Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers.

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 µM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 µM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 µM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 µM, compared to sorafenib (IC50 = 0.0416 µM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Synthesis, description, and application of novel corrosion inhibitors for CS AISI1095 in 1.0 M HCl based on benzoquinoline derivatives.

This study aims to synthesize and evaluate the corrosion inhibition properties of three newly prepared organic compounds based on benzo[h]quinoline hydrazone derivatives. The compounds structure were characterised using FTIR, 1H-NMR, 13C-NMR and Mass spectroscopy. Electrochemical methods, including Potentiodynamic Polarization (PP), Electrochemical Frequency Modulation (EFM), and Electrochemical Impedance Spectroscopy (EIS) were employed to evaluate the compounds as corrosion inhibitors in HCl (1.0 M) for carbon steel (CS). Additionally, surface examination techniques such as scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) were used to investigate the surface morphology and elemental composition of the CS before and after exposure to the synthesized compounds. The electrochemical measurements showed that compound VII achieved corrosion inhibition efficiency. SEM and EDX analysis further confirmed the creation of a passive film on the CS surface. These findings demonstrated the potential of benzo[h]quinoline hydrazone derivatives as effective organic corrosion inhibitors for CS in aggressive solution.

New thiadiazole modified chitosan derivative to control the growth of human pathogenic microbes and cancer cell lines.

The emergence of multidrug-resistant microbes and the propagation of cancer cells are global health issues. The unique properties of chitosan and its derivatives make it an important candidate for therapeutic applications. Herein, a new thiadiazole derivative, 4-((5-(butylthio)-1,3,4-thiadiazol-2-yl) amino)-4-oxo butanoic acid (BuTD-COOH) was synthesized and used to modify the chitosan through amide linkages, forming a new thiadiazole chitosan derivative (BuTD-CH). The formation of thiadiazole and the chitosan derivative was confirmed by FT-IR, 1H/13C-NMR, GC-MS, TGA, Elemental analysis, and XPS. The BuTD-CH showed a high antimicrobial effect against human pathogens Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Candida albicans with low MIC values of 25-50 µg ml-1 compared to unmodified chitosan. The in-vitro cytotoxicity of BuTD-CH was evaluated against two cancer cell lines (MCF-7 and HepG2) and one normal cell (HFB4) using the MTT method. The newly synthesized derivatives showed high efficacy against cancerous cells and targeted them at low concentrations (IC50 was 178.9 ± 9.1 and 147.8 ± 10.5 µg ml-1 for MCF-7 and HepG2, respectively) compared with normal HFB4 cells (IC50 was 335.7 ± 11.4 µg ml-1). Thus, low concentrations of newly synthesized BuTD-CH could be safely used as an antimicrobial and pharmacological agent for inhibiting the growth of human pathogenic microbes and hepatocellular and adenocarcinoma therapy.

Synthesis and characterization of new functionalized chitosan and its antimicrobial and in-vitro release behavior from topical gel.

Recently, chitosan and its derivatives have been gaining more attention due to their high integration into various biomedical applications. Herein, a new chitosan derivative was prepared by linking the chitosan (Cs) with a novel heterocyclic compound, Benzoimidazolyl-thiadiazole (BzimTD) to form Cs-BzimTD. The synthesis of the new chitosan derivative was confirmed by Fourier-Transform Infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (1H NMR), thermogravimetric (TGA-DTG) analysis, elemental analysis, and UV-Visible spectrophotometer. Data showed the high efficacy of functionalized Cs-BzimTD to inhibit the growth of pathogenic microbes, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans, with inhibition zones of 15.3 ± 0.6 - 9.2 ± 0.3 mm. Also, Cs-BzimTD was applied in a topical gel formulation by using two different polymers, Carbopol 940 (CP) and Carboxymethyl Cellulose (CMC) to form three gel formulations: Cs-BzimTD-CP, Cs-BzimTD-CMC, and Cs-BzimTD-CP-CMC. The new gels were checked for physical appearance, viscosity, Cs-BzimTD release, pH, spread-ability, and drug content. The results showed that all formulations were clear, transparent, and homogeneous with non-irritant pH values for skin (6.4 - 6.8). The spread-ability was found in the range of 7.1 - 9.4 g.cm/s. The Cs-BzimTD-CP formula showed the maximal Cs-BzimTD content percentage (86.5%) and the Cs-BzimTD release varied from 89.9 to 81.6% after 8 h depending on the gel formulation, with a maximum release achieved for Cs-BzimTD-CMC.

