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

Alshabani, Lama A., Kumar, Amit, Willcocks, Sam J., Srithiran, Gayathri, Bhakta, Sanjib, Estrada, D. Fernando and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2022. Synthesis, biological evaluation and computational studies of pyrazole derivatives as Mycobacterium tuberculosis CYP121A1 inhibitors. RSC Medicinal Chemistry 13 (11) , pp. 1350-1360. 10.1039/D2MD00155A

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Abstract

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 Kd 11.73 and 17.72 μM respectively compared with the natural substrate cYY (Kd 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 (Kd 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Royal Society of Chemistry
ISSN:	2632-8682
Date of First Compliant Deposit:	15 September 2022
Date of Acceptance:	12 August 2022
Last Modified:	23 May 2023 14:42
URI:	https://orca.cardiff.ac.uk/id/eprint/152619

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