Antibacterial and antibiofilm activities of selenium nanoparticles-antibiotic conjugates against anti-multidrug-resistant bacteria.

The crucial demand to overcome the issue of multidrug resistance is required to refine the performance of antibiotics. Such a process can be achieved by fastening them to compatible nanoparticles to obtain effective pharmaceuticals at a low concentration. Thus, selenium nanoparticles (Se NPs) are considered biocompatible agents that are applied to prevent infections resulting from bacterial resistance to multi-antibiotics. The current evaluated the effectiveness of Se NPs and their conjugates with antibiotics such as amikacin (AK), levofloxacin (LEV), and piperacillin (PIP) against Pseudomonas aeruginosa (P. aeruginosa). In addition, the study determined the antibacterial and antibiofilm properties of Se NPs and their conjugates with LEV against urinary tract pathogens such as Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), P. aeruginosa, and Escherichia coli (E. coli). The result of minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) for eight isolates of P. aeruginosa revealed that the conjugation of Se NPs with AK, LEV, and PIP resulted in a reduction in the concentration of antibiotic-conjugated Se NPs. The concentration was found to be about 10-20 times lower than that of bare antibiotics. The MIC of the Se NPs with LEV (i.e., Se NPs:LEV) for S. aureus, E. faecalis, P. aeruginosa, and E. coli was found to be 1.4:0.5, 0.7:0.25, 22:8, and 11:4 µg/mL, respectively. The results of the half-maximal inhibitory concentration (IC50) demonstrated that Se NPs:LEV conjugate have inhibited 50 % of the mature biofilms of S. aureus, E. faecalis, P. aeruginosa, and E. coli at a concentration of 27.5 ± 10.5, 18.8 ± 3.1, 40.6 ± 10.7, and 21.6 ± 3.3 µg/mL, respectively compared to the control. It has been suggested that the antibiotic-conjugated Se NPs have great potential for biomedical applications. The conjugation of Se NPs with AK, LEV, and PIP increases the antibacterial potency against resistant pathogens at a low concentration.

Design, Synthesis, in silico and in vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents.

BACKGROUND: Combretastatin A-4 (CA-4) binds ß-tubulin at the colchicine-binding site preventing tubulin from polymerizing into microtubules. CA-4 and cis combretastatin analogs isomerize to the trans form resulting in decreased cytotoxicity and anti-tubulin activity. However, the excellent anti-cancer potential and relatively simple molecular structure of CA-4 provide an encouraging starting point for the development of new, more stable and more potent anti-tubulin compounds. OBJECTIVE: This study aimed to synthesize a new series of compounds derived from 4-(3,4,5- trimethoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives (compounds 10-12) with substituted phenyl group at C5 of the triazole ring (B-ring) as analogs of CA-4, with different alkyl and aryl side chain substituents at the triazole moiety, resulting in the permanent cis configuration of the two phenyl rings. Moreover, the anti-cancer activities of the new compounds were assessed. METHODS: Chemical synthesis was carried out by conventional organic methods. The newly synthesized CA-4 analogs were characterized by FT-IR, 1HNMR, 13CNMR, and HR-MS(ESI) techniques. Molecular docking studies, including docking score (ΔG), ADMET, DFT, and molecular similarities, were performed. The anti-proliferative activity of the new compounds against three human cancer cell lines (A549, Hep G2, and HCT-116) and the normal cell line WI-38 was evaluated using the MTT assay, and their ability to inhibit tubulin polymerization, and consequently, their effects on cell cycle progression and induction of apoptosis were assessed. RESULTS: Molecular docking studies showed that compounds 11b and 11d exhibited the highest docking scores (-13.30 and -14.01 Kcal/mol, respectively) into the colchicine-binding site, scores very close to the reference drug colchicine (-13.50 Kcal/mol), and that hydrogen bonding and hydrophobic interaction are essential for binding. The most active cytotoxic compound, 11b, had potent IC50 values against the three human cancer cell lines (3.83, 10.20, and 10.67 µM against Hep G2, HCT- 116, and A549, respectively) while exhibiting low cytotoxicity against non-cancer-human WI-38, suggesting that compound 11b targets rapidly growing cancer cells. Moreover, compound 11b exhibited potent anti-tubulin activity which was comparable to CA-4. Targeting microtubules caused cell cycle arrest at the G2/M phase resulting in the induction of apoptosis. CONCLUSION: These findings indicate that compound 11b is a promising ß-tubulin-binding compound with antimitotic action that has the potential to treat cancer.

