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• A series of natural bioactive (R)-Carvone-based 1,2,3-triazole were synthesized and their anti-cancer potential was tested under both in-silico and in-vitro conditions. • Chemical reactivity and chemical stability parameters were observed via density functional theory calculations (DFT). • Molecular Docking results were supported by molecular dynamic simulations • Through network pharmacology screening identifies potential targets for the treatment of cancer. Cancer is a global health burden with escalating incidence and mortality rates, necessitating the exploration of novel therapeutic strategies. 1,2,3-Triazoles, recognized for their diverse biological activities, have emerged as attractive candidates in drug discovery targeting key proteins associated with various cancers. This study presents the synthesis of a library of 1,2,3-triazole hybrids incorporating thiazolidinone and isoxazoline moieties. The antitumor potential of these compounds was evaluated using both in-silico and in-vitro assays. Structure-activity relationship (SAR) analysis revealed that strategic substitution of the para position of the phenyl ring, particularly with a nitro (NO 2) group, is promising to enhance cytotoxic activity. The binding potential of the synthesized compounds with the XIAP BIR2 domain, the specific receptor of caspase-3/7 activators, was explored through molecular docking. The stability of the protein-compound complexes procured from the docking was assessed through molecular dynamics (MD) simulation. The docking study demonstrated that the synthesized compounds had the potential to bind to the target protein. Among the compounds and their stereoisomers, compounds (R)-6d and (S)-6e exhibited a better binding potential to the protein. The MD simulation study revealed that the protein-(R)-6d complex was relatively stable. [Display omitted] [ABSTRACT FROM AUTHOR]

• A series of natural bioactive (R)-Carvone-based 1,2,3-triazole were synthesized and their anti-cancer potential was tested under both in-silico and in-vitro conditions. • Chemical reactivity and chemical stability parameters were observed via density functional theory calculations (DFT). • Molecular Docking results were supported by molecular dynamic simulations • Through network pharmacology screening identifies potential targets for the treatment of cancer. Cancer is a global health burden with escalating incidence and mortality rates, necessitating the exploration of novel therapeutic strategies. 1,2,3-Triazoles, recognized for their diverse biological activities, have emerged as attractive candidates in drug discovery targeting key proteins associated with various cancers. This study presents the synthesis of a library of 1,2,3-triazole hybrids incorporating thiazolidinone and isoxazoline moieties. The antitumor potential of these compounds was evaluated using both in-silico and in-vitro assays. Structure-activity relationship (SAR) analysis revealed that strategic substitution of the para position of the phenyl ring, particularly with a nitro (NO 2) group, is promising to enhance cytotoxic activity. The binding potential of the synthesized compounds with the XIAP BIR2 domain, the specific receptor of caspase-3/7 activators, was explored through molecular docking. The stability of the protein-compound complexes procured from the docking was assessed through molecular dynamics (MD) simulation. The docking study demonstrated that the synthesized compounds had the potential to bind to the target protein. Among the compounds and their stereoisomers, compounds (R)-6d and (S)-6e exhibited a better binding potential to the protein. The MD simulation study revealed that the protein-(R)-6d complex was relatively stable. [Display omitted] [ABSTRACT FROM AUTHOR]

