Synthesis, spectroscopic, DFT calculations, biological activity, SAR, and molecular docking studies of novel bioactive pyridine derivatives.

Enaminonitrile pyridine derivative was used as a precursor for preparation of fourteen heterocyclic compounds using both conventional thermal and microwave techniques. Diverse organic reagents, such as chloroacetyl chloride, acetic anhydride, chloroacetic acid, carbon disulfide, p-toluene sulfonyl chloride, maleic anhydride, phthalic anhydride, were used. The chemical formulae and structures of isolated derivatives were obtained using different analytical and spectroscopic techniques such as IR, 1H-, 13C-NMR as well as mass spectrometry. The spectroscopic analyses revealed diverse structure arrangements for the products. Molecular structure optimization of certain compounds were performed by the density functional theory (DFT/B3LYP) method and the basis set 6-31 G with double zeta plus polarization (d,p). The antimicrobial inhibition and the antioxidant activity of the reported compounds were screened. Compounds 5, 6, 11 and 13 exhibited the highest antibacterial inhibition, while compound 8 gave the highest scavenging activity (IC50 43.39 µg/ml) against the DPPH radical. Structure-activity relationship of the reported compounds were correlated with the data of antibacterial and the antioxidant activity. The global reactivity descriptors were also correlated with the biological properties of compounds. The molecular docking studies of reported compounds were investigated, and the analysis showed that the docked compounds have highly negative values for the functional binding scores. The binding interaction was found to be correlated with the substituent fragments of the compounds.

In silico investigation and potential therapeutic approaches of isoquinoline alkaloids for neurodegenerative diseases: computer-aided drug design perspective.

Microtubule affinity regulating kinase (MARK4) has been proposed as a potential therapeutic target for diabetes, cancer, and neurological diseases. We used a variety of computational studies techniques to examine the binding affinity and MARK4 inhibitory potential of several isoquinoline alkaloids. MARK4 has been associated with tau protein phosphorylation and, consequently, Alzheimer's disease. The three molecules with the highest binding affinities inside the 5ES1 receptor, according to molecular docking experiments, are isoliensinine, liensinine, and methylcorypalline. Isoliensinine had the highest drug score and drug likeness, coming in at 1.17, while Liensinine and Methylcorypalline came in at 1.15 and 1.07, respectively. The thesis claims that three compounds have a better chance than the others of being identified as therapeutic leads. The bulk of the compounds under investigation didn't break any of Lipinski's five rules, especially methylcorypalline, which did and is probably orally active. The majority of the compounds under investigation, particularly Isoliensinine, Liensinine, and Methylcorypalline, show the potential to exhibit drug-like behaviour, which is strongly confirmed by ADMET characteristics estimates. The chemicals Isoliensinine, Liensinine, and Methylcorypalline, especially Methylcorypalline, form the most stable combination with the 5ES1, according to a 100 ns molecular dynamics simulation of these compounds docked inside 5ES1 complexes. Methylcorypalline has a higher binding affinity inside 5ES1, according to additional MM/GBSA experiments using MD trajectories. Overall, research supports the use of the drug development tool methylcolipalin for its ability to inhibit MARK4, which may have implications for the treatment of neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.

Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment.

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg12O12 and Zn12O12 nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg12O12 and Zn12O12 nanoclusters. Favipiravir-Mg12O12 and favipiravir-Zn12O12 lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg12O12 and Zn12O12 nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg12O12 and Zn12O12 nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg12O12, and favipiravir-Zn12O12 docked inside the Mpro complexes established that favipiravir-Mg12O12, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg12O12 inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg12O12 and Zn12O12 nanoclusters.Communicated by Ramaswamy H. Sarma.

Computational and Molecular Docking Studies of New Benzene Sulfonamide Drugs with Anticancer and Antioxidant Effects.