New Combretastatin Analogs as Anticancer Agents: Design, Synthesis, Microtubules Polymerization Inhibition, and Molecular Docking Studies.

A new series of 4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives were synthesized as analogs for the anticancer drug combretastatin A-4 (CA-4) and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. The new CA-4 analogs were designed to meet the structural requirements of the highest expected anticancer activity of CA-4 analogs by maintaining ring A 3,4,5-trimethoxyphenyl moiety, and at the same time varying the substituents effect of the triazole moiety (ring B). In silico analysis indicated that compound 3 has higher total energy and dipole moment than colchicine and the other analogs, and it has excellent distribution of electron density and is more stable, resulting in an increased binding affinity during tubulin inhibition. Additionally, compound 3 was found to interact with three apoptotic markers, namely p53, Bcl-2, and caspase 3. Compound 3 showed strong similarity to colchicine, and it has excellent pharmacokinetics properties and a good dynamic profile. The in vitro anti-proliferation studies showed that compound 3 is the most cytotoxic CA-4 analog against cancer cells (IC50 of 6.35 µM against Hep G2 hepatocarcinoma cells), and based on its selectivity index (4.7), compound 3 is a cancer cytotoxic-selective agent. As expected and similar to colchicine, compound 3-treated Hep G2 hepatocarcinoma cells were arrested at the G2/M phase resulting in induction of apoptosis. Compound 3 tubulin polymerization IC50 (9.50 µM) and effect on Vmax of tubulin polymerization was comparable to that of colchicine (5.49 µM). Taken together, the findings of the current study suggest that compound 3, through its binding to the colchicine-binding site at ß-tubulin, is a promising microtubule-disrupting agent with excellent potential to be used as cancer therapeutic agent.

Experimental (FT-IR, NMR and UV) and theoretical (M06-2X and DFT) investigation, and frequency estimation analyses on (E)-3-(4-bromo-5-methylthiophen-2-yl)acrylonitrile.

The spectroscopic properties of (E)-3-(4-bromo-5-methylthiophen-2-yl)acrylonitrile have been investigated by FT-IR, UV, (1)H and (13)C NMR techniques. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths and angles) have been calculated using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr) and DFT/M06-2X (the highly parameterized, empirical exchange correlation function) quantum chemical methods with 6-311++G(d,p) basis set by Gaussian 03 software, for the first time. The assignments of the vibrational frequencies have been carried out by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies were in good agreement with the corresponding experimental data, and with the results in the literature. (1)H and (13)C NMR chemical shifts were calculated by using the gauge-invariant atomic orbital (GIAO) method. The electronic properties, such as excitation energies, oscillator strength wavelengths were performed by B3LYP methods. In addition, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and the other related molecular energy values have been calculated and depicted.

2,2-Dimethyl-N-(4-methyl-pyridin-2-yl)propanamide.

In the title compound, C11H16N2O, the dihedral angle between the mean plane of the 4-methypyridine group and the plane of the amide link is 16.7 (1)°, and there is a short intra-molecular C-H⋯O contact. Hydrogen bonding (N-H⋯O) between amide groups forms chains parallel to the b axis. Pairs of methyl-pyridine groups from mol-ecules in adjacent chains are parallel but there is minimal π-π inter-action.

4-(5-{2-[5-(4-Cyano-phen-yl)-3-methyl-thio-phen-2-yl]-3,3,4,4,5,5-hexa-fluoro-cyclo-pent-1-en-1-yl}-4-methyl-thio-phen-2-yl)benzo-nitrile chloro-form hemisolvate.

The crystal structure of the title compound, C29H16F6N2S2·0.5CHCl3, consists of mol-ecules with disordered perfluoro-cyclo-pentene rings [occupancy ratio 0.685 (3):0.315 (3)] and close F⋯F contacts (in the range 2.45-2.73 Å) between mol-ecules. The short contacts are associated with the disorder. The dihedral angle between thiophene rings is 57.44 (8)°. The 5-(4-cyano-phen-yl)-3-methyl-2-thienyl groups of adjacent mol-ecules are parallel, leading to zigzag chains of mol-ecules along [101]. The dihedral angles between each thiophene ring and its adjacent cyanobenzene ring are 8.9 (2) and 7.15 (10)°.

(E)-3-(4-Bromo-5-methyl-thio-phen-2-yl)acrylo-nitrile.

In the title structure, C8H6BrNS, the molecules are planar with the exception of the methyl H atoms. In the crystal, molecules are linked by intermolecular C-H⋯N interactions to form ribbons parallel to the b axis. Groups of ribbons are arranged in a herringbone pattern to form a layered structure parallel to the ab plane.