Synthesis, biological evaluation and computational studies of pyrazole derivatives as Mycobacterium tuberculosis CYP121A1 inhibitors.

Autor: Alshabani LA; School of Pharmacy & Pharmaceutical Sciences, Cardiff University King Edward VII Avenue Cardiff CF10 3NB UK simonsc@cardiff.ac.uk., Kumar A; Department of Biochemistry, Jacobs School of Medicine and Biomedical Science, University at Buffalo Buffalo New York-14203 USA., Willcocks SJ; Department of Infection Biology, The London School of Hygiene and Tropical Medicine London WC1E 7HT UK.; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London London WC1E 7HX UK., Srithiran G; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London London WC1E 7HX UK., Bhakta S; Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London London WC1E 7HX UK., Estrada DF; Department of Biochemistry, Jacobs School of Medicine and Biomedical Science, University at Buffalo Buffalo New York-14203 USA., Simons C; School of Pharmacy & Pharmaceutical Sciences, Cardiff University King Edward VII Avenue Cardiff CF10 3NB UK simonsc@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: RSC medicinal chemistry [RSC Med Chem] 2022 Aug 16; Vol. 13 (11), pp. 1350-1360. Date of Electronic Publication: 2022 Aug 16 (Print Publication: 2022).
DOI: 10.1039/d2md00155a
Abstrakt: A series of imidazole and triazole diarylpyrazole derivatives were prepared using an efficient 5-step synthetic scheme and evaluated for binding affinity with Mycobacterium tuberculosis (Mtb) CYP121A1 and antimycobacterial activity against Mtb H37Rv. Antimycobacterial susceptibility was measured using the spot-culture growth inhibition assay (SPOTi): the imidazoles displayed minimum inhibitory concentration (MIC 90 ) in the range of 3.95-12.03 μg mL -1 (10.07-33.19 μM) with 11f the most active, while the triazoles displayed MIC 90 in the range of 4.35-25.63 μg mL -1 (11.88-70.53 μM) with 12b the most active. Assessment of binding affinity using UV-vis spectroscopy showed that for the imidazole series, the propyloxy (11f) and isopropyloxy (11h) derivatives of the 4-chloroaryl pyrazoles displayed Mtb CYP121A1 type II binding affinity with K d 11.73 and 17.72 μM respectively compared with the natural substrate cYY ( K d 12.28 μM), while in the triazole series, only the methoxy substitution with the 4-chloroaryl pyrazole (12b) showed good type II Mtb CYP121A1 binding affinity ( K d 5.13 μM). Protein-detected 1D 19 F-NMR spectroscopy as an orthogonal strategy was used to evaluate ligand binding independent of perturbations at the haem. For imidazole and triazole compounds, perturbations were more intense than cYY indicating tighter binding and confirming that ligand coordination occurs in the substrate-binding pocket despite very modest changes in UV-vis absorbance, consistent with computational studies and the demonstrated potential anti-tuberculosis properties of these compounds.
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE