Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: In Vitro Studies with Computational Predictions.

In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, 5a-f, 6a-f, and 7a-f, to evaluate their biological applications. The data from in vitro biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases 5a-f, 6a-f, and 7a-f showed that the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases 5d, 5e, and 7a are active against lung (A549) cells, while the two Schiff bases 5e and 7a exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f were evaluated. Furthermore, we assessed the in silico absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.

Synthesis, structural, molecular docking, and in vitro biological activities of Cu-doped ZnO nanomaterials.

Copper-doped ZnO nanoparticles with the formula Zn1-x(Cu)O, where x = 0.0, 0.03, 0.05, and 0.07 were produced using the co-precipitation process. Physical, chemical, and structural properties were properly examined. Powdered X-ray diffraction (P-XRD) patterns revealed the formation of hexagonal wurtzite crystal structure in all samples, through atomic substitutional incorporation in the Cu-doped ZnO lattice. The presence of Cu ions and their dissolution in the host ZnO crystal structure was supported by FT-IR spectra. HR-TEM images were used to assess the average size, morphology, and shape regularity of the synthesized samples. The form and homogeneity of the ZnO changed when Cu ions were substituted, as evidenced by FE-SEM/EDX analysis. The presence of copper signals in the Cu-doped samples indicates that the doping was successful. The decrease in zeta potential with an increased copper doping percentage designates that the nanoparticles (NPs) are more stable, which could be attributed to an increase in the ionic strength of the aqueous solution. The synthesized NPs were evaluated for their substantial in vitro antioxidant properties. In addition, the antimicrobial efficacy of the materials was tested against pathogenic microorganisms. Regarding the anti-diabetic activity, the 7Cu ZnO sample showed the highest inhibitory effect on the α-amylase enzyme. No variations were observed in the activities of the acetylcholinesterase enzyme (AChE) and proteinase enzymes with ZnO and samples doped with different concentrations of Cu. Therefore, further studies are recommended to reveal the in-vitro anti-diabetic activity of the studied doped samples. Finally, molecular docking provided valuable insights into the potential binding interactions of Cu-doped ZnO with α-amylase, FabH of E. coli, and Penicillin-binding proteins of S. aureus. These outcomes suggest that the prepared materials may have an inhibitory effect on enzymes and hold promise in the battle against microbial infections and diabetes.

In vitro biological studies and computational prediction-based analyses of pyrazolo[1,5-a]pyrimidine derivatives.

There is a need for new pharmaceutical discoveries from bioactive nitrogenous derivatives due to the emergence of scourges, numerous pandemics, and diverse health problems. In this context, pyrazolo[1,5-a]pyrimidine derivatives 12a and 12b were synthesized and screened to evaluate their biological potentials in vitro as antioxidants, anti-diabetics, anti-Alzheimer's, anti-arthritics, and anti-cancer agents. Additionally, the computational pharmacokinetic and toxicity properties of the two pyrazolo[1,5-a]pyrimidines 12a and 12b were calculated and analyzed. The preliminary studies and results of this work represent the initial steps toward more advanced studies and define the bioactive chemical structure of pyrazolo[1,5-a]pyrimidine derivatives with the goal of exploring new drugs to address numerous health problems.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents.

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7-9, 11-13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (1H and 13C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure-activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic.

In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base-pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer's (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer's (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

Exploring novel derivatives of isatin-based Schiff bases as multi-target agents: design, synthesis, in vitro biological evaluation, and in silico ADMET analysis with molecular modeling simulations.

Recently, scientists developed a powerful strategy called "one drug-multiple targets" to discover vital and unique therapies to fight the most challenging diseases. Novel derivatives of isatin-based Schiff bases 2-7 have been synthesized by the reaction of 3-hydrazino-isatin (1) with aryl aldehydes, hetero-aryl aldehydes, and dialdehydes. The structure of the synthesized derivatives was proved by physical and spectral analysis. Additionally, in vitro biological studies were performed, including antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic activities. The four derivatives 3b, 5a, 5b, and 5c possess the highest activities. Among the four potent derivatives, compound 5a exhibited the highest antioxidant (TAC = 68.02 ± 0.15 mg gallic acid per g; IRP = 50.39 ± 0.11) and scavenging activities (ABTS = 53.98 ± 0.12% and DPPH = 8.65 ± 0.02 µg mL-1). Furthermore, compound 5a exhibited an α-amylase inhibitory percentage of 57.64 ± 0.13% near the acarbose (ACA = 69.11 ± 0.15%) and displayed inhibitor activity of the acetylcholinesterase (AChE) enzyme = 36.38 ± 0.08%. Moreover, our work extended to determining the anti-arthritic effect, and compound 5a revealed good inhibitor activities with very close values for proteinase denaturation (PDI) = 39.59 ± 0.09% and proteinase inhibition (PI) = 36.39 ± 0.08%, compared to diclofenac sodium PDI = 49.33 ± 0.11% and PI = 41.88 ± 0.09%. Additionally, the quantum chemical calculations, including HOMO, LUMO, and energy band gap were determined, and in silico ADMET properties were predicted, and their probability was recorded. Finally, molecular docking simulations were performed inside α-amylase and acetylcholinesterase enzymes.

