2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase

In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6 μM and 0.6 μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer

In vitro and in silico evaluations of diarylpentanoid series as a-glucosidase inhibitor

A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor

Impact of within-row plant spacing and fixed fruit setting on yield and quality of rockmelon fruit cultivated by drip irrigation in a greenhouse

Experiments were conducted in a ventilated greenhouse located in a commercial farm (2°56′N, 101°54′E) at Broga, Malaysia from 2014 to 2015. The objective of this study was to evaluate the interaction between within-row plant spacing and fruit-set position on the yield and quality of 'Glamour' rockmelon fruit. Rockmelon was grown at 1.57 m between rows with 0.15 m, 0.30 m, and 0.60 m of within-row plant spacing. The plants were fixed to set fruit at T1 (one fruit, 1-7 lateral branches), T2 (one fruit, 8-14 lateral branches), T3 (two fruits, 1-7 lateral branches), and T4 (two fruits, 8-14 lateral branches). As within-row plant spacing decreased from 0.30 m to 0.15 m, yield per ha was increased by 58.1%, and a 3.7-fold increase in yield was seen from 0.60-m to 0.15-m spacing. Total soluble solids (11.96°Brix) and total carbohydrate content (86.60 g GE 100 g DW) were highest at a plant spacing of 0.60 m. Our results demonstrated that the interaction between 0.30-m within-row plant spacing with two fruits set at 8-14 lateral branches showed the most commercially viable outcome in fresh fruit weight as these conditions produced two fruits with an average fruit weight of 2.20 kg per fruit

Response surface modeling of processing parameters for the preparation of phytosterol Nanodispersions using an emulsification-evaporation technique.

The purpose of this study was to optimize the production parameters for water-soluble phytosterol nanodispersions. Response surface methodology (RSM) was employed to model and optimize three of the processing parameters: mixing time (t) by conventional homogenizer (1–20 min), mixing speed (v) by conventional homogenizer (1,000–9,000 rpm) and homogenization pressure (P) by high-pressure homogenizer (0.1–80 MPa). All responses [i.e., mean particle size (PS), polydispersity index (PDI) and phytosterols concentration (Phyto, mg/l)] fitted well to a reduced quadratic model by multiple regressions after manual elimination. For PS, PDI and Phyto, the coefficients of determination (R 2) were 0.9902, 0.9065 and 0.8878, respectively. The optimized processing parameters were 15.25 min mixing time, 7,000 rpm mixing speed and homogenization pressure 42.4 MPa. In the produced nanodispersions, the corresponding responses for the optimized preparation conditions were a PS of 52 nm, PDI of 0.3390 and a Phyto of 336 mg/l

Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors

Rheological properties of modified starch-whey protein isolate stabilized soursop beverage emulsion systems

The rheological properties of soursop beverage emulsions as a function of main emulsion components, namely modified starch (5–12 % w/w), whey protein isolates (WPI) (0–2 % w/w), soursop flavor oil (5–15 % w/w), and deionized water (67.4–86.4 % w/w) were investigated using a fourcomponent with constrained extreme vertices mixture design. The apparent viscosity, flow index, yield stress, viscoelastic behavior (G′ and G′′) and consistency coefficient were evaluated. In general, analysis of variance (ANOVA) showed high coefficients of determination values (R2), ranging between 0.795 and 0.999 for the regression models, thus confirming a satisfactory adjustment of the polynomial regression models with the experimental data. Increase in both modified starch and oil phase concentration had increased the apparent viscosity of the emulsions. Contrary, higher concentrations of oil phase had negative effects on flow index and consistency coefficient, resulting in the changes of flow behavior. In addition, modified starch showed solid-like elastic properties at low concentration but behaved as liquid-like viscous as the concentration of modified starch increased. Oil phase concentration had a significant (p0.05) effect on neither the apparent viscosity nor the flow index at low concentrations but was an important element in providing elastic properties to the emulsion film

Ternary copper(II)-polypyridyl enantiomers: aldol-type condensation, characterization, DNA-binding recognition, BSA-binding and anticancer property

Chiral enantiomers [Cu(phen)(l-threo)(H2O)]NO31 and [Cu(phen)(d-threo)(H2O)]NO32 (threo = threoninate) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz.l- and d-[Cu(phen)(5MeOCA)(H2O)]NO3·xH 2O (3 and 4; phen = 1,10-phenanthroline; 5MeOCA = 5-methyloxazolidine-4-carboxylate; x = 0-3) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-Visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. Analysis of restriction enzyme inhibition by these four complexes revealed modulation of DNA binding selectivity by the type of ligand, ligand modification and chirality. Their interaction with bovine serum albumin was investigated by FL and electronic spectroscopy. With the aid of the crystal structure of BSA, spectroscopic evidence suggested their binding at the cavity containing Trp134 with numerous Tyr residues in subdomain IA. The products were more antiproliferative than cisplatin against cancer cell lines HK-1, MCF-7, HCT116, HSC-2 and C666-1 except HL-60, and were selective towards nasopharyngeal cancer HK-1 cells over normal NP69 cells of the same organ type

Inhibition of prostaglandin E2 production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation

The discovery of potent inhibitors of prostaglandin E2 (PGE2) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE2 triggers a vast array of biological signals and physiological events that contributes to inflammatory diseases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthesis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE2 production with an IC50 value of 2.1 μM. The suppression upon PGE2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE2 inhibition concentration. The obtained atomic coordinates for the single-crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites

Synthesis of flavone-based compounds as ros-dependent apoptosis inducers in colorectal cancer

Apoptosis is essential for maintaining cell homeostasis. It hinders the cancer cells survival and excessive ROS can induce DNA damage in cancer cells, which lead to apoptosis. Therefore, targeting apoptosis may be a universal cancer therapeutic technique. Twelve flavone-based compounds were synthesised and characterised. All compounds were evaluated for cytotoxicity against four human cancer cell lines: kidney, breast, colorectal, and bladder cancer cells. Only compound 8 exhibited excellent cytotoxicity against all investigated cancer cell lines, with notably potent cytotoxicity against colorectal (SW620) cells (IC50: 3.2 μM) and higher cytotoxicity than control (IC50: 4.2 μM). Mechanistic analyses such as colony formation, cell cycle arrests and flow cytometry analyses demonstrated an increase in intracellular ROS-induced apoptosis in SW620 cells, which is a potential mode of action for compound 8. Western blot research confirmed the apoptotic mechanism of 8 by showing overexpression of c-PARP, BAD, BAK, and AMPK and downregulation of BCL-2 and AKT. Taken together, the data showed that 8 induces apoptosis by increasing ROS. According to this study, a 4-chloromethyl substituent at the C3-phenyl group may be required for 8's cytotoxicity since other para substituents are inactive. Therefore, structure-activity analysis of 8 in related proteins can be studied