[4-(3-Amino-4-mehoxy-5-methylphenyl)-1-oxo-1H-phthalaz-2-yl] acetic acid hydrazide and its synergetic effect with KI as a novel inhibitor for low carbon steel corrosion in 0.5 M H2SO4.

We report the synthesis of novel [4-(3-amino-4-mehoxy-5-methyl phenyl)-1-oxo-1H-phthalaz-2-yl] acetic acid hydrazide (APPH), followed by its characterization using X-ray diffraction (XRD), Fourier transforms infrared (FT-IR) spectroscopy, 1H-NMR spectroscopy, and LC/MS. Further, the inhibition effect of the varying concentration of APPH on the corrosion of low steel (LCS) in 0.5 M H2SO4 was investigated by weight loss and electrochemical measurements at 30 °C. The percentage inhibition efficacy of APPH increased with concentration and reached about 84% at 0.5 mM at 30 °C, also rising to 88% after 6 h of exposure. According to the polarization measurements, the investigated APPH works as a mixed-type inhibitor. Furthermore, the synergistic corrosion inhibition mechanism APPH showed that the inhibition efficiency maximizes with increasing inhibitor concentration, and the maximum value was 83% at 0.5 mM APPH. The adsorption of APPH on the LCS surface is more fitting to the Langmuir isotherm model. The free energy value (-ΔG° ads) was 33.3 kJ mol-1. Quantum chemical calculation was applied to APPH and acted as excellent support for the experimental data.

Synthesis, Antiproliferative Activity, and Apoptotic Profile of New Derivatives from the Meta Stable Benzoxazinone Scaffold.

BACKGROUND: Cancer exerts a huge strain on the health system. The emerging resistance to the current chemotherapies demands the continuous development of new anticancer agents with lower cost, higher efficacy, and greater specificity. OBJECTIVE: This study aimed at developing selective small molecules as targeted anticancer agents. METHODS: The behavior of benzoxazinone 2 towards nitrogen nucleophiles, such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemicarbazide, was described. The behavior of the amino quinazolinone 3 towards carbon electrophiles and P2S5 was also investigated. The antiproliferative activity of 17 new benzoxazinone derivatives was examined against the growth of three human cancer cell lines; liver HepG2, breast MCF-7, and colon HCT-29, in addition to the normal human fibroblasts WI-38, and the selectivity index was calculated. The possible molecular pathways, such as the cell cycle and apoptosis, were investigated. RESULTS: Derivatives 3, 7, 8, 10, 13, and 15 had a significant (less than 10 µM) antiproliferative activity against the three cancer cell lines investigated. Derivative 7 showed the best antiproliferative profile comparable to that of doxorubicin. The selectivity index for all the effective derivatives ranged from ~5-12 folds, indicating high selectivity against the cancer cells. Derivative 15 caused ~ 7-fold and 8-fold inductions in the expression of p53 and caspase3, respectively. It also caused a ~ 60% reduction in the expression of both topoisomerase II (topoII) and cyclin-dependent kinase 1 (cdk1). Derivatives 3, 7, and 8 had a similar profile; ~ 6-8-fold increased in the expression of p53 and caspase3 but these compounds were devoid of any significant effect on the expression of topoII and cdk1. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression ofcaspase3, and more than 60% downregulation in the expression of topoII. The results of the gene expression of topoII and caspase3 were confirmed by the measurement of the topoII concentration and caspase3 activity in the HepG2 cells. CONCLUSION: Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing cdk1), preventing the DNA duplication (downregulating topo II), and inducing apoptosis (inducing p53 and caspase3). One common feature in all the six active derivatives is the presence of a free amino group. These compounds have merit for further investigations.

Assessment of the protective effect of yeast cell wall ß-glucan encapsulating humic acid nanoparticles as an aflatoxin B1 adsorbent in vivo.

