Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base-Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity.

A new series of Schiff-benzimidazole hybrids 3a-o has been designed and synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analysis tools. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI single- and five-dose protocols. Consequently, four compounds were further examined against the most sensitive lung cancer A549 and NCI-H460 cell lines. Compounds 3e and 3g were the most active, achieving 3.58 ± 0.53, 1.71 ± 0.17 and 1.88 ± 0.35, 0.85 ± 0.24 against A549 and NCI-H460 cell lines, respectively. Moreover, they showed remarkable inhibitory activity on the VEGFR-2 TK with 86.23 and 89.89%, respectively, as compared with Sorafenib (88.17%). Moreover, cell cycle analysis of NCI-H460 cells treated with 3e and 3g showed cellular cycle arrest at both G1 and S phases (supported by caspases-9 study) with significant pro-apoptotic activity, as indicated by annexin V-FITC staining. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay with, and a similar binding mode and pose to, Sorafenib, a reference VEGFR-2 inhibitor.

Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties.

Novel series of amidines were synthesized via the interaction between alicyclic amines, cyclic ketones, and a highly electrophilic 4-azidoquinolin-2(1H)-ones without any catalyst or additive. All the obtained products were elucidated based on NMR spectroscopy, mass spectrometry, and elemental analysis. The reaction conditions were optimized using cyclohexanone (2), piperidine (3a), and 4-azido-quinolin-2(1H)-one (1a) under an air atmosphere. The new compounds 4a-l and 5a-c were tested for antiproliferative activity against four cancer cell lines using doxorubicin as a reference drug. The most potent derivatives were compounds 4b, 4d, 4e, 4i, and 5c, with GI50 ranging from 1.00 µM to 1.50 µM. Compound 5c was the most effective derivative against the four cancer cell lines, outperforming doxorubicin. The compounds 4b, 4d, 4e, 4i, and 5c were studied further as topoisomerase I and IIα inhibitors. The compounds tested showed selective inhibition of topo I over topo IIα. Finally, docking studies explain why these compounds prefer topo I over topo IIα.

New potent ciprofloxacin-uracil conjugates as DNA gyrase and topoisomerase IV inhibitors against methicillin-resistant Staphylococcus aureus.

A series of ciprofloxacin-uracil conjugates 5a-t were synthesized and identified by 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The antibacterial results revealed that the new derivatives exhibited better activity against Gram-positive than the Gram-negative strains; most of the target compounds exhibited good activities against S. aureus ATCC 6538. Compounds 5b and 5g possess the highest activities with MICs of 1.25 and 2.37 µM, respectively, which are more potent than the parent drug ciprofloxacin, MIC, 7.58 µM. In addition, they also exhibited potent activities against MRSA AUMC 261 with MICs, 0.031 and 0.046 µM respectively, higher than ciprofloxacin with MIC, 0.57 µM. Moreover, compounds 5b and 5g showed potent inhibitory activities against DNA gyrase (IC50 = 1.72 and 5.72 µM) and topoisomerase IV (4.36 and 7.77 µM) compared to ciprofloxacin with IC50 values 0.66 and 8.16 µM, respectively. The molecular docking study revealed that compounds 5b and 5g may formed stable interaction with the active sites of DNA gyrase and topoisomerase IV similar to ciprofloxacin. Hence, 5b and 5g are considered promising antibacterial candidated against MRSA AUMC 261 strains that requires further optimization.

Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity.

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.

Design and Synthesis of (2-oxo-1,2-Dihydroquinolin-4-yl)-1,2,3-triazole Derivatives via Click Reaction: Potential Apoptotic Antiproliferative Agents.

A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3'-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC50 = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining.

Identification and molecular modeling of new quinolin-2-one thiosemicarbazide scaffold with antimicrobial urease inhibitory activity.

A new series of 6-substituted quinolin-2-one thiosemicarbazides 6a-j has been synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analyses. All the designed final compounds were evaluated for their in vitro activity against the urease-producing R. mucilaginosa and Proteus mirabilis bacteria as fungal and bacterial pathogens, respectively. Moreover, all compounds were in vitro tested as potential urease inhibitors using the cup-plate diffusion method. Compounds 6a and 6b were the most active with (IC50 = 0.58 ± 0.15 and 0.43 ± 0.09 µM), respectively, in comparison with lead compound I (IC50 = 1.13 ± 0.00 µM). Also, the designed compounds were docked into urease proteins (ID: 3LA4 and ID: 4UBP) using Open Eye® software to understand correctly about ligand-receptor interactions. The docking results revealed that the designed compounds can interact with the active site of the enzyme through multiple strong hydrogen bonds. Moreover, rapid overlay of chemical structures' analysis was described to understand the 3D QSAR of synthesized compounds as urease inhibitors. The results emphasize the importance of polar thiosemicarbazide directly linked to 6-substituted quinolone moieties as promising antimicrobial urease inhibitors.

Arylidenes of Quinolin-2-one scaffold as Erlotinib analogues with activities against leukemia through inhibition of EGFR TK/ STAT-3 pathways.

A new series of 6-substiuted-4-(2-(4-substituted-benzylidene)hydrazinyl)quinolin-2(1H)-one derivatives have been designed and synthesized. The structure of the synthesized compounds was proved by 1H NMR, 13C NMR, 2D NMR, mass and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, the most active compounds were further examined against the most sensitive leukemia RPMI-8226 and on healthy cell lines. 6-Chloro-derivative was the most active one; with IC50 = 15.72 ± 1.21 and 46.05 ± 2.36 µM against RPMI-8226 and normal cell lines, respectively. Also, it showed a remarkable inhibitory activity compared to gefitinib on the EGFR TK mutant, wild and on H-RAS in addition to STAT-3 with IC50 = 695.49 ± 21.8, 263.15 ± 15.13, 10.61 ± 0.27 and 1.753 ± 0.81 nM, respectively. Cell cycle analysis of RPMI-8226 cells treated with the 6-chloro-derivative showed cell cycle arrest at G2/M phase (supported by Caspases-3,8, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking studies ROCS analysis and Tanimoto scores supported the results. The study illustrated the effect of several factors on compounds activity.

Novel Pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors.

Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50 = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds' activity.