Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, proceeds independently of caspase activation and can remain effective in apoptosis-resistant and mesenchymal-like tumor populations, providing a pharmacologically addressable route around treatment resistance. Its regulation by enzymes, transporters and metabolic pathways, including glutathione peroxidase 4 (GPX4), the cystine/glutamate antiporter system xc⁻, ferroptosis suppressor protein 1 (FSP1), mitochondrial dihydroorotate dehydrogenase (DHODH), and iron and lipid metabolism, has created multiple starting points for small-molecule design. Unlike prior target-by-target surveys, this review cross-examines structure–activity relationships across these target classes to distinguish transferable design principles from mechanism-specific effects, and chemical probes from pharmacologically viable leads. Cross-target analysis shows that no single SAR pattern governs ferroptosis induction: scaffold requirements are target-dependent, linker length and rigidity produce mechanism-dependent effects, and electrophilic warheads require calibrated rather than maximal reactivity. Substituent modifications that improve one chemotype do not reliably transfer to another, while hybrid and multi-target compounds require evidence for target-specific contributions to activity. Translational evaluation reveals a recurring gap between cellular potency and the solubility, metabolic stability, systemic exposure, in vivo efficacy and tolerability required for development. Most compounds remain chemical probes, with PK/ADMET characterization, therapeutic-window data, off-target control and validated biomarkers for patient selection frequently lacking. Progress will therefore depend less on increasing ferroptotic potency than on converting active chemotypes into target-selective, pharmacokinetically viable and tolerable agents for biomarker-defined patient populations.
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.
Breast cancer remains one of the most common cancers worldwide and continues to present major therapeutic challenges due to tumor diversity, drug resistance, and recurrence. These issues highlight the need for new treatments with better selectivity and multitarget effects. Coumarins, a class of naturally occurring benzopyran-2-one derivatives, have attracted significant interest in medicinal chemistry because of their structural flexibility, favorable drug-like properties, and broad range of biological activities. The coumarin scaffold offers several chemically accessible sites for extensive structural modification, facilitating the development of derivatives and hybrid molecules with improved pharmacological profiles. This review covers recent advances in developing coumarin-based derivatives and hybrid compounds as potential agents for breast cancer treatment. Overall, coumarin scaffolds remain promising platforms for designing multitarget anticancer agents and continue to offer valuable opportunities for creating new therapeutic strategies against breast cancer.
The HEG1–KRIT1 interaction is essential for endothelial cerebral cavernous malformation complex localization and signaling, making this interface a relevant target for chemical disruption. This study aimed to identify acridone alkaloids capable of inhibiting HEG1 binding to KRIT1 through integrated virtual screening, molecular simulations, binding-energy analysis, drug-likeness prediction, and experimental validation. Screening of 2,449 acridone alkaloids prioritized five candidates: 5-hydroxynoracronycine, acronycine, arborinine, glycocitrine I, and rutacridone. Computational analyses showed stable binding within the HEG1-recognition pocket of KRIT1 and predicted interface weakening, with rutacridone and 5-hydroxynoracronycine producing the strongest destabilizing effects. A bead-based flow-cytometry competition assay confirmed concentration-dependent inhibition, with half-maximal inhibitory concentration values of 2.21 ± 0.31 µM for rutacridone, 2.30 ± 0.30 µM for arborinine, and 2.90 ± 0.35 µM for 5-hydroxynoracronycine. These findings identify rutacridone, arborinine, and 5-hydroxynoracronycine as promising acridone-based starting points for developing HEG1–KRIT1 interaction disruptors.