Synthesis, anticancer evaluation and molecular docking studies of new heterocycles linked to sulfonamide moiety as novel human topoisomerase types I and II poisons.

A series of heterocyclic compounds with a sulfonamide moiety were synthesized from reaction of enaminone 4 with active methylene compounds, glycine derivatives, 1,4-benzoquinone, hydroxylamine hydrochloride, hydrazonyl halides and dimethylacetylenedicarboxylate. The newly synthesized sulfonamide derivatives were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and alternative synthetic routes. The reactions products were evaluated for their antiproliferative activity against a panel of three different human cancerous cell lines, MCF-7 (breast), HepG-2 (liver) and HCT-116 (colon) and the results were deployed to derive the structure-activity relationships (SAR). Various test compounds were potent antiproliferative to cancerous cells; reaching very low micromolar levels, as in case of 21 which showed IC50 value of 6.2 µM against HepG-2 cell. In addition, treatment of cancerous cells with the synthesized compounds induced cell apoptosis and G2/M phase arrest evidenced by flow cytometric analysis. Furthermore, the activity of the synthesized compounds against TOP I and II were documented by DNA relaxation assays. Data revealed that compound 24 significantly interfered with TOP I- and II-mediated DNA relaxation, nicking and decatenation, with IC50 values 27.8 and 33.6 µM, respectively. Moreover, the molecular docking studies supported the results from enzymatic assays, where compound 24 was intercalated between nucleotides flanking the DNA cleavage site via pi-pi stacking and hydrophobic interactions. In conclusion, aromatic heterocycles linked to sulfonamides are excellent molecular frameworks amenable for optimization as dual TOP I and II poisons to control various human malignancies.

Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors.

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4-33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 µM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

Vibrational assignments, normal coordinate analysis, B3LYP calculations and conformational analysis of methyl-5-amino-4-cyano-3-(methylthio)-1H-pyrazole-1-carbodithioate.

The Raman and infrared spectra of solid methyl-5-amino-4-cyano-3-(methylthio)-1H-pyrazole-1-carbodithioate (MAMPC, C7H8N4S3) were measured in the spectral range of 3700-100 cm(-1) and 4000-200 cm(-1) with a resolution of 4 and 0.5 cm(-1), respectively. Room temperature 13C NMR and (1)H NMR spectra from room temperature down to -60 °C were also recorded. As a result of internal rotation around C-N and/or C-S bonds, eighteen rotational isomers are suggested for the MAMPC molecule (Cs symmetry). DFT/B3LYP and MP2 calculations were carried out up to 6-311++G(d,p) basis sets to include polarization and diffusion functions. The results favor conformer 1 in the solid (experimentally) and gaseous (theoretically) phases. For conformer 1, the two -CH3 groups are directed towards the nitrogen atoms (pyrazole ring) and CS, while the -NH2 group retains sp2 hybridization and C-CN bond is quasi linear. To support NMR spectral assignments, chemical shifts (δ) were predicted at the B3LYP/6-311+G(2d,p) level using the method of Gauge-Invariant Atomic Orbital (GIAO) method. Moreover, the solvent effect was included via the Polarizable Continuum Model (PCM). Additionally, both infrared and Raman spectra were predicted using B3LYP/6-31G(d) calculations. The recorded vibrational, 1H and 13C NMR spectral data favors conformer 1 in both the solid phase and in solution. Aided by normal coordinate analysis and potential energy distributions, confident vibrational assignments for observed bands have been proposed. Moreover, the CH3 barriers to internal rotations were investigated. The results are discussed herein are compared with similar molecules whenever appropriate.