This study aimed to assess the protective effect of encapsulating humic acid-iron complexed nanoparticles (HA-Fe NPs) inside glucanmannan lipid particles (GMLPs) extracted from yeast cell wall against aflatoxin B (AFB1 ) toxicity in vivo. Four groups of male Sprague-Dawley rats were treated orally for 2 weeks included the control group, AFB1 treated group (80 µg/kg b.w); GMLP/HA-Fe NPs treated group (0.5 mg/kg b.w), and the group treated with AFB1 plus GMLP/HA-Fe NPs. GMLPs are empty 3-4 micron permeable microspheres that provide an efficient system for the synthesis and encapsulation of AFB1 -absorbing nanoparticles (NPs). Humic acid nanoparticles (HA-NPs) were incorporated inside the GMLP cavity by complexation with ferric chloride. In vivo study revealed that AFB1 significantly elevated serum alanine aminotransferase, aspartate aminotransferase, creatinine, uric acid, urea, cholesterol, triglycerides, LDL, malondialdehyde, and nitric oxide. It significantly decreased total protein, high-density lipoprotein, hepatic and renal CAT and glutathione peroxidase content and induced histological changes in the liver and kidney (p ≤ 0.05). The coadministration of the synthesized formulation GMLP/HA-Fe NPs with AFB1 has a protective effect against AFB1 -induced hepato-nephrotoxicity, oxidative stress and histological alterations in the liver and kidney.

Design, synthesis, molecular docking and in silico ADMET profile of pyrano[2,3-d]pyrimidine derivatives as antimicrobial and anticancer agents.

Pyrano[2,3-d]pyrimidine derivatives were synthesized by treating cyclic compounds containing active methylene group with aldehyde and malononitrile in butanol. The behavior of pyrano[2,3-d]pyrimidine towards some electrophlies namely triethylorthoformate followed by nitrogen nucleophiles as isobutylamine, urea, phenylthiourea, p-toluidine, o-phenylenediamine, o-aminophenol, 2-amino-4-methyl-pyridine and acetic acid with the aim of obtaining some interesting non-mixed heterocyclic compounds. All synthesized compounds to some extent have shown good antimicrobial activity against different microbial strains that had been extracted by inhibiting cell wall synthesis. Compound 5b showed the highest antibacterial activities against B. subtilis, S. aureus and E. coli. On the other hand compound 5 g exhibited the highest antibacterial and antifungal activities against P. aeruginosa and A. niger respectively. In addition, they explore cytotoxic potentialities against different cell lines via DNA intercalation and Top-II inhibition. The cytotoxic activities clarify the strong inhibitory activity of derivative 5a against HepG2 cells with IC50 = 2.09 µM, while HCT-116 cells were highly susceptible to derivative 5c with IC50 = 2.61 µM, in the meantime, derivative 5f showed pronounced negative impact against MCF-7 (IC50 = 2.43 µM) when compared with other prepared compounds. All derivatives exhibited higher anticancer activities than doxorubicin against the three cell lines except compound 2 against both HepG2 and MCF-7 and compound 5e against HepG2 cell lines. Compounds 5a, 5c and 5f potently intercalate DNA at IC50 values of 26.96, 27.13 and 29.86 µM respectively, which were more potent than doxorubicin (IC50 value of 31.27 µM). Moreover, compounds 5a, 5c and 5f exhibited very good Topoisomerase II inhibitory activities with IC50 values of 0.752, 0.791 and 0.776 µM respectively, that were more potent than that of doxorubicin (IC50 = 0.94 µM). For a great extent, the molecular modeling studies were in agreement with that of in vitro cytotoxicity activity, DNA binding and Top-II inhibition results.

A green microwave method for synthesizing a more stable phthalazin-1-ol isomer as a good anticancer reagent using chemical plasma organic reactions.

Conventional synthesis of the phthalazine has already allowed affording the phthalazin-1-one phthalazin-1-ol dynamic equilibrium that decreases the anticancer activity due to diminishing the concentration of the phthalazin-1-ol product. Nowadays, pure phthalazin-1-ol (5) can be gaining by using green microwave tools that increase the power of the phthalazine nucleus as an anticancer drug. A microscopic thermal kinetic parameter like activation energy and the pre-exponential factor of the chemical plasma organic reactions affording pure phthalazin-1-ol (5) is calculated by using DFT simulation is obtained. Then we fed these parameters into the exact Arrhenius model to evaluate the distribution of chemical equilibrium conditions for producing phthalazin-1-ol. The proposed novel models that matching between microscopic and macroscopic show that the thermal stability of the equivalent temperature of phthalazin-1-ol is more stable than phthalazinone-1-one (4) in case of using plasma organic effect (green microwave) at 485 K. The structures of the prepared compounds were explained by physical and spectral data like FT-IR, 1H-NMR. Moreover, the theoretical calculations of Gibbs entropy of the phase transfer confirmed the equilibrium state of phthalazin-1-ol with the experimental result is achieved. Briefly, we introduce a good study for obtaining more stable phthalazin-1-ol isomer by using a green microwave method which is considered as good anticancer reagents of phenolic group (OH) and p-propenyl-anisole precursor as anise oil analogous.

Eco-friendly sequential one-pot synthesis, molecular docking, and anticancer evaluation of arylidene-hydrazinyl-thiazole derivatives as CDK2 inhibitors.

One current approach in the treatment of cancer is the inhibition of cyclin dependent kinase (CDK) enzymes with small molecules. CDK are a class of enzymes, which catalyze the transfer of the terminal phosphate of a molecule of ATP to a protein that acts as a substrate. Among CDK enzymes, CDK2 has been implicated in a variety of cancers, supporting its potential as a novel target for cancer therapy across many tumor types. Here the discovery and development of arylidene-hydrazinyl-thiazole as a potentially CDK2 inhibitors is described, including details of the design and successful synthesis of the series analogs (27a-r) using one-pot approach under eco-friendly ultrasound and microwave conditions. Most of the newly synthesized compounds showed good growth inhibition when assayed for their in-vitro anti-proliferative activity against three cancer cell lines (HepG2, MCF-7 and HCT-116) compared to the reference drug roscovitine, with little toxicity on the normal fibroblast cell lines (WI-38). Furthermore, the compounds exhibiting the highest anti-proliferative activities were tested against a panel of kinase enzymes. These derivatives displayed an outstanding CDK2 inhibitory potential with varying degree of inhibition in the range of IC50 0.35-1.49 µM when compared with the standard inhibitor roscovitine having an IC50 value 0.71 µM. The most promising CDK2 inhibitor (27f) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in HepG2 cell line. The results indicated that this compound implied inhibition in the G2/M phase of the cell cycle, and it is a good apoptotic agent. Finally, Molecular docking study was performed to identify the structural elements which involved in the inhibitory activity with the prospective target, CDK2, and to rationalize the structure-activity relationship (SAR).

Synthesis and Reactivity of 6,8-Dibromo-2-ethyl-4H-benzo[d][1,3]oxazin-4-one Towards Nucleophiles and Electrophiles and Their Anticancer Activity.

BACKGROUND: The genetic heterogeneity of tumor cells and the development of therapy-resistant cancer cells in addition to the high cost necessitate the continuous development of novel targeted therapies. METHODS: In this regard, 14 novel benzoxazinone derivatives were synthesized and examined for anticancer activity against two human epithelial cancer cell lines; breast MCF-7 and liver HepG2 cells. 6,8-Dibromo-2- ethyl-4H-benzo[d][1,3]oxazin-4-one was subjected to react with nitrogen nucleophiles to afford quinazolinone derivatives and other related moieties (3-12). Benzoxazinone 2 responds to attack with oxygen nucleophile such as ethanol to give ethyl benzoate derivative 13. The reaction of benzoxazinone 2 with carbon electrophile such as benzaldehyde derivatives afforded benzoxazinone derivatives 14a and 14b.The structure of the prepared compounds was confirmed with spectroscopic tools including IR, 1H-NMR, and 13C-NMR. RESULTS: Derivatives 3, 9, 12, 13, and 14b exhibited high antiproliferative activity and were selective against cancer cells showing no toxicity in normal fibroblasts. Derivative 3 with NH-CO group in quinazolinone ring was effective only against breast cells, while derivative 12 with NH-CO group in imidazole moiety was only effective against liver cells probably through arresting cell cycle and enabling repair mechanisms. The other derivatives (9, 13, and 14b) had broader antiproliferative activity against both cell lines. These derivatives enhance the expression of the p53 and caspases 9 and 3 to varying degrees in both cell lines. Derivative 14b caused the highest induction in the investigated genes and was the only derivative to inhibit the EGFR activity. CONCLUSIONS: The unique features about derivative 14b could be attributed to its high lipophilicity, high carbon content, or its extended conjugation through planar aromatic system. More investigations are required to identify the lead compound(s) in animal models.