In vitro enzymatic evaluation of some pyrazolo[1,5-a]pyrimidine derivatives: Design, synthesis, antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic activities with molecular modeling simulation.

The strategy of utilizing nitrogen compounds in various biological applications has recently emerged as a powerful approach to exploring novel classes of therapeutics to face the challenge of diseases. A series of pyrazolo[1,5-a]pyrimidine-based compounds 3a-l and 5a-f were prepared by the direct cyclo-condensation reaction of 5-amino-1H-pyrazoles 1a, b with 2-(arylidene)malononitriles and 3-(dimethylamino)-1-aryl-prop-2-en-1-ones, respectively. The structures of the new pyrazolo[1,5-a]pyrimidine compounds were confirmed via spectroscopic techniques. The in vitro biological activities of all pyrazolo[1,5-a]pyrimidines 3a-l and 5a-f were evaluated by assaying total antioxidant capacity, iron-reducing power, the scavenging activity against 1-diphenyl-2-picryl-hydrazyl (DPPH) and 2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals, anti-diabetic, anti-Alzheimer, and anti-arthritic biological activities. All compounds displayed good to potent bioactivity, and three compounds 3g, 3h, and 3l displayed the most active derivatives. Among these derivatives, compound 3l exhibited the highest antioxidant (total antioxidant capacity [TAC] = 83.09 mg gallic acid/g; iron-reducing power [IRP] = 47.93 µg/ml) and free radicals scavenging activities with (DPPH = 18.77 µg/ml; ABTS = 40.44%) compared with ascorbic acid (DPPH = 4.28 µg/ml; ABTS = 38.84%). Furthermore, compound 3l demonstrated the strongest inhibition of α-amylase with a percent inhibition of 72.91 ± 0.14 compared to acarbose = 67.92 ± 0.09%. Similarly, it displayed acetylcholinesterase inhibition of 62.80 ± 0.06%. However, compound 3i showed a significantly higher inhibition percentage for protein denaturation and proteinase at 20.66 ± 0.00 and 26.42 ± 0.06%, respectively. Additionally, some in silico ADMET properties were predicted and studied. Finally, molecular docking simulation was performed inside the active site of α-amylase and acetylcholinesterase to study their interactions.

Green Synthesis, Characterization, Antimicrobial and Anticancer Screening of New Metal Complexes Incorporating Schiff Base.

A Schiff base ligand of o-vanillin and 4-aminoazobenzene and its transition metal complexes of Ni(II), Co(II), Zn(II), Cu(II), Mn(II), and Zr(IV) were prepared under microwave irradiation as a green approach compared to the conventional method. The structures of new compounds have been characterized and elucidated via elemental and spectroscopic analyses. In addition, magnetic susceptibility, electron spin resonance, and electronic spectra of the synthesized complexes explained their geometrical structures. The thermal stability of Cu(II), Zn(II), and Zr(IV) complexes was studied by thermo-gravimetric analyses (TGA). Coats-Redfern and Horowitz-Metzger equations were used to calculate the thermal and dehydration decomposition activities of proposed structures kinetically. Surface morphologies of the solid compounds were imaged by scanning electron microscopy (SEM). The particle size of prepared complexes was measured by using a particle size analyzer at a diffraction angle of 10.9°. The geometry structures of the synthesized compounds were verified utilizing electronic spectra, ESR spectrum, and magnetic moment value. The newly synthesized compounds were screened for antimicrobial activity. Also, the anticancer activity of the free Schiff base ligand and its metal complexes were studied against two cell lines: human colon (HCT-116) and human liver cancer cells (HepG-2). The obtained results showed that the Cu(II) complex displayed the highest cytotoxic activity (IC50 = 18 and 22 µg/mL for HepG-2 and HCT, respectively) compared to the free Schiff base ligand.

