10779/crick.11559861.v1 Safaa M Kishk Safaa M Kishk Kirsty J McLean Kirsty J McLean Sakshi Sood Sakshi Sood Darren Smith Darren Smith Jack WD Evans Jack WD Evans 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 Colin W Levy Colin W Levy Andrew W Munro Andrew W Munro Claire Simons Claire Simons Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors. The Francis Crick Institute 2020 Binding affinity Imidazole derivatives X-ray crystallography molecular modelling mycobacterium tuberculosis Carvalho FC001060 0302 Inorganic Chemistry 0305 Organic Chemistry 0306 Physical Chemistry (incl. Structural) 2020-01-09 16:45:23 Journal contribution https://crick.figshare.com/articles/journal_contribution/Design_and_synthesis_of_imidazole_and_triazole_pyrazoles_as_Mycobacterium_tuberculosis_CYP121A1_inhibitors_/11559861 The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 Å3, topological polar surface area <40 Å2.