A new imidazolium ionic liquid (IL) halide conjugated with dimethylcardamonin (DMC, 1), namely [Bbim]Br-DMC (3), was synthesised to improve the biological activity of the natural chalcone. DMC was isolated from seeds of Syzygium nervosum A. Cunn. ex DC. which was an effective anti-breast cancer agent. The compound 1 and 3 showed anticancer activity in MDA-MB-231 cells with IC₅₀ values of 14.54 ± 0.99 μM and 7.40 ± 0.15 μM, respectively. MTT assay showed that compound 3 had cytotoxic effect at least two-fold greater than compound 1 but was low toxic to normal cells of Hs 578Bst. After 48 h, compound 3 at concentration of IC₅₀ value inhibited the proliferation and induced morphological changes of MDA-MB-231 cells in a time-dependent manner. The cell cycle profile also showed that compound 3 exerted anti-proliferation activity with the cell cycle arrest at G0/G1 phase and compound 3 also induced apoptosis and reduced mitochondrial membrane potential in MDA-MB-231 cells in a dose-dependent manner. In gene expression assay, compound 3 up-regulated pro-apoptotic genes such as Bax and p53 and suppressed anti-apoptotic Bcl-2 whereas there was no effect on DNA repair gene such as PARP1. The Bax/Bcl-2 ratio was significantly increased after treated with compound 3. In the molecular docking study, the interactions between compound 3 and B-DNA structure in the minor groove region via hydrogen bonds was reported. In conclusion, [Bbim]Br-DMC or compound 3 is a potential candidate to induce apoptosis and inhibits proliferation via cell cycle arrest and decreases mitochondrial membrane of triple-negative breast cancer MDA-MB-231 cells.

DMC (1) is a phytochemical found in the seeds of Syzygium nervosum, exhibiting anticancer activity in various cells through multiple pathways. Herein, the bioactivity of DMC (1) was enhanced by chemical modification through esterification, attaching fatty acid and amino acid moieties to yield 27 semi-synthetic derivatives. These compounds were evaluated for their in vitro cytotoxicity against three main types of cervical cancer cells, including SiHa, HeLa, and C-33A. As a result, the amino acid DMC derivative, 4´-(L-tyrosinyloxy)-DMC (7j), exhibited potent cytotoxicity against SiHa cells, which was approximately two-fold greater than that of 1. Further investigation into the mechanism of action of 7j was conducted, revealing its ability to induce cell cycle arrest and apoptosis. Gene expression analysis showed the downregulation of CDK2 and upregulation of the BAX/BCL2 ratio. Atomistic insight was studied on HPV 16 E6 via molecular dynamics simulation, revealing key interactions between tyrosinyl portion and C51 residue.

The chemical structures of the parental compounds of flavonoids from Boesenbergia rotunda were modified by conjugation with cinnamic acid to form cinnamoyl-flavonoid hybrid derivatives with enhanced anti-inflammatory and SARS-CoV-2 M^pro-inhibitory properties. Cinnamoyl-flavonoid hybrid derivatives 6 and 10 showed the potential to inhibit SARS-CoV-2 M^pro with IC₅₀ values of 52.49 and 22.62 μM. Compounds 6 and 10 showed lower cytotoxicity in the human lung cell lines MRC-5 and A549 at concentrations greater than 50 μM. The effects of compounds 6 and 10 on cell viability were studied in a 3D co-culture model of A549 and MRC-5 treated with lipopolysaccharide (LPS) and observed through confocal microscopy. Compounds 6 and 10 downregulated p65 mRNA expression, resulting in a reduction of pro-inflammatory cytokines, including Interleukin 8 (IL-8) and Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), leading to an anti-inflammatory response through Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways. Compound 6 showed potential anti-inflammatory activity, downregulating Bcl-2 Associated X gene (BAX), which resulted in inhibition of apoptotic cell death when compared to compound 10. In silico molecular dynamic simulation shed light on how these cinnamoyl-flavonoid hybrid derivatives interact with myeloid differentiation factor 2 (MD-2), which is involved in the inflammatory response. Our findings suggest that cinnamoyl-flavonoid hybrid derivatives show potential as anti-inflammatory drugs and anti-SARS-CoV-2 drugs.

Lung cancer is the leading cause of cancer-related mortality worldwide. Phytochemical compounds, particularly chalcones derived from Syzygium nervosum A. Cunn. ex DC., have demonstrated notable anticancer potential. The major constituent, 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC, compound 1), exhibits anticancer effects against multiple cancer types. Chemical modifications of DMC, including conjugation with gallic acid (compound 2), have been explored to enhance its pharmacological activities. This study evaluated the gallic acid-2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) hybrid derivative (compound 3) using an integrated experimental and computational workflow. In vitro 2D cytotoxicity assays demonstrated potent antiproliferative activity, with IC₅₀ values of 3.93 ± 0.47 μM in A549 and 4.88 ± 1.42 μM in non-small cell lung cancer (NSCLC) cells, while showing reduced cytotoxicity in normal fibroblasts (MRC-5; IC₅₀ = 10.48 ± 1.83 μM) compared with osimertinib. Flow cytometry confirmed a three-fold increase in apoptosis relative to controls. Pharmacological pathway analysis identified VEGFR-2 as a central regulatory node in PI3K/Akt signaling. The cytotoxic potential of compound 3 was further validated in 3D spheroid models using confocal imaging and LDH release assays. mRNA expression analysis confirmed this signaling pathway, revealing significant downregulation of PTGER4, AKT1, PDPK1, and PRKCA. Molecular docking and in silico conformational analyses demonstrated strong binding affinity of compound 3 to the VEGFR-2 kinase domain, stabilizing critical active-site residues and supporting a structure-based mechanism of action. Collectively, these findings validate VEGFR-2 as a therapeutic target and highlight compound 3 as a promising scaffold for structure-based drug development against non-small cell lung cancer.

Chalcones from medicinal plants are attractive starting points for anticancer lead discovery, and this study aimed to improve the anti-NSCLC potential of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) from Syzygium nervosum through targeted structural modification and mechanistic computational analysis. Air-dried seeds were extracted with CH₂Cl₂, DMC was purified by silica gel chromatography and crystallization, and its structure was confirmed by HRMS, FTIR and NMR; 4′-O-derivatization with meta– or para–[(bromomethyl)phenyl]methyl groups afforded derivatives 2a and 2b (89–92% yield). Antiproliferative activity and cytotoxicity were evaluated by MTT assay in NSCLC cell lines (A549, NCI-H460) and normal lung fibroblasts (MRC-5) with osimertinib as a reference. Derivatives 2a and 2b showed enhanced activity against NCI-H460 (IC₅₀ = 7.97 ± 0.62 µM and 7.91 ± 2.77 µM) while remaining weak against A549, and they were less cytotoxic to MRC-5 (IC₅₀ ≥ 50 µM and 16.08 ± 0.45 µM) than osimertinib (IC₅₀ = 3.43 ± 0.35 µM). DFT/MEP analyses, docking to wild-type EGFR (1M17; redocking RMSD 1.228 Å), and 500 ns × 3 replica MD simulations supported improved EGFR binding stability for 2a/2b, with MM/GBSA indicating favorable binding free energies (−28.78 ± 6.11 and −21.99 ± 9.39 kcal/mol). Overall, 4′-O-functionalization of DMC generated lead derivatives with improved in vitro activity in NCI-H460 and computationally supported target–ligand stabilization.