munro
Andrew W
Munro
Claire Simons
Claire
Simons
Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1
The Francis Crick Institute
2019
1,4-Dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives
Binding affinity assays
CYP121A1
Molecular modelling
Mycobacterium tuberculosis
Carvalho FC001060
Medicinal & Biomolecular Chemistry
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
0305 Organic Chemistry
2019-12-16 17:40:58
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Synthesis_and_biological_evaluation_of_novel_cYY_analogues_targeting_Mycobacterium_tuberculosis_CYP121A1/11371590
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 CC 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.