Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N'-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH3, 4-OCH3, and 4-N(CH3)2, were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH3 substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most of the compounds, in this series, especially compounds 5c, 5b and 5h, also significantly activated caspase-3 activity. Among these, compound 5c displayed 1.61-fold more potent than PAC-1 as caspase-3 activator. Cell cycle analysis showed that compounds 5b, 5c, and 5h significantly arrested the cell cycle in G1 phase. Further apoptotic studies also demonstrated compounds 5b, 5c, and 5h as strong apoptotic cell death inducers. The docking simulation studies showed that these compounds could activate procaspase via chelating Zn2+ ion bound to the allosteric site of the zymogen.

Phytochemical composition, antioxidant, antibacterial, and enzyme inhibitory activities of organic extracts from flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry.

Cleistocalyx operculatus flower buds have been widely used in traditional medicine because of their rich content of bioactive constituents. In this study, we obtained seven solvent extracts from the flower buds and evaluated their total phenolic (TPC), flavonoid (TFC), tannin (TTC), triterpenoid saponin (TSC), and alkaloid (TAC) contents. We assessed antioxidant activities using the DPPH assay and also looked at antimicrobial and enzyme inhibitory effects. The water extract possessed the highest TPC (328.9 mg GAE/g extract), followed by ethanol, methanol, and hexane extracts (85.4-101.5 mg GAE/g extract). Chloroform, butanol, ethyl acetate, and ethanol extracts had high TSCs (245.4-287.2 mg OAE/g extract). The hexane extract was richest in TTC and TFC (32.7 mg CE/g extract and 81.1 mg QE/g extract, respectively). Ethanol and methanol extracts exhibited the strongest antioxidant activities (IC50 values of 25.2 and 30.3 µg/ml, respectively), followed by the water extract (IC50 of 40.2 µg/ml). The hexane extract displayed the most growth-inhibitory activity against Helicobacter pylori ATCC51932 and ATCC43504 strains and Salmonella enterica serovar Typhimurium ATCC13311 (MIC values of 0.06, 0.13, and 0.4 mg/ml, respectively). Moreover, the hexane extract revealed the strongest inhibition of H. pylori urease activity (IC50 of 4.51 µg/ml), whereas the water and methanol extracts had potent inhibitory effects on α-glucosidase activity (IC50 values of 9.9 and 15.1 µg/ml, respectively). These flower bud extracts could be used for health protection, especially in preventing bacterial infections and inhibiting enzymes associated with various human diseases. Further investigation into the application of C. operculatus flower buds in the food and pharmaceutical industries is necessary.

Toxicity of Zanthoxylum piperitum and Zanthoxylum armatum oil constituents and related compounds to Stomoxys calcitrans (Diptera: Muscidae).

Zanthoxylum plants (Rutaceae) have drawn attention because they contain insecticidal principles against insects. An assessment was made of the insecticidal and acetylcholinesterase (AChE) inhibitory activities of Zanthoxylum piperitum steam distillate and Zanthoxylum armatum seed oil, their 28 constituents, and eight structurally related compounds against female stable fly, Stomoxys calcitrans (L.). Results were compared with those of two organophosphorus insecticides chlorpyrifos and dichlorvos. Potent fumigant toxicity was observed with cuminaldehyde, thymol, (1S)-(-)-verbenone, (-)-myrtenal, carvacrol, (S)-(Z)-verbenol, Zanthoxylum piperitum steam distillate, cuminyl alcohol, Zanthoxylum armatum seed oil, piperitone, (-)-(Z)-myrtanol, and citronellal (LC50, 0.075-0.456 microg/cm3). However, they were five orders of magnitude less toxic than either chlorpyrifos or dichlorvos. An in vitro bioassay using female fly heads indicates that strong AChE inhibition was produced by citronellyl acetate, alpha-pinene, thymol, carvacrol, and alpha-terpineol (1.20-2.73 mM), but no direct correlation between fly toxicity and AChE inhibition by the test compounds was observed. Structure-activity relationships indicate that structural characteristics, such as carbon skeleton, degrees of saturation and types of functional groups, and vapor pressure parameter, appear to play a role in determining toxicities of the test monoterpenoids to stable flies. Global efforts to reduce the level of highly toxic synthetic insecticides in the agricultural environment justify further studies on Z. piperitum and Z. armatum oil-derived materials as potential insecticides for the control of stable fly populations.

Characteristics of Ag-incorporated bioactive glasses prepared by a modified sol-gel method with a shortened synthesis time and without the use of catalysts.

