Azole chroman-4-one, tetralone and chromen-4-one derivatives: synthesis, Mycobacterium tuberculosis CYP121A1 enzyme inhibition and antimycobacterial activity

Abdali, Jabril M., Alshabani, Lama A., Brown, Alistair K., Kumar, Amit, Wilcocks, Sam, Alhejaili, Ahmed Y. G., Kalam, Sanjida Y., Estrada, D. Fernando and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2026. Azole chroman-4-one, tetralone and chromen-4-one derivatives: synthesis, Mycobacterium tuberculosis CYP121A1 enzyme inhibition and antimycobacterial activity. Medicinal Chemistry Research 10.1007/s00044-026-03631-5

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Abstract

Tuberculosis (TB) remains a major global health challenge, driven by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and the limitations of existing treatment regimens. Twenty CYP enzymes unique to Mtb represent an underexploited class of targets, offering opportunities for selective inhibition. Among these, CYP121A1 enzyme has been identified as a promising target. Three series of azole derivatives employing either a chroman-4-one, tetralone or chromen-4-one pharmacophore were synthesised and evaluated against Mtb CYP121A1 (binding affinity, KD) and against wild type and resistant Mtb strains. From these three series, the tetralones with a propyloxy linked to a 4-F (6g) and 4-Cl (6h) benzene ring showed the most promising activity overall considering binding affinity (CYP121A1 KD6g 0.18 ± 0.1 μM; 6h 0.22 ± 0.12 μM, cf. cYY 12.3 ± 1.1 μM) and antimycobacterial activity against wild-type H37Rv strain (MIC 6g 12.5 μM, 2.7 μg/mL; 6h 6 μM. 2.4 μg/mL) and mc27902 triple auxotrophic drug susceptible strain (MIC 6g 2.6 μM, 1 μg/mL; 6h 2.5 μM. 1 μg/mL) comparable with ethambutol and ethionamide. Importantly, the choman-4-one and tetralone derivatives all retained antimycobacterial activity against isoniazid (INH), rifampicin (RIF) and INH + RIF resistant strains. Tetralone derivative 6h and chromen-4-one 12c displayed mycobacteriostatic properties and both compounds displayed favourable SI values in A459 cells and macrophages with the tetralone 6h showing an improved therapeutic window with SI > 10. Type II direct CYP121A1 binding was generally supported by computational studies with all compounds near the haem. Generally, correlation was observed between binding affinity and antimycobacterial activity.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Pharmacy
Publisher:	Springer
ISSN:	1054-2523
Date of First Compliant Deposit:	27 October 2026
Date of Acceptance:	5 October 2026
Last Modified:	27 Oct 2026 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/190450

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