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

Lama A Alshabani; Amit Kumar ORCID logo; Sam J Willcocks ORCID logo; Gayathri Srithiran; Sanjib Bhakta; D Fernando Estrada; Claire Simons ORCID logo; (2022) Synthesis, biological evaluation and computational studies of pyrazole derivatives as Mycobacterium tuberculosis CYP121A1 inhibitors. RSC Medicinal Chemistry, 13 (11). pp. 1350-1360. ISSN 2632-8682 DOI: 10.1039/d2md00155a
Copy

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 (MIC90) 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 MIC90 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 19F-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.


picture_as_pdf
Alshabani_etal_2022_Synthesis-biological-evaluation-and-computational.pdf
subject
Published Version
Available under Creative Commons: 4.0

View Download

Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads