A convenient protocol was developed for the transformation of
-aryl-substituted benzamides to
-aryl-substituted benzothioamides using
-isopropyldithiocarbamate isopropyl ammonium salt as a novel ...thiating reagent. The major advantages of this protocol are its
procedure, short reaction times, mild conditions, simple work-up, high yields and pure products.
The parent 2-(4-benzyl-1-oxophthalazin-2(1
H
)-yl)-acetohydrazide
(4)
has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene ...compounds were produced by chemoselective
N
-alkylation of 4-Benzyl-2
H
-phthalazin-1-one
(2)
with ethyl chloroacetate to afford (4-benzyl-1-oxo-1
H
-phthalazin-2-yl) methyl acetate
(3)
. The ester
3
was hydrazinolyzed to give hydrazide
4
, then azide
5
coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1
H
)-yl) acetyl) glycinate
(7a)
was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1
H
)-yl)-
N
-(2-hydrazineyl-2-oxo ethyl) acetamide
(8a)
. The hydrazide
8a
under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide
8a
was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds
11d
,
12c
and
12d
exhibited potent cytotoxic activities with IC
50
values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC
50
= 1.02 μM). Interestingly compound
12d
exhibited promising potent EGFR inhibition with an IC
50
value 21.4 nM compared to Erlotinib (IC
50
= 80 nM). For apoptosis, compound
12d
induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound
12d
towards EGFR protein. Hence, compound
12d
may serve as a potential and selective anti-breast cancer agent.
Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. ...The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carboxylic acid with amino acid methyl esters following the
,
-dicyclohexylcarbodiimide (DCC) method and 1-hydroxy-benzotriazole (HOBt), as coupling reagents. The synthesized compounds were screened towards VEGFR2, and topoisomerase IIα proteins to highlight their binding affinities and virtual mechanism of binding. Interestingly, compounds
(Tyr) and
(β-Ala-L-Met) shared the activity towards the three proteins by forming the same interactions with the key amino acids, such as the co-crystallized ligands. Both compounds
and
exhibited potent cytotoxic activities against MCF-7 cells with IC
values of 4.98 and 5.85 µM, respectively causing cell death by 97.82 and 97.35%, respectively. Validating the molecular docking studies, both compounds demonstrated promising VEGFR-2 inhibition with IC
values of 23.6 and 34.2 µM, compared to Sorafenib (30 µM) and topoisomerase-II inhibition with IC
values of 4.1 and 8.6 µM compared to Doxorubicin (9.65 µM). Hence, these two promising compounds could be further tested as effective and selective target-oriented active agents against cancer.
Aflatoxin B1 (AFB1) is a common environmental pollutant that poses a major hazard to both humans and animals. Acacia senegal (Gum) is well-known for having antioxidant and anti-inflammatory bioactive ...compounds. Our study aimed to scout the nephroprotective effects of Acacia gum (Gum) against AFB1-induced renal damage. Four groups of rats were designed: Control, Gum (7.5 mg/kg), AFB1 (200 µg/kg b.w) and AFB1-Gum, rats were co-treated with both Gum and AFB1. Gas chromatography-mass spectrometry (GC/MS) analysis was done to determine the phytochemical constituents in Gum. AFB1 triggered profound alterations in kidney function parameters (urea, creatinine, uric acid, and alkaline phosphatase) and renal histological architecture. Additionally, AFB1 exposure evoked up-regulation of mRNA expression levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), and nuclear factor kB p65 (NF-κB/P65) in renal tissue. The oxidative distress and apoptotic cascade are also instigated by AFB1 intoxication as depicted in down-regulated protein expression of the nuclear factor erythroid 2–related factor 2 (Nrf2) and superoxide dismutase type 1 (SOD1) along with upregulation of cytochrome c (Cyto c), and cleaved Caspase3 (Casp3–17 and 19) in renal tissue. In conclusion, current study obviously confirms the alleviating effects of Gum supplementation against AFB1-induced renal dysfunction, oxidative harm, inflammation, and cell death. These mitigating effects are suggested to be attributed to Gum's antioxidant and anti-inflammatory activities. Our results recommend Gum supplementation as add-on agents to food that might aid in protection from AFB1-induced nephrotoxicity.
•Aflatoxin B1- provoked renal damage via oxidative stress and inflammatory pathways.•Acacia senegal (Gum) ameliorates AFB1-induced renal damage.•Gum inhibits oxidative stress and inflammation in the AFB1-induced renal damage.•Gum reduces AFB1-induced apoptosis in rats’ kidney.•Gum supplementation has therapeutic potential against AFB1-induced renal damage.