This work presents the preparation of bioactive glasses 70SiO2-(26 - x)CaO-4P2O5-xAg2O (with x = 0, 1, 3, 10 mol%) by a modified sol-gel method with reduced synthesis time based on hydrothermal reaction in a medium without acid or base catalysts. The synthetic materials were characterized by several physical-chemical techniques such as TG-DSC, XRD, SEM, TEM, and N2 adsorption/desorption measurement. The analysis data confirmed that the glass sample not containing Ag has a completely amorphous structure, while glass samples containing Ag exhibited a pure phase of metallic nano-silver in the glass amorphous phase. All the synthetic glasses have mesoporous structures with particle sizes of less than 30 nm. The addition of silver to the bioactive glass structure in general did not drastically reduce the specific surface areas and pore volumes of glasses as in previous studies. The bioactivity of the silver-incorporated glasses did not reduce, and even increased in the cases of bioactive glass containing 3, and 10 mol% of Ag2O. The biocompatibility of synthetic glasses with fibroblast cells (L-929) was confirmed, even with glass containing high amounts of Ag. Representatively, Ag-incorporated glass samples (sample x = 3, and x = 10) were selected to check the antibacterial ability using bacterial strain Pseudomonas aeruginosa ATCC 27853 (Pa). The obtained results indicated that these glasses exhibited good antibacterial ability to Pseudomonas aeruginosa. Thus, the synthetic method in this study proved to be a fast, environmentally friendly technique for synthesizing Ag-incorporated glass systems. The synthesized glasses show good bioactive, biocompatible, and antibacterial properties.

Repellency to Stomoxys calcitrans (Diptera: Muscidae) of plant essential oils alone or in combination with Calophyllum inophyllum nut oil.

The repellency to female Stomoxys calcitrans (L.) (Diptera: Muscidae) of 21 essential oils (EOs) alone or in combination with Calophyllum inophyllum L. (Clusiaceae) nut oil (tamanu oil) was examined using an exposed human hand bioassay. Results were compared with those of commonly used repellent N,N-diethyl-3-methylbenzamide (DEET). In tests with six human male volunteers at a dose of 0.5 mg/cm2, patchouli (protection time [PT], 3.67 h) was the most effective EO but less active than DEET (4.47 h), as judged by the PT to first bite. Very strong repellency also was produced by clove bud, lovage root, and clove leaf EOs (PT, 3.50-3.25 h), whereas strong repellency was obtained from thyme white EO (2.12 h). Thyme red, oregano, and geranium EOs exhibited moderate repellency (PT, 1.24-1.11 h). At 0.25 mg/cm2, protection time of clove bud, clove leaf, and lovage root EOs (PT, approximately equal to 1 h) was shorter than that of DEET (2.17 h). An increase in the protection time was produced by binary mixtures (PT, 2.68-2.04 h) of five EOs (clove bud, clove leaf, thyme white, patchouli, and savory) and tamanu oil (0.25:2.0 mg/cm2) compared with that of either the constituted essential oil or tamanu oil alone (PT, 0.56 h). The protection time of these binary mixtures was comparable with that of DEET. With the exception of savory EO, the other EOs, tamanu oil, and binary mixtures did not induce any adverse effects on the human volunteers at 0.5 mg/cm2. Thus, binary mixtures of essential oils and tamanu oil described merit further study as potential repellents for protection from humans and domestic animals from biting and nuisance caused by S. calcitrans.

Toxicity of Myristica fagrans seed compounds against Blattella germanica (Dictyoptera: Blattellidae).

The insecticidal constituents of hexane-soluble fraction from a methanolic extract of the seeds from Myristica fragrans (Myristicaceae) against adult females of Blattella germanica (L.) (Dictyoptera: Blattellidae) were analyzed by gas chromatography and gas chromatography-mass spectrometry. The insecticidal activity of 13 Myristica seed compounds against female B. germanica was examined by using the filter-paper contact toxicity and vapor phase toxicity bioassays. Results were compared with those of the other 23 known compounds of Myristica seed and currently used insecticides: dichlorvos, deltamethrin, permethrin, and propoxur. In contact toxicity tests using female B. germanica, (IS)-(-) -beta-pinene (0.06 mg/cm2) was the most toxic insecticide, based on 24-h LD50 values. The insecticidal activity of this compound was comparable with that of permethrin (0.05 mg/cm2). (1R)-(+) -Camphor, (1S)-(-) -camphor, dipentene, (1R)-(+) -3-pinene, and (+)-alpha-terpineol (0.10-0.14 mg/cm2) were more toxic than propoxur (0.19 mg/cm2). (E)-Sabinene hydrate and propoxur were almost equitoxic. Potent insecticidal activity also was observed with (R)-(+) -citronellal, (S)-(-) -citronellal, (R)-(-) -alpha-phellandrene, (1S)-(-) -alpha-pinene, (1R)-(+) -alpha-pinene, and safrole (0.27-0.48 mg/cm2). In vapor phase toxicity tests, the compounds tested were effective in closed but not in open containers. These results indicate that the effect of these compounds was largely a result of action in the vapor phase. Myristica seed compounds described merit further study as potential insecticides or as leads for the control of cockroaches.

