Novel tropane analogues as Hsp90 inhibitors targeting colon cancer: Synthesis, biological estimation, and molecular docking study.

New derivatives of tropane scaffold were prepared from the reaction of their thione or thioamide derivatives with α-halocarbonyl compounds. The structures of all new derivatives were assured and proved with their spectral data. The novel tropane derivatives were examined for their cytotoxicity on two colon tumor cell lines; Caco2 and HCT116 cells. The most active compounds 3, 4, 5, 9d and 14a displayed significant antitumor activities with IC50 range of 9.50 - 30.15 µM compared to doxorubicin. Moreover, they revealed reduced cytotoxic effect on WI-38 normal ones, signifying their great safety. With the aim of better understanding the inhibitory potential of such compounds on heat-shock protein 90 (Hsp90), there activities were assessed against such enzyme demonstrating high inhibitory activities with IC50 range of 56.58-78.85 nM. Western blotting was carried out to ensure the inhibitory activity on Hsp90, results showed that 3 markedly suppressed Hsp90 expression on Caco2 cell line. Additionally, a molecular docking analysis of the most potent derivatives at the Hsp90 binding site was carried out in order to approve the performed in vitro assays.

Synthesis and in vitro study of pyrimidine-phthalimide hybrids as VEGFR2 inhibitors with antiproliferative activity.

Aim: Thalidomide, a once notorious sedative, is now clinically used as an antitumor agent. We aimed to use it as a lead compound for designing pyrimidine-phthalimide hybrids. Materials & methods: Nucleophilic substitution reaction of thalidomide analog 4 with primary and/or secondary aliphatic amines afforded pyrimidine-phthalimide hybrids 5a-g, 6 and 7a-d. Results & conclusion: Compound 7c showed high antiproliferative activity against four cell lines: HepG-2 (IC50: 7.86 ± 0.5 µM), MCF-7 (IC50: 2.77 ± 0.1 µM), HCT-116 (IC50: 5.73 ± 0.4 µM) and PC-3 (IC50: 8.32 ± 0.5 µM), with selective cytotoxicity for WI-38 (IC50: 43.2 ± 2.56 µM). 7c arrested MCF-7 cells at S phase of the cell cycle and increased the total apoptotic cells by 50-fold. 7c inhibited VEGFR2 in vitro (IC50: 0.130 ± 0.02 µM). 7c was capable of binding at the VEGFR2 binding site, forming hydrogen bond interactions with Asp1046 and Glu885 in a similar way to sorafenib.

Conductive polythiophene/graphitic-carbon nitride nanocomposite for the detection of ethanol mixing in petrol.

The automobile vehicles must be operated on fuel containing no more than 10% ethanol. Use of fuel having more than 10% ethanol may cause engine malfunction, starting and running issues, and material degradation. These negative impacts could cause irreversible damage to the vehicles. Therefore, ethanol mixing in petrol should be controlled below 10% level. The current work is the first to report sensing of ethanol mixing in petrol with reference to the variation in the DC electrical conductivity of polythiophene/graphitic-carbon nitride (PTh/gC3N4) nanocomposite. The in situ chemical oxidative method of polymerization was used for synthesizing PTh and PTh/gC3N4 nanocomposite. Fourier transform infrared spectroscopy (FT-IR), X-rays diffraction (XRD), thermo-gravimetric analysis (TGA), transmittance electron microscopy (TEM) as well as scanning electron microscopy (SEM) analysis were used for confirmation of the structure along with morphology of the PTh and PTh/gC3N4 nanocomposite. The thermal stability of DC electrical conductivity of PTh and PTh/gC3N4 nanocomposite were tested under isothermal and cyclic ageing condition. The sensing response of PTh and PTh/gC3N4 nanocomposite as a function of DC electrical conductivity were recorded in petrol and ethanol atmosphere. The sensing response of PTh/g-C3N4 nanocomposite in petrol atmosphere was 6.1 times higher than that of PTh with lower detection limit to 0.005 v/v% of ethanol prepared in n-hexane.

Fighting Antibiotic Resistance: New Pyrimidine-Clubbed Benzimidazole Derivatives as Potential DHFR Inhibitors.

The present work describes the design and development of seventeen pyrimidine-clubbed benzimidazole derivatives as potential dihydrofolate reductase (DHFR) inhibitors. These compounds were filtered by using ADMET, drug-likeness characteristics calculations, and molecular docking experiments. Compounds 27, 29, 30, 33, 37, 38, and 41 were chosen for the synthesis based on the results of the in silico screening. Each of the synthesized compounds was tested for its in vitro antibacterial and antifungal activities using a variety of strains. All the compounds showed antibacterial properties against Gram-positive bacteria (Staphylococcus aureus and Staphylococcus pyogenes) as well as Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Most of the compounds either had a higher potency than chloramphenicol or an equivalent potency to ciprofloxacin. Compounds 29 and 33 were effective against all the bacterial and fungal strains. Finally, the 1,2,3,4-tetrahydropyrimidine-2-thiol derivatives with a 6-chloro-2-(chloromethyl)-1H-benzo[d]imidazole moiety are potent enough to be considered a promising lead for the discovery of an effective antibacterial agent.

Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia.

Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hits. The 7-(4-Bromo-phenyl)-3-(3-chloro/2-chloro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamines 5 h and 5i revealed the best CDK2 inhibitory activity with comparable potency (IC50 = 22 and 24 nM, respectively) to that of dinaciclib (IC50 = 18 nM). Additionally, both analogues showed potent activities against CDK1, CDK5 and CDK9 at nanomolar concentrations (IC50 = 28-80 nM). The anti-leukemia screening of the target compounds showed strong to moderate cytotoxicity against the used leukemia cell lines (MOLT-4 and HL-60). Compound 5 h inhibited MOLT-4 and HL-60 by 1.4 and 2.3 folds (IC50 = 0.93 and 0.80 µM), respectively, compared to dinaciclib (IC50 = 1.30 and 1.84 µM). Furthermore, compound 5i was comparable to dinaciclib against MOLT-4 and exhibited twice its activity against HL-60. Besides, the cytotoxicity of the promising analogues on normal human blood cells indicated the safety of 5h and 5i as compared to the reference dinaciclib. The pharmacokinetic properties of 5h and 5i were predicted using ADME calculations revealing good oral bioavailability and high GI absorption. The molecular docking simulations indicated, as expected, that the dinaciclib analogues can well-accommodate the CDK2 binding site, forming a variety of interactions.

Phytoassisted synthesis and characterization of palladium nanoparticles (PdNPs); with enhanced antibacterial, antioxidant and hemolytic activities.

With increasing demand for the treatment of microbial resistance around the globe, it is necessary to develop metallic nanoparticles , ideally by the use of nontoxic medium i.e. plant constituents, that could arrest the microbial growth. For this reason, small and highly crystalline PdNPs were effectively synthesized by using Eryngium caeruleum leaf extract as both the reducing and capping agent. During the synthesis of PdNPs, the size and shape were made controlled by using different solvents i.e., ethanol, methanol and aqueous extract of Eryngium caeruleum. A series of physicochemical characterizations were applied to inquire the synthesis, crystal structure, particles size, and surface morphology of PdNPs. Furthermore, the PdNPs demonstrated excellent potential for the inactivation of gram-positive and gram-negative bacteria, where the methanol-PdNPs exhibited maximum growth inhibition zones against tested bacteria as compared to ethanol-PdNPs and aqueous-PdNPs. Besides, PdNPs showed better antioxidant activity to effectively scavenge 2, 2 diphenyl-1-picrylhydrazyl (DPPH). More importantly, the synthesized PdNPs are not only active for ROS generation but also show no hemolytic activity. We believe that this greener approach uncovered the useful and efficient applications of highly active PdNPs and their biocompatibility.

Preparation of multifunctional long-persistent photoluminescence cellulose fibres.

Simple preparation of flame-retardant, photoluminescent, and superhydrophobic smart nanocomposite coating was developed and applied onto cotton fibres using the simple pad-dry-cure technique. This novel strategy involved the immobilization of rare-earth-doped aluminium strontium oxide (ASO; SrAl2 O4 :Eu+2 ,Dy+3 ) nanoparticles, environmentally friendly room temperature vulcanizing silicone rubber (RTV) and environmentally friendly Exolet AP422 (Ex). The fabrics were also able to produce a char film in the fire-resistant assessment, providing fibres with a self-extinguishing characteristic. Furthermore, the fire-retardant performance of the coated cotton samples remained resistant to washing over 35 laundry cycles. The superhydrophobicity of the treated fabrics was monitored to improve by increasing the photoluminescent phosphor nanoparticles. The produced transparent photoluminescent film displayed an absorption at 360 nm and an emission at 526 nm. The photoluminescent fabrics were observed to generate different colorimetric shades, including white, green-yellow and bright white as monitored by Commission Internationale de l'Éclairage laboratory colorimetric coordinates. Slow emissions were detected for the treated cotton fabrics as monitored by emission, ultraviolet-visible light absorption, lifetime, and decay time spectral profiles to indicate glow in the dark phosphorescence effect. Both comfort and mechanical properties of the coated fibres were evaluated by measuring their bending length and air permeability.

Novel biologically active polyurea derivatives and its TiO2-doped nanocomposites.

A new series of polyurea derivatives and its nanocomposites were synthesised by the solution polycondensation method through the interaction between 4(2-aminothiazol-4-ylbenzylidene)-4-(tert-butyl) cyclohexanone and diisocyanate compound in pyridine. The PU1-3 structure was confirmed using Fourier transform-infrared (FTIR) spectroscopy and characterised by solubility, viscometry, gel permeation chromatography (GPC), and X-ray diffraction (XRD) analysis. In addition, PU1-3 was evaluated by TGA. Polyurea-TiO2nanocomposites were synthesised using the same technique as that of PU1-3 by adding TiO2 as a nanofiller. The thermal properties of PU2TiO2a-d were evaluated by TGA. Moreover, the morphological properties of a selected sample were examined by SEM and TEM. In addition, PU1-3 and PU2TiO2a-d were examined for antimicrobial activity against certain bacteria and fungi. The PU1-3 showed antibacterial activity against some of the tested bacteria and fungi, as did PU2TiO2a-d, which increased with the increase in TiO2 content. Furthermore, molecular docking studies were displayed against all PU1-3 derivatives against two types of proteins. The results show that the increase in the strength of π-H interactions and H-donors contributed to improved binding of PU2 compared to PU1 andPU3. The docking of 1KZN against the tested polymers suggests an increase in the docking score of PU2, then PU1, and PU3, which is in agreement with the antibacterial study.