Aflatoxin B1 (AF) is an unavoidable environmental pollutant that contaminates food, feed, and grains, which seriously threatens human and animal health. Arabic gum (AG) has recently evoked much ...attention owing to its promising therapeutic potential. Thus, the current study was conducted to look into the possible mechanisms beyond the ameliorative activity of AG against AF-inflicted hepatic injury. Male Wistar rats were assigned into four groups: Control, AG (7.5 g/kg b.w/day, orally), AF (200 µg/kg b.w), and AG plus AF group. AF induced marked liver damage expounded by considerable changes in biochemical profile and histological architecture. The oxidative stress stimulated by AF boosted the production of plasma malondialdehyde (MDA) level along with decreases in the total antioxidant capacity (TAC) level and glutathione peroxidase (GPx) activity. Additionally, AF exposure was associated with down-regulation of the nuclear factor erythroid2–related factor2 (Nrf2) and superoxide dismutase1 (SOD1) protein expression in liver tissue. Apoptotic cascade has also been evoked following AF-exposure, as depicted in overexpression of cytochrome c (Cyto c), cleaved Caspase3 (Cl. Casp3), along with enhanced up-regulation of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, inducible nitric oxide synthase (iNOS), and nuclear factor kappa-B transcription factor/p65 (NF-κB/p65) mRNA expression levels. Interestingly, the antioxidant and anti-inflammatory contents of AG may reverse the induced oxidative damage, inflammation, and apoptosis in AF-exposed animals.
The scientific impact and novelty of the present work come from comparing the properties of analcime nanoparticles synthesized in the absence of polyethylene glycol 400 (abbreviated as AF) and in the ...presence of different volumes (3 mL (abbreviated as A3), 6 mL (abbreviated as A6), and 9 mL (abbreviated as A9)) of polyethylene glycol 400 as an organic structure template. The average crystallite size of the AF, A3, A6, and A9 samples is 150.83, 75.22, 47.64, and 87.58 nm, respectively. The BET surface area of the AF, A3, A6, and A9 samples is 17.61, 28.13, 58.24, and 23.77 m
2
/g, respectively. The FE-SEM images displayed that the A3 and A6 samples display a combination of spherical and polyhedral forms with mean diameters of 13.46 and 8.79 μm, respectively. The AF and A9 samples exhibit polyhedral forms with mean diameters of 20.36 and 19.03 μm, respectively. The maximum adsorption capacity of the AF, A3, A6, and A9 samples towards Zn(II) ions is 83.68, 115.61, 151.52, and 105.71 mg/g, respectively. The maximum adsorption capacity of the AF, A3, A6, and A9 samples towards Cd(II) ions is 59.95, 105.59, 134.23, and 93.19 mg/g, respectively. The removal of Zn(II) and Cd(II) ions by the AF, A3, A6, and A9 samples is chemical, spontaneous, and follows the Langmuir equilibrium isotherm and pseudo-second-order kinetic model. The synthesized adsorbents were regenerated using ethylenediaminetetraacetic acid tetrasodium salt dihydrate solution and have the ability to be used several times without significantly affecting their efficiency.
The parent ethyl 3-(4-benzyl-1-oxophthalazin-2(1
H
)-yl) propanoate (
3
) has 25 compounds. Their respective mono, dipeptides and hydrazones derivatives were produced by chemoselective
N
-alkylation
...via
addition reaction of 4-benzylphthalazin-1(2
H
)-one (
2
) with ethyl acrylate and anhydrous potassium carbonate to give ethyl 3-(4-benzyl-1-oxophthalazin-2(1
H
)-yl) propanoate (
3
). The ester
3
was hydrazinolyzed to give the corresponding hydrazide 3-(4-benzyl-1-oxophthalazin-2(1
H
)-yl) propanehydrazide (
5
), then azide
6
coupled with amino acid ester hydrochloride and/or amines to afford several parent esters
8a-c
, then a series of hydrazinolyzed reactions occurred to give corresponding hydrazides
9a-c
. The hydrazide
9a
was subjected to the azide coupling procedure, which resulted in the formation of various dipeptides. Subsequently, it was condensed with various aldehydes to yield hydrazone derivatives
13a-d
. Interestingly, compounds
9c
,
12b
, and
13c
exhibited potent cytotoxicity with IC
50
values of 1.58, 0.32 and 0.64 μM compared to sorafenib (IC
50
= 2.93 μM). Compound
12b
exhibited potent VEGFR2 inhibition by 95.2% with an IC
50
value of 17.8 μM compared to sorafenib (94.7% and IC
50
of 32.1 μM). For apoptosis activity,
12b
-treatment induced apoptosis in HCT-116 cells by 21.7-fold, arresting the cell proliferation at S-phase. Finally, it formed a good binding affinity towards VEGFR2 protein with a binding energy of −10.66 kcal mol
−1
, and it formed binding interactions with the key interactive amino acids.
