Scientia Pharmaceutica

4-Thiazolidinone derivatives, a group of compounds with a broad spectrum of activity and anticancer properties, are used in medicine as anti-inflammatory, antiviral, antibacterial, antidiabetic, and blood pressure-lowering drugs; some of them are now in phase II and III clinical trials as anticancer drugs. Here, we evaluated the anticancer potential of 4-thiazolidinones (2b, 12b, 14b) targeting tubulin and metastasis-related pathways in breast cancer models. Molecular docking revealed that compound 14b exhibited the strongest binding affinity to the paclitaxel-binding site of β-tubulin, outperforming 2b and 12b, though slightly weaker than Taxol. Biological assays confirmed significant tubulin inhibition, with 14b reducing β-tubulin levels up to eight-fold in MCF-7 cells and two-fold in MDA-MB-231 cells. All compounds promoted tubulin polymerization, showing paclitaxel-like activity, with comparable the maximum velocity (V_max) values. Cell cycle analysis demonstrated G2/M arrest in MCF-7 cells and S-phase accumulation in MDA-MB-231 cells. Overall, compound 14b demonstrated the most promising multitarget anticancer activity in vitro.

Three series of benzylidene cinnamoylhydrazides (21 compounds) were synthesized and evaluated for cytotoxic activity against malignant and non-malignant cell lines. Among the compounds tested, 2d and 3c were the most active against Jurkat and CEM leukemia cells, with CC₅₀ values in the low micromolar range. Both compounds were more potent against these leukemia cell lines than the reference compounds 5-fluorouracil, curcumin, and melphalan. However, 2d and 3c showed only modest selectivity over non-malignant Hs27 fibroblasts, with selectivity index values of 2.50 and 2.09, respectively, in CEM cells. Further studies in CEM cells showed that treatment with 2d and 3c was associated with apoptosis, caspase activation, increased ROS accumulation, mitochondrial membrane depolarization, and changes in cell-cycle distribution, with the most notable change being an increase in the sub-G0-G1 population. The compounds also showed growth-inhibitory and cytotoxic activity against several cell lines in the NCI-60 panel. Semi-empirical PM3 calculations suggested possible relationships between cytotoxic activity, electronic polarization of the α,β-unsaturated carbonyl system, and molecular dimensions. However, these relationships were not consistent across the series and should be considered preliminary. Overall, 2d and 3c represent useful hit structures for further investigation, although additional structural optimization and biological studies will be needed to improve their selectivity and better define their mechanisms of action.

Alzheimer’s disease (DA) remains a major therapeutic challenge, and selective butyrylcholinesterase (BChE) inhibition has emerged as a promising strategy for symptomatic treatment, particularly in advanced stages. Herein, a series of novel quinoline–acylguanidine hybrids was designed through a bioisosteric replacement of acridine–thiosemicarbazones and synthesized via a convergent route combining the Pfitzinger reaction with acylguanidine formation. All derivatives were evaluated against BChE and AChE (acetylcholinesterase), and the 2-phenylquinoline derivative 2c (IC₅₀ = 7.14 µM) was identified as the most potent BChE inhibitor, comparable to donepezil (IC₅₀ = 2.39 µM), with selectivity over AChE. Structure–activity relationships revealed that the 2-phenyl substituent is essential for activity, whereas bulky groups (4-bromophenyl) or replacement with methyl abolished inhibition. Molecular docking showed that active compounds bind within the BChE catalytic anionic site with Trp110, Met465, and Trp458, while inactive analogs undergo a 180° flip of the quinoline scaffold, disrupting key interactions. In silico ADME evaluation indicated a favorable CNS drug-like profile (TPSA < 90 Ų, LogBB > −1, no Lipinski violations, and no predicted P-glycoprotein substrate liability). These findings establish the quinoline–acylguanidine scaffold as a promising new chemotype for the development of selective BChE inhibitors with potential applications in Alzheimer’s disease.