Phyto-Phospholipid Complexation as a Novel Drug Delivery System for Management of Cancer with Better Bioavailability: Current Perspectives and Future Prospects.

Cancer is the foremost cause of death, and it supports the need for the identification of novel anticancer drugs to improve the efficacy of current-therapy. While the synthetic anticancer drug is associated with numerous side effects. Hence the plant active or phytoconstituents are in high demand for the treatment of cancer due to minimum side effects. But the polar nature of phytoconstituents hindered the absorption of the drug and lowered the therapeutic efficacy. The plant activity incorporated into Phyto-phospholipid Complexation can enhance bioavailability and improved therapeutic efficacy. In this review article, advantages, limitation and application of Phyto-phospholipid complexes have been illustrated. The article highlights the application of Phyto-phospholipid complexes as a promising drug carrier system to treat cancer.

Withdrawal Notice: Electrophoresis as a Tool for Early Cancer Diagnosis

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Hepato-Renal protective Effects of Egyptian Purslane Extract against Experimental Cadmium Toxicity in Rats with Special Emphasis on the Functional and Histopathological Changes.

The study was designed to clarify the hapato-nephroprotective effects of purslane ethanolic extract (PEE) against cadmium toxicity. Cadmium (Cd) is a toxic heavy metal. Cd occurs as environmental and food/ feed contamination causing public and animals health hazards. Liver and kidney are the main target organs for acute and chronic cadmium toxicity. Portulaca oleracea is rich in several vitamins, minerals, antioxidant components, and omega-3 fatty acids mainly α-linolenic acid and eicosapentaenoic acid. Results showed significant elevation of the liver and kidney functions, lipid profile and lipid peroxidation. In contrast to the antioxidants enzymatic were greatly decreased. The hepatic and renal tissues showed severe degeneration and necrosis accompanied by severe congestion and multifocal hemorrhages in Cd intoxicated rats. All parameters and tissues showed no changes in rates-treated with both Cd and purslane extract as compared with the control rats. The administration of PEE provided a significantly protection against Cd-induced hepato-nephrotoxicity.

Bio and phyto-chemical effect of Amphora coffeaeformis extract against hepatic injury induced by paracetamol in rats.

Paracetamol is the most commonly used analgesic-antipyretic drugs. Its excess use causes an acute hepatotoxicity. It is well known that the Bacillariophyta alga Amphora coffeaeformis is rich in many photosynthetic pigments with antioxidant activities as well as a series of biologically active substances. The current work has been designed to study the phytochemical composition of different A. coffeaeformis algal extracts to select the most effective one. It was verified that acetone A. coffeaeformis algal extract is rich in various pigments and polyphenolic compounds (ß-carotene (9.31 ± 0.06 mg·g-1), gallic acid (28.31 µg·g-1), catechin (38.08 µg·g-1) and p-coumaric acid (38.69 µg·g-1)). The pigments and phenolic profiles in acetone extract were determined in addition to isolation of ß-carotene and fucoxanthin which exhibited free radical scavenging activity by 74.80% and 69.40%, respectively. Therefore, the highest total antioxidant capacity and free radical scavenging activity were noticed with this extract. Consequently, efficiency of this algal extract was evaluated against hepatic intoxication induced by paracetamol in rats. The biochemical measurements (liver functions and markers of oxidative stress) were  assayed. Moreover, the native protein, lipid and calcium moieties of native protein patterns in addition to catalase (CAT); peroxidases (POX); α- and ß-esterase (EST) isoenzymes and genomic DNA patterns were electrophoretically detected in liver tissues. It was found that paracetamol caused significant (P < 0.05) elevation in serum liver functions associated with decline in activities of the antioxidant enzymes in that tissues. Also, it caused alterations represented electrophoretically at qualitative level from variations in the bands number and arrangement. So that, the paracetamol treated group was noticed with the lowest similarity index (SI). In addition, it caused abnormalities at the quantitative level through variations in quantity of normal bands. Algal extract restored all the biochemical functions to normal levels in the algal extract simult-treated and pre-treated groups. Furthermore, it exhibited ameliorative effect against the electrophoretic alterations through restoring the absent normal bands and hiding the abnormal ones and hence increasing the SI values especially in the extract simult-treated group. Algal extract exhibited antagonistic effect against the hepatic injury and the deleterious effects induced by paracetamol in the extract simult-treated group.