A novel phthalazine derivative exhibited potent cytotoxicity against HCT-116 cells as VEGFR2 inhibitor and apoptosis cell death.
A series of methyl 2-3-(3-phenyl-quinoxalin-2-ylsulfanyl)propanamidoalkanoates and their corresponding hydrazides and N-alkyl 3-((3-phenylquinoxalin-2-yl)sulfanyl)propanamides were prepared on ...the basis of the chemoselective Michael reaction of acrylic acid with the parent substrate 3-phenylquinoxaline-2(1H)-thione. The parent thione was produced by a convenient novel thiation method from the corresponding 3-phenylquinoxalin-2(1H)-one. The chemical structures of the newly synthesized compounds were confirmed by elemental analyses, 1H and 13C NMR. The antiproliferative activity of the synthesized compounds was tested against human HCT-116 and MCF-7 cell lines. Out of 25 screened derivatives, 10 active compounds exhibited IC50’s in the range 1.9–7.52 μg/mL on the HCT-116, and 17 active compounds exhibited IC50’s in the range 2.3–6.62 μg/mL on the MCF-7 cell lines compared to the reference drug doxorubicin (IC50 3.23 μg/mL). The structure–activity relationship of the tested compounds was studied through their binding affinity to the human thymidylate synthase allosteric site in silico using molecular docking and proved the quinoxaline ring as a suitable scaffold carrying a peptidomimetic side chain in position 3.
The parent ester methyl-3-2-(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy)-acetylamino has 18 compounds. The starting material for alkanoates, their corresponding hydrazides, hydrazones, and ...dipeptides were produced by chemoselective O-alkylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione with ethyl chloroacetate(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy) acetic acid methyl ester. The starting ester was hydrazinolyzed, then azide coupled with amino acid ester hydrochloride to produce several parent esters, and then hydrazinolyzed to produce parent hydrazides. These hydrazides were used to make a series of dipeptides by reacting them with amino acid ester hydrochloride under azide coupling conditions, and they were also condensed with a number of aldehydes to make the hydrazones. These derivatives were subjected to cytotoxicity against HCT-116 and MDA-MB-231 cells and anti-bacterial and molecular docking studies. Results indicated that the tested compounds, especially 7c and 8b with the phenyl phthalazinone moieties, had promising cytotoxicity against the HCT-116 cells with IC50 values of 1.36 and 2.34 μM, respectively. Additionally, the promising compounds 7c and 8b exhibited poor cytotoxicity against WISH cells with much higher IC50 values, so they were safe against normal cells. Compound 8c exhibited potent anti-bacterial activity with inhibition zones of 12 and 11 mm against Staphylococcus aureus and Escherichia coli, respectively. The molecular docking results of compounds 7c and 8b revealed a good binding disposition and the ligand–receptor interactions like the co-crystallized ligand of the VEGFR2 protein, which may be the proposed mode of action. Finally, compounds 7c and 8b exhibited good ADME pharmacokinetics with good drug-likeness parameters. Hence, detailed studies for the mechanism of action of such compounds are highly recommended for the development of new potent anti-cancer and anti-bacterial agents.
In this work, calcium silicate/sodium calcium silicate nanostructures were facilely produced by sol–gel method. The sol–gel process involves the transformation of a colloidal solution into a gel and ...then further processing the gel to form a solid material. After that, the produced nanostructures were functionalized with chitosan and chitosan/glutaraldehyde as novel nanocomposites. In addition, the produced nanostructures and their corresponding nanocomposites were employed for the effective sorption of Cd(II) and Cu(II) ions from aqueous solutions by ion exchange and complexation processes. The maximum adsorption capacity of the produced nanostructures, nanostructures/chitosan, and nanostructures/chitosan/glutaraldehyde samples towards Cd(II) ions is 166.94, 236.97, and 324.68 mg/g, respectively. Besides, the maximum adsorption capacity of the same samples towards Cu(II) ions is 202.84, 287.36, and 348.43 mg/g, respectively. The adsorption of Cd(II) and Cu(II) ions was chemical, spontaneous, exothermic, and best described by the pseudo-second-order kinetic model and the Langmuir equilibrium isotherm. The study found that 9 M HCl effectively removed Cd(II) or Cu(II) ions from the synthesized adsorbents, achieving a desorption efficiency exceeding 99%. Furthermore, the produced adsorbents demonstrated excellent reusability over five consecutive adsorption/desorption cycles for the sorption of Cd(II) and Cu(II) ions.
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