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Twenty CYP enzymes unique to\n                    <jats:italic>Mtb<\/jats:italic>\n                    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\n                    <jats:italic>Mtb<\/jats:italic>\n                    CYP121A1 (binding affinity, K\n                    <jats:sub>D<\/jats:sub>\n                    ) and against wild type and resistant\n                    <jats:italic>Mtb<\/jats:italic>\n                    strains. From these three series, the tetralones with a propyloxy linked to a 4-F (\n                    <jats:bold>6g<\/jats:bold>\n                    ) and 4-Cl (\n                    <jats:bold>6h<\/jats:bold>\n                    ) benzene ring showed the most promising activity overall considering binding affinity (CYP121A1 K\n                    <jats:sub>D<\/jats:sub>\n                    <jats:bold>6g<\/jats:bold>\n                    0.18\u2009\u00b1\u20090.1 \u03bcM;\n                    <jats:bold>6h<\/jats:bold>\n                    0.22\u2009\u00b1\u20090.12 \u03bcM, cf. cYY 12.3\u2009\u00b1\u20091.1 \u03bcM) and antimycobacterial activity against wild-type\n                    <jats:italic>H37Rv<\/jats:italic>\n                    strain (MIC\n                    <jats:bold>6g<\/jats:bold>\n                    12.5 \u03bcM, 2.7\u00a0\u03bcg\/mL;\n                    <jats:bold>6h<\/jats:bold>\n                    6 \u03bcM. 2.4\u00a0\u03bcg\/mL) and mc\n                    <jats:sup>2<\/jats:sup>\n                    7902 triple auxotrophic drug susceptible strain (MIC\n                    <jats:bold>6g<\/jats:bold>\n                    2.6 \u03bcM, 1\u00a0\u03bcg\/mL;\n                    <jats:bold>6h<\/jats:bold>\n                    2.5 \u03bcM. 1\u00a0\u03bcg\/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\u2009+\u2009RIF resistant strains. Tetralone derivative\n                    <jats:bold>6h<\/jats:bold>\n                    and chromen-4-one\n                    <jats:bold>12c<\/jats:bold>\n                    displayed mycobacteriostatic properties and both compounds displayed favourable SI values in A459 cells and macrophages with the tetralone\n                    <jats:bold>6h<\/jats:bold>\n                    showing an improved therapeutic window with SI\u2009&gt;\u200910. 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.\n                  <\/jats:p>","DOI":"10.1007\/s00044-026-03631-5","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:07:58Z","timestamp":1792732078000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Azole chroman-4-one, tetralone and chromen-4-one derivatives: synthesis, Mycobacterium tuberculosis CYP121A1 enzyme inhibition and antimycobacterial activity"],"prefix":"10.1007","author":[{"given":"Jabril M.","family":"Abdali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama A.","family":"Alshabani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair K.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Wilcocks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Y. 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