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A variety of hybrid compounds, combining a camphor thiazolidinone skeleton with either 1,2,3‐triazole or isoxazole nucleus, have been synthesized from natural (R)‐camphor. Our efficient procedure consists in a transformation of the (R)‐camphor into the corresponding thiazolidin‐4‐one. The latter is then N‐alkylated with propargyl bromide before submitting the resulting product to 1,3‐dipolar cycloaddition reactions, with a series of nitrile oxides and arylazides respectively. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. Preliminary in‐vitro cytotoxic assays on three human cancer cell lines MCF‐7 (breast), A‐549 (prostate) and HT‐1080 (fibrosarcoma) were performed on all the compounds. The thiazolidinone‐1,2,3‐isoxazole hybrid 8 c was revealed to be the most active with IC50 values ranging from 11.62±4.52 μM to 16.92±1.22 μM against selected cancer cells. Molecular docking studies carried out on the three compounds 8 c, 9 a and 9 c, confirmed, as expected, that these compounds possess a great inhibition potential against BCl‐2 protein, Caspase‐3 and COX‐2 enzymes. The results showed that the selected compounds had a significant binding property which could lead to the development of novel BCl‐2, Caspase‐3 and −2 inhibitors with improved selectivity. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti‐inflammatory agent. [ABSTRACT FROM AUTHOR]

A variety of novel thiazolidin‐4‐one himachalene derivatives were designed and synthesized through hetero‐cyclization of thiosemicarbazone analogs that have previously exhibited strong anticancer activity. The synthesized products 2 a–4 f were completely characterized by 1H NMR, 13C NMR, IR, and HRMS and were later submitted for in vitro evaluation of their anticancer activity and cytotoxicity on a panel of four human cancer cell lines (i.eHT‐1080, MCF‐7, A‐549, and MDA‐MB‐231). Most of the evaluated compounds showed potent antiproliferative activities against the four human cancer cell lines with tested IC50 values ranging from 5.25±0.32 to 9.26±0.73 μM. The mechanism of action revealed that compounds 2 b and 4 b induced caspase‐3/7‐activated apoptosis and cell cycle arrest in the G0/G1 stage in HT‐1080 and A‐549 cells. Furthermore, molecular docking studies were conducted to evaluate the binding affinities and the possible binding modes of the top‐performing compounds 2 b and 4 b. This was later supported by Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis predicting their prospective pharmacological profiles. The outcome of this study supports the validity of our strategy and presents 2 b and 4 b as a pattern for the discovery of novel cancer therapeutics. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of a novel series of β‐himachalene derivatives, including semicarbazones, thiosemicarbazones, and thiazoles. The structures of these compounds were elucidated by NMR, IR, and HRMS analysis methods. The in vitro antitumor activity of these compounds was evaluated by the MTT assay against four human cancer cell lines, such as fibrosarcoma (HT‐1080), breast adenocarcinoma (MCF‐7 and MDA‐MB‐231), and lung carcinoma (A‐549), and the results indicated that all compounds showed moderate to significant cytotoxic activities against all cancer cell lines with IC50 values ranging from 7.19±0.30 to 50 μM. The mechanism of action of the most cytotoxic compounds 2 b and 7 b suggested that they induced apoptosis through caspase‐3/7 activation, and elicited G2/M‐phase arrest with the loss of mitochondrial membrane potential in HT‐1080 cells. The molecular docking showed that compounds 2 b and 7 b activated the caspase‐3 by forming a stable protein‐ligand complex. [ABSTRACT FROM AUTHOR]

• A novel series of 1,2,3-triazole based 1,3,4-thiadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activity. • Anti-proliferative activity was assessed against HT-1080, A-549, MCF-7 and MDA-MB-231 cells lines. • Hybrid compound 14a showed important inhibitory activity against MCF-7 and MDA-MB-231 cells lines. • Binding modes of all compounds were identified via molecular docking. • Compounds had higher affinity for Bcl-XL as compared to other compounds. One sets of 1,3,4-thiadiazole analogs 14a-c and 15a-c were synthesized by the incorporation of two heterocyclic nuclei (1,2,3-triazole & 1,3,4-thiadiazoles) in objective of developing multifunctional molecules for anticancer disease. (R)-Carvone was used as precursors for the synthesis of new heterocycles. The 1,2,3-triazole-1,3,4-thiadiazoles 14a-c and 15a-c were synthesized in good yields from the precursors using simple procedures. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. The in vitro assessment of the activity of the resultant 1,2,3-triazole-1,3,4-thiadiazoles against human cancer cells, namely fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231) was performed using viability testing (MTT). Compound 14a was the most active heterocycle, and its cytotoxic activity was three times less actives comparable to that obtained for Doxorubicin (6 µM) as a reference. The 1,3,4-thiadiazoles 15a-c showed moderate cytotoxic activities with IC 50 values ranging from 25.56 ± 1.13 to 61.81 ± 2.21 μM. Molecular docking studies were conducted against two antiapoptotic proteins namely Bcl-2, and Bcl-XL to elucidate the potential mechanisms of action. The results indicate that compounds interact favorably (binding energy = −7.6 to −9.8 kcal/mol) with the target proteins through hydrophobic, electrostatic interactions, and hydrogen bonding. The negative binding energy indicate the spontaneous nature of the interaction. Further, molecular dynamics simulation parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and solvent accessible surface area provided insights into the stability and dynamics of the protein-ligand complexes. [Display omitted] [ABSTRACT FROM AUTHOR]

