From a natural monoterpene to anticancer leads: Synthesis and integrated in vitro–in silico investigation of (R)-carvone-based thiazolidinones

A new series of (R)-carvone-based thiazolidinone hybrids
(5a-c
) was designed and synthesized to explore their potential as anticancer agents. The structures of the obtained compounds were fully characterized by
1
H and
13
C NMR spectroscopy. Their antiproliferative activity was evaluated against human fibrosarcoma (HT-1080) and non-small cell lung carcinoma (A-549) cell lines. Among the tested derivatives, compound
5b
exhibited the highest potency against HT-1080 cells with an IC
50
value of 26.87 ± 2.72 μM, while compounds
5b
and
5c
showed comparable cytotoxicity toward A-549 cells (IC
50
= 29.71 ± 1.81 and 28.41 ± 3.17 μM, respectively). To rationalize the biological results, molecular docking studies were performed against VEGFR2 and FGFR kinases, revealing favorable predicted binding modes and docking scores (up to -9.8 kcal/mol). Subsequent 100 ns molecular dynamics simulations demonstrated stable ligand–protein complexes, particularly for
5c-VEGFR2
and
5b-FGFR
systems, supported by root-mean-square deviation (RMSD), radius of gyration (Rg), and solvent accessible surface area (SASA) analyses. Molecular mechanics-generalized born surface area (MM-GBSA) calculations further indicated moderate binding free energies consistent with docking trends. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling suggested good intestinal absorption for most derivatives and acceptable drug-likeness properties, although potential hERG liability was predicted. Overall, these findings identify (R)-carvone–thiazolidinone hybrids as promising scaffolds for further structural optimization toward multi-target anticancer agents.