BACKGROUND: The studies on the potential usage of benzene sulfonamide derivatives as anticancer agents are limited. benzene sulfonamide derivatives are currently used as anticancer agents against different breast cancer cell lines, such as MCF-7, lung cancer cells (A549), prostate cancer cells (Du-145), and cervical cells (HeLa). OBJECTIVE: A series of new sulfonamide drugs are synthesized by reacting aldehydes thio-semi-carbazones derivatives with benzene sulphonyl chloride to form benzylidene-N-(phenylsulfonyl) hydrazine-1-carbothioamide derivatives. Studying the anticancer effects against MCF-7 breast carcinoma cell lines and the antioxidant activities of these newly synthesized compounds. METHODS: Studying the anticancer effects against MCF-7 breast carcinoma cell lines and the antioxidant activities of these newly synthesized compounds. To study the anti-breast cancer activity of the newly synthesized compounds, a molecular docking study is used to analyze the binding energy for the nonbonding interactions between the ligands (studied compounds) and receptor (4PYP (pdb code: 4FA2)) against human breast cancer (MCF-7) cells. The bioavailability of all studied compounds is confirmed by pharmacological investigations using Mol inspiration and absorption, distribution, metabolism, excretion, and toxicity online servers. RESULTS: The two derivatives, 2-(4- methoxy benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4c) and 2-(4-dimethylamino) benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4e) show the most potent anticancer effects against MCF-7 breast carcinoma cell lines. Meanwhile, these two derivatives show the lowest antioxidant activities. CONCLUSION: The different spectral techniques were used to confirm the structure of the novel synthesized compounds. Further, 2-(4-(dimethyl amino) benzylidene)-N- (phenylsulfonyl)hydrazine-1-carbothioamide (4e) and 2-(4- methoxy benzylidene)-N-(phenylsulfonyl) hydrazine-1 carbothioamide (4c) were the most potent anticancer derivatives against MCF-7 breast carcinoma cell lines. Furthermore, they exhibited the most potent antioxidant activities. Meanwhile, the 2-benzylidene-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4a) and 2-(4-chloro benzylidene)-N-(phenylsulfonyl) hydrazine-1-carbothioamide (4d) had the lowest antioxidant potentials. The estimated binding energies, inhibition constant, intermolecular energies, and reference RMSD produced from docking for all studied compounds were reported. These values showed that all studied compounds formed stable complexes with the receptor with high binding affinity. It was further noted from the ADMET analysis that compounds 4c, 4d, and 4e have good absorption, low toxicity in the human liver, and medium BBB penetration. Hence, these studied compounds (4c-4e) may be suggested as potential compounds against human breast cancer MCF-7 cells.

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.

Nanoencapsulation of basil essential oil alleviates the oxidative stress, genotoxicity and DNA damage in rats exposed to biosynthesized iron nanoparticles.

The application of essential oils in food and pharmaceutical sectors face several challenges due to their sensitivity to oxidation process. Additionally, the biosynthesis of nanometals is growing rapidly; however, the toxicity of these particles against living organisms did not well explore yet. This study aimed to determine the bioactive compounds in basil essential oil (BEO) using GC-MS, to encapsulate and characterize BEO and to evaluate its protective role against the oxidative stress and genotoxicity of biosynthesized iron nanoparticles (Fe-NPs) in rats. Six groups of male Sprague-Dawley rats were treated orally for 4 weeks included the control group, Fe-NPs-treated group (100 mg/kg b.w.); EBEO-treated groups at low (100 mg/kg b.w.) or high (200 mg/kg b.w.) dose and the groups treated with Fe-NPs plus the low or the high dose of EBEO. The GC-MS analysis revealed the identification of 48 compounds and linalool was the major compound. The average sizes and zeta potential of the synthesized Fe-NPs and EBEO were 60 ± 4.76 and 120 ± 3.2 nm and 42.42 mV and -6.4 mV, respectively. Animals treated with Fe-NPs showed significant increase in serum biochemical analysis, oxidative stress markers, cytokines, lipid profile, DNA fragmentation and antioxidant enzymes and their gene expression and severe changes in the histology of liver and kidney tissues. Administration of Fe-NPs plus EBEO alleviated these disturbances and the high dose could normalize most of the tested parameters and improved the histology of liver and kidney. It could be concluded that caution should be taken in using the biosynthesized metal nanoparticles in different application. EBEO is a potent candidate to protect against the hazards of metal nanoparticles and can be applied in food and medical applications.

Bioactive phytochemicals from Salvia officinalis attenuate cadmium-induced oxidative damage and genotoxicity in rats.

This study was conducted to identify the bioactive phytochemicals in Salvia officinalis essential oil, to determine the polyphenols in the aqueous extract (SOE), and to evaluate their protective role against cadmium (Cd)-induced oxidative damage and genotoxicity in rats. Six groups of female rats were treated orally for 2 weeks including the control group, CdCl2-treated group, SOE-treated groups at low or high dose (100 and 200 mg/kg b.w), and CdCl2 plus SOE-treated groups at the two doses. The GC-MS analysis identified 39 compounds; the main compounds were 9-octadecenamide, eucalyptol, palmitic acid, and oleic acid. However, the HPLC analysis showed 12 polyphenolic compounds and the majority were coumaric acid, chlorogenic acid, coffeic acid, catechin, vanillin, gallic acid, ellagic acid, and rutin. In the biological study, rats received CdCl2 displayed severe disturbances in liver and kidney indices alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), total protein (TP), total bilirubin (T. Bil), direct bilirubin (D. Bil), creatinine, uric acid, and urea, lipid profile, tumor necrosis factor-alpha (TNF-α), alpha-fetoprotein (AFP) and CEA), glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), malondialdehyde (MDA), nitric oxide (NO), gene expressions, DNA fragmentation, and histological alterations in the liver and kidney tissue. SOE showed a potent antioxidant and mitigated these alterations in serum and tissue. Moreover, the high dose succeeded to normalize most of the tested parameters and histological features. It could be concluded that S. officinalis is a promising source for bioactive compounds with therapeutic benefits against environmental toxicants.

Matlodextrin-cinnamon essential oil nanoformulation as a potent protective against titanium nanoparticles-induced oxidative stress, genotoxicity, and reproductive disturbances in male mice.

