Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors

• DOI: 10.1002/open.201900227
• Publication Date: 2019-07-23T07:45:18Z
• Authors: Safaa M. Kishk; Kirsty J. McLean; Sakshi Sood; Darren Smith; Jack W.D. Evans; Mohamed A. Helal; Mohamed S. Gomaa; Ismail Salama; Samia M. Mostafa; Luiz Pedro S. de ...; Colin W. Levy; Andrew W. Munro; Claire Simons
• Keywords: 0301 basic medicine; cytochrome P450; enzyme inhibitors; Infectious Disease; Biochemistry & Proteomics; 03 medical and health sciences; Ecology,Evolution & Ethology; ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology; name=Manchester Institute of Biotechnology; CYP121A1; enzyme assays; QD1-999; mycobacterium tuberculosis; X-ray crystallography; Computational & Systems Biology; ResearchInstitutes_Networks_Beacons/03/05; name=Biotechnology; Mycobacterium tuberculosis; Full Papers; molecular modelling; 3. Good health; Imidazole derivatives; ResearchInstitutes_Networks_Beacons/02/06; name=Manchester Energy; Chemistry; Binding affinity; Metabolism; heme protein; Genetics & Genomics; Structural Biology & Biophysics

AbstractThe 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.