• Facile synthesis of six novel pyrazole derivatives based on thymol through the 1,3-dipolair cycloaddition reaction. • Structural identification was carried out by NMR, HRMS and X-ray crystallography analyses. • The cytotoxic activity of the targeted compounds 5a-c and 6a-c was evaluated by MTT assay. • Compounds 6b and 6c showed the most promising anticancer activity against A-549 cell lines. • DFT calculations were performed on the investigated compounds. In the present paper, we report the synthesis of novel thymol derivatives containing pyrazole scaffold through 1,3-dipolar cycloaddition reactions between thymol-O-propargyle derivatives with diarylnitrilimines. The structural identification of all compounds was carried out by spectroscopic techniques such as 1H, 13C NMR, FT-IR and X-ray single crystal diffraction. The reaction showed total regioselectivity. Then, the peri‑ and regio-selectivity of the condensation [3 + 2] cycloaddition reaction of the title compounds were determined by Density Functional Theory (DFT) using B3LYP calculations at 6-31G(d,p) level, and the theoretical results agree well with the experimental results. The orbitals frontiers (HOMO, LUMO), Molecular electrostatic potential (MEP), Mulliken atomic charges and Parr functions analysis were studied to determine the electronic interaction properties of the synthesized compounds. Moreover, all targeted compounds were evaluated for their cytotoxic effects against four human cancer cell lines, including MCF-7 and MDA-MB-231 (Human breast adenocarcinoma), A-549 (Human Lung adenocarcinoma) and HT-1080 (human fibrosarcoma). Among the tested compounds, 6b and 6c showed the most promising anticancer activity against A-549 cell lines with IC 50 values of 22.17 ± 1.34 and 23.79 ± 1.8 9 µM, respectively. [ABSTRACT FROM AUTHOR]

• New gem‑dichlorocyclopropane-pyrazole hybrids were synthesized diastereoselectively. • A theoretical study was carried out to explain the non-reactivity of the hybrids towards thiosemicarbazide. • The newly synthesized hybrids revealed interesting antiproliferative activities. • Molecular docking and molecular dynamics confirmed the empirical test results. A new series of four gem -dichlorocyclopropane-pyrazole hybrids 3a-d have been synthesized from (R)-carvone, using a two-step procedure consisting of dichlorocyclopropanation under phase transfer catalysis conditions followed by a 1,3-dipolar cycloaddition reaction of the obtained cyclopropanic product with diarylnitrilimines. The structure of the target products 3a-d was fully established via spectroscopic analysis (1H- & 13C NMR and HRMS) as well as an X-ray crystallographic study carried out on compound 3d An attempt to prepare the corresponding thiosemicarbazones was unsuccessful. So, a succinct theoretical study was carried out to explain the non-reactivity of the hybrids 3a-d vis a vis thiosemicarbazide. Furthermore, all the compunds were evaluated for their anticancer activity against HT-1080 fibrosarcoma, breast adenocarcinoma (MCF-7 and MDA-MB231), and lung carcinoma A-549 cells. The four newly synthesized compounds (3a-d) exhibited interesting antiproliferative activities with IC 50 values ranging from 25.78 ± 0.24 µM to 37.13 ± 0.47 µM. Molecular docking and molecular dynamics confirmed the empirical test results and confirmed the stability of the complex during inhibition of the anti-apoptotic protein for killing cancer cells. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel enaminone sesquiterpenic was synthesized using natural product as a starting material and characterized by HRMS, FT-IR, UV-Visible, 1H and 13C NMR and confirmed by single crystal X-ray diffraction method. • The cytotoxic activity of the novel enaminone was evaluated on four human cancer cell lines. • Interactions in crystal packing were supported by Hirshfeld surface analysis. • DFT calculation have been investigated and compared with X-ray results. In this work, the compound 2 named ethyl (1,1-dichloro-1a,5,5,7-tetramethyl-8-oxo-1a,2,3,4,5,5a,8,9-octahydro-1H-benzo[a]cyclopropa[b][7]annulen-6-yl)glycinate (C 20 H 29 C l2 NO 3) was synthesized from the α,β-unsaturated sesquiterpene ketone 1 using the azido-Schmidt reaction catalyzed by titanium tetrachloride (TiCl 4). The structure of the newly synthesized enaminone 2 was fully identified using its HRMS, FT-IR, UV-Visible, NMR (1H & 13C), and X-ray crystallography analyses. The compounds 1 and 2 were tested for their cytotoxic activity in four human cancer cell lines, fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast (MCF-7 and MDA-MB-231). The obtained results showe that compound 1 is the most active against HT-1080 and A-549 cells with IC 50 values from 13.28 to 16.41 µM. The results of theoretical studies used to predict the molecular proprieties that lead to a high potential of cytotoxic effect are in perfect agreement with the experimental results. [ABSTRACT FROM AUTHOR]