Novel Nicotinonitrile Derivatives Bearing Imino Moieties Enhance Apoptosis and Inhibit Tyrosine Kinase.

BACKGROUND: Fused heterocyclic containing pyrazolopyridine systems have several medicinal activities including cytotoxic and carcinostatic activities. OBJECTIVE: To investigate the antiproliferative activity and associated mechanism(s) of a novel series of nicotinonitrile derivatives. METHOD: The series has been synthesized by the reaction of hydrazonoyl chlorides with each of 4-(4- methoxyphenyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 2-amino-4-(4- methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile in dioxane in basic medium. The assigned structures for each of the new products were identified via elemental and spectral data. Moreover, the cytotoxic activity for some selected products was screened. RESULTS: Derivatives 5g, 7i, 8 and 9 had their IC50 at ~ 1-3 µM and derivatives 7b, 7d, and 7f were similar to 5- fluorouracil and had their IC50 at ~ 5 µM against breast (MCF-7) and colon (HCT-116) cell lines. All derivatives were specific in action and safe to normal fibroblasts (WI38). Only derivative 9 caused some toxicity but at high concentration of 93 µM. These derivatives exerted strong antiproliferative activity through inducing intrinsic apoptosis as indicated from the significant induction of caspases 9 and 3 by 3-6 folds in colon cells and/or inhibiting tyrosine kinase (TK) and hence arresting the cell cycle. CONCLUSION: Compounds 8 and 5g were the most potent anticancer agents inhibiting the TK by 86 and 89% and their IC50 of the enzyme were 311 and 352 nM, respectively. We believe that these derivatives deserve further investigation and these chemical moieties could offer promising anticancer drugs.

Design, synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents.

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF NEW FUSED TRIAZINE DERIVATIVES BASED ON 6-METHYL-3-THIOXO-1,2,4-TRIAZIN-5-ONE.

A one-pot reaction of 6-methyl-3-thioxo-3,4-dihydro-[1,2,4]triazin-5-one 1 with selected aldehydes 2a-d and chloroacetic acid afforded the respective 2-arylidene-6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-diones 4a-d. Compunds 4a-d could be also obtained via the reaction of 1 with chloroacetic acid in refluxing acetic acid to give 6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-dione 3 then, Knoevenagel condensation of 3 with aldehydes 2a-d gave compounds 4a-d. Heterocyclization of 4a-c with hydrazine hydrate and phenylhy- drazine gave the corresponding pyrazolines 5a-c and 6a-c, respectively. Moreover, 7-amino-9-(aryl)-3-methyl-2-oxo-2H-pyrido[2',3':4,5][1,3]thiazolo[3,2-b][1,2,4]triazine-8-carbonitrles 7a-c were synthesized by the reaction of 4a-c with malononitrile in the presence of ammonium acetate. The structures of newly synthesized compounds were confirmed by analytical and spectroscopic measurements. Some selected new compounds were screened for their cytotoxic activities against three human cancer cell lines (HepG2, MCF-7 and A549) using SRB assay and the structure-activity relationship (SAR) was discussed. The biochemical assays including antioxidant enzyme, oxidative stress and estimation of nucleic acids and proteins have been discussed for some selected compounds. The molecular docking of 4c and 7b has been also studied.

Synthesis and Regioselective Reaction of Some Unsymmetrical Heterocyclic Chalcone Derivatives and Spiro Heterocyclic Compounds as Antibacterial Agents.