Toxicity of Lavandula angustifolia oil constituents and spray formulations to insecticide-susceptible and pyrethroid-resistant Plutella xylostella and its endoparasitoid Cotesia glomerata.

BACKGROUND: Plutella xylostella is one of the most serious insect pests of cruciferous crops. This study was conducted to determine the toxicity of 21 constituents from Lavandula angustifolia essential oil (LA-EO) and another 16 previously known LA-EO constituents and the toxicity of six experimental spray formulations containing the oil (1-6 g L(-1) sprays) to susceptible KS-PX and pyrethroid-resistant JJ-PX P. xylostella larvae, as well as to its endoparasitoid Cotesia glomerata adults. RESULTS: Linalool and linalool oxide (LC50 = 0.016 mg cm(-3) ) were the most toxic fumigant compounds and were 10.7-fold less toxic than dichlorvos to KS-PX larvae. Either residual or fumigant toxicity of these compounds was almost identical against larvae from either of the two strains. Against C. glomerata, dichlorvos (LC50 = 7 × 10(-6) mg cm(-3) ) was the most toxic insecticide. LA-EO was ∼1430 times less toxic than dichlorvos. The oil applied as 6 g L(-1) spray and emamectin benzoate 21.5 g L(-1) emulsifiable concentrate provided 100% mortality against larvae from either of the two strains. CONCLUSION: Reasonable P. xylostella control in greenhouses can be achieved by a spray formulation containing the 6 g L(-1) oil as potential contact-action fumigant. © 2015 Society of Chemical Industry.

Enhanced repellency of binary mixtures of Calophyllum inophyllum nut oil fatty acids or their esters and three terpenoids to Stomoxys calcitrans.

BACKGROUND: An assessment was made of the repellency to female stable flies of tamanu nut oil fatty acids or their esters alone (each 0.5 mg cm(-2) ) or in combination with cuminyl alcohol, cuminaldehyde and α-phellandrene (each 0.25 mg cm(-2) ), using an exposed human hand bioassay. Results were compared with those of synthetic repellent DEET (0.25 mg cm(-2) ). RESULTS: Based upon protection time (PT) (time to first bite of stable fly), oleic acid, linoleic acid, methyl oleate or methyl linoleate synergised the repellency of each monoterpenoid and DEET. For example, the binary mixture of oleic acid and cuminyl alcohol (PT 2.05 h) resulted in significantly greater repellency than either oleic acid (0.55 h), cuminyl alcohol (0.70 h) or DEET alone (1.50 h). The binary mixtures of oleic acid and cuminyl alcohol or DEET (PT 2.10 h) did not differ significantly in repellency. The structure-activity relationship indicates that the degree of saturation, the side chain length and the functional group of fatty acids appear to play a role in determining the fatty acid repellency to stable flies. CONCLUSION: Mixtures formulated from fatty acid and monoterpenoid could be useful as potential repellents for protecting humans and possibly domestic animals from bites caused by stable fly.

Enhanced repellency of binary mixtures of Zanthoxylum piperitum pericarp steam distillate or Zanthoxylum armatum seed oil constituents and Calophyllum inophyllum nut oil and their aerosols to Stomoxys calcitrans.

BACKGROUND: The repellency to stable fly, Stomoxys calcitrans (L.), of Zanthoxylum piperitum (L.) DC pericarp steam distillate (ZP-SD), Zanthoxylum armatum DC seed oil (ZA-SO) and their constituents alone or in combination with Calophyllum inophyllum L. nut oil (CI-NO), as well as six aerosol formulations containing ZP-SD or ZP-SO and CI-NO, was compared with that of a synthetic repellent, DEET, using an exposed human hand bioassay. RESULTS: At 0.20 mg cm(-2), ZP-SD treatments resulted in 91 and 68% repellency following 30 and 60 min exposure respectively, while DEET gave 100 and 84% repellency. ZA-SO was less effective than ZP-SD. At 0.2 mg cm(-2), the most active constituents, cuminaldehyde, cuminyl alcohol, limonene and methyl cinnamate, gave 82, 74, 74 and 64% repellency at 30 min respectively, but DEET gave 100 and 87% repellency at 30 and 60 min. An increase in effectiveness and duration of repellency was produced by binary mixtures of ZP-SD, ZA-SO or bioactive constituents (each 0.01 mg cm(-2)) and CI-NO (0.99 mg cm(-2)). The repellency of aerosols containing 2.5% ZP-SD or 2.5% ZA-SO and 2.5% CI-NO was comparable with that of 5% DEET aerosol. CONCLUSION: Mixtures formulated from ZP-SD, ZA-SO or bioactive constituents and CI-NO could be useful as potential repellents for the control of stable fly populations in light of global efforts to reduce the level of highly toxic synthetic repellents.