• A novel series of thiazolidinone based 1,2,3-triazole derivatives were designed, synthesized, and evaluated for their cytotoxic activity. • Anti-proliferative activity was assessed against HT-1080, A-549, MCF-7 and MDA-MB-231 cells lines. • Hybrid compounds 14b and 14d showed important inhibitory activity against HT-1080 and A-549 cancer cell lines with an IC 50 value of 18 μM. • Binding modes of all compounds were identified via molecular docking. • Compounds 14b and 14d had higher affinity for Bcl-2 as compared to other compounds. A novel series of thiazolidinone based 1,2,3-triazole derivatives were designed, synthesized, and evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). NMR (1H and 13C) and HRMS established the newly synthesized compounds' structural identification and molecular weight. Most synthesized compounds displayed moderate cytotoxic activity, with IC 50 values from 20 to 40 μM. Furthermore, hybrid compounds 14b and 14d showed important inhibitory activity against HT-1080 and A-549 cancer cell lines with an IC 50 value of 18 μM. Molecular docking analyses also confirmed a higher binding affinity of compounds 14a-e , as compared to Doxorubicin (control), towards Bcl-2 protein. In particular, compounds 14b and 14d had higher affinity for Bcl-2 as compared to other compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

• 1,3,4-Oxadiazole-5-fluorocytosine hybrids were synthesized and evaluated for their anticancer activity against 4 cancer cell lines. • Compound 5e exhibited the best antiproliferative activities against HT-1080 cells. • Compound 5e induced apoptosis by activation of caspase 3/7 and arrested cell cycle. • Molecular docking suggested that compound 5e activates caspase-3. • Hybrid compounds showed no detectable anti-SARS-CoV-2 activities. Analogs of pyrimidine and 1,3,4-oxadiazole are two well established class of molecules proven as potent antiviral and anticancer agents in the pharmaceutical industry. We envisioned designing new molecules where these two heterocycles were conjugated with the goal of enhancing biological activity. In this vein, we synthesized a series of novel pyrimidine-1,3,4-oxadiazole conjugated hybrid molecules as potential anticancer and antiviral agents. Herein, we present a new design for 5-fluorocytosine-1,3,4-oxadiazole hybrids (5a - h) connected via a methylene bridge. An efficient synthesis of new derivatives was established, and all compounds were fully characterized by NMR and MS. Eight compounds were evaluated for their cytotoxic activity against fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), lung carcinoma (A-549), and for their antiviral activity against SARS-CoV-2. Among all compounds tested, the compound 5e showed marked growth inhibition against all cell lines tested, particularly in HT-1080, with IC 50 values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC 50 >100 µM. The mechanism of cell death was investigated using Annexin V staining, caspase-3/7 activity, and analysis of cell cycle progression. The compound 5e induced apoptosis by the activation of caspase-3/7 and cell-cycle arrest in HT-1080 and A-549 cells at the G2M phase. The molecular docking suggested that the compound 5e activated caspase-3 via the formation of a stable complex protein-ligand. [Display omitted] [ABSTRACT FROM AUTHOR]