A number of novel heterocyclic chalcone derivatives can be synthesized by thermal and microwave tools. Treatment of 4-(4-Acetylamino- and/or 4-bromo-phenyl)-4-oxobut-2-enoic acids with hydrogen peroxide in alkaline medium were afforded oxirane derivatives 2. Reaction of the epoxide 2 with 2-amino-5-aryl-1,3,4-thiadiazole derivatives yielded chalcone of imidazo[2,1-b]thiadiazole derivative 4 via two thermal routes. In one pot reaction of 4-bromoacetophenone, diethyloxalate, and 2-amino-5-aryl-1,3,4-thiadiazole derivatives in MW irradiation (W 250 and T 150 °C) under eco-friendly conditions afforded an unsuitable yield of the desired chalcone 4d. The chalcone derivatives 4 were used as a key starting material to synthesize some new spiroheterocyclic compounds via Michael and aza-Michael adducts. The chalcone 4f was similar to the aryl-oxo-vinylamide derivatives for the inhibition of tyrosine kinase and cancer cell growth. The electron-withdrawing substituents, such as halogens, and 2-amino-1,3,4-thiadiazole moeity decreasing the electron density, thereby decreasing the energy of HOMO, and the presence of imidazothiadiazole moiety should improve the antibacterial activity. Thus, the newly synthesized compounds were evaluated for their anti-bacterial activity against (ATCC 25923), (ATCC 10987), (ATCC 274,) and (SM514). The structure of the newly synthesized compounds was confirmed by elemental analysis and spectroscopic data.

Uses of 2-ethoxy-4(3H) quinazolinone in synthesis of quinazoline and quinazolinone derivatives of antimicrobial activity: the solvent effect.

2- Ethoxy-4(3H) quinazolinone 1 was synthesized and allowed to react with various halides, namely: alkyl, benzyl, allyl, acyl, haloacetyl, crotonyl, benzoyl, 2-furoyl and 1-naphthalenesulphonyl halides affording quinazoline and quinazolinone derivatives. The reactions of compound 1 with phosphorus oxychloride, phosphorus pentasulfide, ethyl chloroformate, ethyl chloroacetate, ?-bromoglucose tetraacetate, p-acylaminobenzenesulfonyl chloride, acrylonitrile, chalcone and chalcone oxide were also investigated. Depending on the reaction condition and reactant halide, the type of substituent (alkyl, acyl, aroyl, etc.) that will reside on either of the expected positions (3 or 4) on the quinazoline moiety can control the reaction pathway for synthesis of the promising products. The significant role of solvent responsible for determining both the reaction pathway and type of products synthesized was also discussed. Some derivatives were chosen for biological screening test against Gram (-ive) and Gram (+ive) bacteria and two strains of fungi.

Reactivity of 2-ethoxyquinazolin- 4-yl hydrazine and its use in synthesis of novel quinazoline derivatives of antimicrobial activity.

The reactions of 2-ethoxy-4-hydrazinoquinazoline 2 with diethyl oxalate and ethyl chloroacetate gave 6-ethoxy-2H-[1,2,4]triazino[4,3-c]quinazoline-3,4-dione 3 and 6-ethoxy-2,3-dihydro-4H-[1,2,4]triazino[4,3-c]quinazolin-4-one 4 respectively. A series of 5-ethoxy-2-X-[1,2,4]triazolo[1, 5-c]quinazolines 5a-d was also produced by reacting 2 with the acid chlorides namely: benzoyl, crotonyl, cinnamyl and 2-furoyl chlorides via Dimroth rearrangement. Also, 2 reacted with ethyl chloroformate giving 6. Condensation of 2 with acetone gave Schiff base 7, and with monosaccharides gave the sugar hydrazones 8a-e which were thereafter acetylated giving the corresponding 9a-e. Cyclization of 8a-e by iron(III) chloride gave triazoloquinazolines 10a-e acyclic C-nucleosides which, by acetylation, afforded 11a-e. All products were confirmed by elemental, IR, MS, and 1H-NMR analysis. Products 8-11 were chosen for biological screening test against gram(+ ive) and gram(- ive) bacteria.