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Herein, we report the design and synthesis of a novel series of 6-((1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxalines (22–29) via the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. The target compounds formed through two pathways (A and B). The structures of the newly click synthesised 1,2,3-triazole-6H-indolo[2,3-b]quinoxalines (22–29) were confirmed on the basis of their elemental analysis and spectral data. Some of these compounds exhibited significant antiproliferative effects against tested cancer cells, including hepatocellular carcinoma (Hep-G2), breast cancer (MCF-7), and colon cancer (HCT116), relative to healthy noncancerous control skin fibroblast cells (BJ-1) to evaluate their cytotoxic effects. Among the tested compounds, compound 27 exhibited strong activity with IC50 = 9.3 ± 1.1, 1.5 ± 0.1, 2.4 ± 0.2, and 17.3 ± 1.2 against cancer cell lines HCT-116, HepG-2, MCF-7, and BJ-1, respectively. Therefore, compound 27 was selected for further investigation. Cell cycle analysis of liver cancer (HepG-2) cells treated with 27 showed cell cycle arrest in the S and G0/G1 phases and strong apoptotic activity, as indicated by Annexin V-FITC staining. Compound 27 was also found to fit in the ATP binding pocket during docking experiments combined with molecular dynamics simulation. Lastly, we conducted a Petra/Osiris/Molinspiration (POM) study on the synthesized compound. The most promising candidates were identified by evaluating primary in silico parameters, which showed considerable differences among individual synthesized compounds. These features can promote future drug candidate design to produce better derivatives in the search for anticancer agents, particularly those with favorable ADME parameters, low toxicity, anticipated bioactivity, and bright futures. [ABSTRACT FROM AUTHOR]

This study emphasizes the synthesis of a novel series of 1,2,3-triazolo-benzoquinoline-3-carbonitriles by using Cu(I)-catalyzed azide–alkyne cycloaddition known as the click reaction. The reaction of novel acetylenic aryl-benzoquinoline-3-carbonitriles 7–12 with 1-azido-2,5-dimethoxy-4-nitrobenzene 13 afforded the corresponding 1,2,3-triazolo-benzoquinoline-3-carbonitriles 14–19 in good yields. The desired products were examined against different tumor cells such as the human colon (HCT-116), hepatocellular carcinoma (HepG2), human breast adenocarcinoma (MCF-7) and one human healthy cell line (BJ-1) using the LDH assay. Generally, the five compounds (11, 10, 9, 12 and 15, respectively) can be considered good colon anticancer drug candidates as their cytotoxic activities on the colon cancer cells are higher than their cytotoxic activities on the normal cells. In the case of HepG2 human liver cancer cells, compounds 16, 12 and 9 have more potent cytotoxic activities relative to doxorubicin as the standard reference. Supporting the experimental antiproliferative IC50 of the compounds tested against the cancer cell line, the molecular electrostatic potential (MEP) distribution and frontier molecular orbitals (FMOs) of all compounds have been calculated in the ground state theoretically by the DFT/B3LYP method using the 6-31G(d) basis set. Compounds 10, 15 and 19 showed a chemical softness value of 14.59 eV−1 higher than those of all of the compounds. The highest values of the electrophilicity index were observed in compounds 17, 10, 16 and 15. [ABSTRACT FROM AUTHOR]

Isatin–quinoline conjugates 10a–f and 11a–f were assembled by the reaction of N-(bromobutyl) isatin derivatives 3a, b with aminoquinolines 6a–c and their corresponding hydrazinyl 9a–c in good yields. The structures of the resulting conjugates were established by spectroscopic tools and showed data consistent with the proposed structures. In vitro antibacterial activity against different bacterial strains was evaluated. All tested conjugates showed significant biocidal activity with lower MIC than the first line drugs chloramphenicol and ampicillin. Conjugates 10a, 10b and 10f displayed the most potent activity against all clinical isolates. The antibiofilm activity for all tested conjugates was screened against the reference drug vancomycin using the MRSA strain. The results revealed that all conjugates had an inhibitory activity against biofilm formation and conjugate. Conjugate 11a showed 83.60% inhibition at 10 mg/mL. In addition, TEM studies were used to prove the mechanism of antibacterial action of conjugates 10a and 11a against (MRSA). Modeling procedures were performed on 10a–f and 11a–f and interestingly the results were nearly consistent with the biological activities. In addition, in silico pharmacokinetic evaluation was performed and revealed that the synthesized compounds 10a–f and 11a–f were considered drug-like molecules with promising bioavailability and high GI absorption. The results confirmed that the title compounds caused the disruption of bacterial cell membranes and could be used as potential leads for the further development and optimization of antibacterial agents. [ABSTRACT FROM AUTHOR]

New 1,3,4-thiadiazole thioglycosides linked to a substituted arylidine system were synthesized via heterocyclization via click 1,3-dipolar cycloaddition. The click strategy was used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycoside-based indolyl systems as novel hybrid molecules by reacting azide derivatives with the corresponding acetylated glycosyl terminal acetylenes. The cytotoxic activities of the compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds, the triazole glycosides linked to p-methoxyarylidine derivatives and the free hydroxyl glycoside had potent activity comparable to the reference drug, doxorubicin, against MCF-7 human cancer cells. Docking simulation studies were performed to check the binding patterns of the synthesized compounds. Enzyme inhibition assay studies were also conducted for the epidermal growth factor receptor (EGFR), and the results explained the activity of a number of derivatives. [ABSTRACT FROM AUTHOR]

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2‐Acetylbenzofuran derivatives 1a,b and 3‐acetylindole 1c were condensed with Wittig reagents 2a–d and Wittig‐Horner reagents 3a–e to afford the respective 2‐ethylidene derivatives 5a–j and 7a–e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran‐2‐ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a–c to give 1:1 adduct for which the Oxaphospholo[4,3‐b]benzofuran‐7‐yl)diazene derivatives 8a–f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma. [ABSTRACT FROM AUTHOR]

The coumarin ring was used as a central scaffold that was substituted with a variety of bioactive functional groups, for designing and synthesizing novel MDM2 inhibitors targeting breast cancer. The synthesized derivatives, 3c, 3d, 3g, 7b, 7c and 8 with IC50s ranging from 9.4 to 9.9 µM were evaluated for their safety on MCF10a normal breast cell line. The compounds showed selectivity indices of 2.15, 3.85, 2.75, 1.38, 3.72 and 5.20 respectively. 7c was selected for further investigation, the compound was capable of down‐regulating MDM2 and the anti‐apoptosis proteins Bcl‐2 and Bcl‐xL, up‐regulating the level of p53 and the pro‐apoptosis protein BAX, causing cell cycle arrest at G2/M phase and activating Caspase‐9 to induce apoptosis. Molecular docking study revealed the capability of derivative 7c to interact with the key amino acids in p53 binding pocket of MDM2 protein. Moreover, the physicochemical properties of compound 7c were studied in silico. [ABSTRACT FROM AUTHOR]