• A new series of (R)-carvone-isoxazoline-pyrazole and (R)-carvone-pyrazole-1,2,3-triazole hybrids were designed and synthesized. • In vitro cytotoxic activity for all synthesized compounds was carried against four human cancer cell lines. • A molecular docking study of certain (R)-carvone-pyrazole-1,2,3-triazoles derivatives. In the current study, (R)-carvone was utilized as a starting material for the efficient synthesis of several hybrid compounds of the type pyrazole-isoxazole 4a-l and pyrazole-1,2,3-triazole 5a-c using 1,3-dipolar cycloaddition reaction. The target products were obtained in good yields and were characterized by NMR (1H and 13C) and HRMS analysis. The newly synthesized hybrid compounds pyrazole-isoxazole (4a-l) and pyrazole-1,2,3-triazole (5a-c) were evaluated for their cytotoxic activity against four human cancer cells, namely, HT-1080, MCF-7, A549, and MDA-MB-231 using viability testing tetrazolium dye (3-[4,5- dimethyl - thiazol -2- yl ]-2,5-diphenyl tetrazolium bromide) (MTT). All the hybrid compounds 4a-d derivatives showed a very low anti-cancer activity (IC 50 ≥ 100 μM) against the selected cells. However, the combination of pyrazole and 1,2,3-triazole nucleus caused an average cytotoxic effect with an IC 50 value of 18.25 µM against HT-1080 cells. 15 compounds (4a to 4l , and 5a, 5b , and 5c) were docked in the active site of Bcl-2 protein as the most targeted protein in cancer research, and the results were good enough to confirm experimental results supporting that the compound 4d is a potential Bcl-2 inhibitor. [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]

[Display omitted] • 1,2,3-Triazole-Thiazolidinone hybrids were synthesized and evaluated for their anticancer activity against four cancer cells. • Compounds 14e and 14f exhibited the better antiproliferative activities against HT-1080 and A-549 cells. • Compounds 14e and 14f induced apoptosis through activation of caspase 3/7 and arrested cell cycle. • Molecular docking suggested that compounds 14e and 14f activate caspase-3. A novel series of 1,2,3-triazole-thiazolidinone-carvone hybrid compounds has been designed and synthesized using the copper-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC) process based on (R)-Carvone-O-propargylated 5-hydroxybenzylidene-thiazolidin-4-one derivative as starting material. All compounds were characterized and identified based on their NMR and HRMS spectroscopic data. HMBC correlations confirm that under the CuAAC reaction conditions, only the 1,4-disubstituted triazole regioisomers were formed. The targeted 1,2,3-triazole-thiazolidinone-carvone hybrids and their precursors were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC 50 values between 15.04 ± 0.71 and 42.22 ± 1.20 µM. The mechanism of action of the most active compounds 14e and 14f suggested that they induce apoptosis through caspase-3/7 activation, and the compound 14e elicited S-phase arrest, while compound 14f evoked G2/M phase blockade. The molecular docking confirmed that compounds 14e and 14f were nicely bonded with caspace-3 leading up to stable protein-ligand complexes. [ABSTRACT FROM AUTHOR]

• 1,3,4-Oxadiazole homonucleosides and their double-headed were synthesized • Compound 18 exhibited the better antiproliferative activities against HT-1080 cells • Compound 18 induced apoptosis via activation of caspase 3/7 and arrested cell cycle • Molecular docking suggested that compound 18 activate caspase-3 A novel series of homonucleosides and their double-headed analogs containing theophylline, 1,3,4-oxadiazole, and variant nucleobases was designed and synthesized. The new derivatives were fully characterized by HRMS, FT-IR, 1H NMR, and 13C NMR. The cytotoxic activities of all prepared compounds were screened in vitro against four cell lines, including fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). The double-headed analogue 18 showed marked growth inhibition against all the cell lines tested, specifically in HT-1080, with an IC 50 values of 17.08 ± 0.97 µM. The possible mechanism of apoptosis was investigated using Annexin V staining, caspase-3/7 activity, and analysis cell cycle progression. The compound 18 induced apoptosis through caspase-3/7 activation and cell-cycle arrest in HT-1080 and A-549 cells. The molecular docking confirms that the compound 18 activated caspase-3 via the formation of hydrogen bonds and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

• Novel synthetic method for preparation of 1,2,4-oxadiazole derivatives was developed. • A novel series of uracil analogues-1,2,4-oxadiazole hybrids were synthesized and evaluated for their anticancer activity against 5 cancer cells. • The compounds 22 and 23 exhibited better antiproliferative activities than reference drug DOX against MCF-7. • Compound 22 induced apoptosis through activation of caspase 3/7 and arrested S-phase in cell cycle. • Molecular docking suggested that compound 22 activate caspase-3. A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SO 3 H as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human cancer cell lines: melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC 50 inferior to 1 µM. The possible mechanism of apoptosis induction by the derivatives was investigated using Annexin V staining, caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced apoptosis through caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the caspase-3 by forming a stable protein-ligand complex. [ABSTRACT FROM AUTHOR]