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.