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Lookup NU author(s): Dr Alistair BrownORCiD, Ahmed Alhejaili
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
This journal is © The Royal Society of Chemistry, 2026CYP121A1 is a promising cytochrome P450 (CYP) drug target in Mycobacterium tuberculosis (Mtb) owing to its physiological importance in bacterial cell viability. The continuing rise of multidrug resistant (MDR) and extremely drug resistant (XDR) tuberculosis (TB), offers potential therapeutics with a new mechanism of action to add to the multidrug TB regime. A series of 3-(pyridine-3-ylmethylene)chromanone derivatives (5) with 7-O-alkyl/aryl substitutions were explored for CYP121A1 binding and antimycobacterial activity in susceptible and resistant Mtb strains. The 3-(pyridine-3-ylmethylene)chroman-4-one derivatives (5) with the 7-O-(CH2)3-phenyl substitution displayed the strongest CYP121A1 binding affinity (KD 0.3 to 3.6 μM) compared with the natural substrate (dicyclotyrosine, KD 16.8 ± 1.0 μM). Improvements observed in binding affinity from 7-O-benzyl to (CH2)2-phenyl to (CH2)3-phenyl substitutions are supported by computational studies. Minimum inhibitor concentration (MIC) of the alkyoxyaryl substituted chromanones ranged from 1.5–50 μM (0.5–22.5 μg mL−1) against the H37Rv wild type strain (c.f. isoniazid 1.8 μM (0.2 μg mL−1), rifampicin 0.3 μM (0.2 μg mL−1), kanamycin 16.1 μM (7.8 μg mL−1)) with antimycobacterial activity retained against mono-resistant (isoniazid or rifampicin) and MDR (isoniazid and rifampicin) Mtb strains. In contrast, the tetralone derivatives (8) with either the O-(CH2)2-phenyl or O-(CH2)3-phenyl substitutions showed no binding affinity with CYP121A1, possibly owing to binding further away from the haem and failing to displace the 6th axial water ligand, but the O-(CH2)3-phenyl substituted tetralones were the most consistently effective against H37Rv strain with MIC of 3 μM (1.1–1.2 μg mL−1) and retained activity against the mono-resistant and MDR Mtb strains.
Author(s): Alshabani LA, Abdali JM, Brown AK, de Sousa DP, Willcocks S, Kumar A, Alhejaili AYG, Estrada DF, Simons C
Publication type: Article
Publication status: Published
Journal: RSC Medicinal Chemistry
Year: 2026
Pages: epub ahead of print
Online publication date: 04/02/2026
Acceptance date: 20/12/2025
Date deposited: 23/02/2026
ISSN (print): 2632-8682
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D5MD00738K
DOI: 10.1039/d5md00738k
Data Access Statement: The data supporting this article is included in the main text or have been included as part of the supplementary information (SI). Supplementary information: Fig. S1, protein–ligand schematic for compounds 5m, 5o, 8h and 8j; Fig. S2. Protein ligand RMSD of Mtb CYP121A1 and (A) 5m (B) 5o (C) 8h (D) 8j over 200 ns molecular dynamics simulation; Table S1, yields and mp of final products; Table S2, MIC in µg mL-1; Table S3, Mtb strains used in study; experimental methods; NMR spectra for final compounds. See DOI: https://doi.org/10.1039/d5md00738k
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