Recently, bio-nanofabrication becomes one of the widest methods for synthesizing nanoparticles (NPs); however, there is scanty literature exploring the toxicity of these green NPs against living organisms. This study aimed to evaluate the potential protective role of encapsulated cinnamon oil (ECO) against titanium oxide nanoparticle (TiO2NP)-induced oxidative stress, DNA damage, chromosomal aberration, and reproductive disturbances in male mice. Sixty male Balb/c mice were distributed into six groups treated orally for 3 weeks and included control group, TiO2NP-treated group (25 mg/kg b.w), ECO at low or high dose-treated groups (50 or 100 mg/kg b.w), and the groups that received TiO2NPs plus ECO at a low or high dose. The results of GC-MS revealed the isolation of 21 compounds and the majority was cinnamaldehyde. The average size zeta potential of TiO2NPs and ECO were 28.9 and 321 nm and -33.97 and -17.35 mV, respectively. TiO2NP administration induced significant changes in liver and kidney function, decreased antioxidant capacity, and increased oxidative stress markers in liver and kidney, DNA damage in the hepatocytes, the number of chromosomal aberrations in the bone marrow and germ cells, and sperm abnormalities along with histological changes in the liver, kidney, and testis. Co-administration of TiO2NPs and ECO could alleviate these disturbances in a dose-dependent manner. It could be concluded that ECO is a promising and safe candidate for the protection against the health hazards of TiO2NPs.

Synthesis of new uracil derivatives and their sugar hydrazones with potent antimicrobial, antioxidant and anticancer activities.

6-(4-Chloro-3-nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4) was prepared and was reacted with ethyl chloroacetate, hydrazine hydrate, 4-chloroaniline, formaldehyde, acetic anhydride, formic acid, carbon disulfide, 4-cyanobenzaldehyde, triethyl orthoformate, D-sugars, 4-aminoacetophenone, benzoyl choride and cyclohexanone to afford a series of new uracil derivatives (5-18). Examination of some of the prepared compounds for their antimicrobial, antioxidant and anticancer activities was conducted. Among the tested samples, compound 17 was the most active substance against the gram-positive bacteria and was more potent than the reference drug Cefoperazone. Moreover, the antibacterial activity of 17 was higher against gram-negative bacteria. Compounds 6 and 13 reached a higher scavenging ability toward DPPH radicals and are better candidates for antioxidant activity. Also, compounds 6 and 13 had no significant anticancer activity toward liver cancer (Hep G2) and breast cancer (MCF-7) cell lines.

Preparation and characterization of yeast cell wall beta-glucan encapsulated humic acid nanoparticles as an enhanced aflatoxin B1 binder.

This study aimed to assess the effect of encapsulating humic acid inside yeast cell walls (YCW) to detoxify AFB1 in in vitro gastrointestinal models. Glucan Mannan Lipid Particles (GMLPs) from Saccharomyces cerevisiae cell walls showed the highest AFB1 adsorption in simulated gastric fluid (SGF) after 10 min, and in simulated intestinal fluid (SIF) after 1 h. GMLPs are hollow 3-4 micron porous microspheres that provide an efficient system for the synthesis and encapsulation of AFB1-absorbing nanoparticles (NPs). Humic acid nanoparticles (HA-NPs) were synthesized within the GMLP cavity by complexation with ferric chloride. Encapsulating HA-NPs in GMLPs increased HA-NP stability in SIF. The hybrid GMLP HA-NP formulation synergistically enhanced AFB1 binding compared to individual GMLP and HA components in SGF and in SIF. Cytotoxicity on a murine macrophage cell line demonstrated that GMLP HA-NP-AFB1 complexes were stable in both SGF and SIF, detoxified AFB1 and are suitable for in vivo testing.

CYTOTOXIC EFFECTS OF THE RED SEA SOFT CORAL SARCOPHYTON TROCHELIOPHORUM.

The present study describes the in vitro cytotoxic effects of soft coral (Sarcophyton tiocheliophorum). Soft corals of genus Sarcophyton were reported to contain compounds that are active against brine shrimp and promote paclitaxel cytotoxicity in the human colon cancer Caco-2 cell line. The n-hexane extract of the soft coral Sarcophyton tiocheliophorum induced significant dose-dependent toxicity (LC50 96.7 ppm) compared with ethyl acetate (LC50. 120 ppm). We reported the most active cytotoxic level to be correspondence to LC50 values of 20.2, 59.2 ppm and 18.9 and 26 ppm. Accordingly, bio-assay guided fractionation was conducted to identi- fy the bioactive compounds. Arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid were characterized based on GC-MS analyses. Our results demonstrate the value of marine products as a natural source of medicinally interesting cytotoxic compounds.

Antibacterial effect of the red sea soft coral Sarcophyton trocheliophorum.

The marine soft corals Sarcophyton trocheliophorum crude extracts possessed antimicrobial activity towards pathogenic bacterial strains, i.e. Bacillus cereus, Salmonella typhi, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Bioassay-guided fractionation indicated that the antimicrobial effect was due to the presence of terpenoid bioactive derivatives. Further biological assays of the n-hexane fractions were carried out using turbidity assay, inhibition zone assay and minimum inhibitory concentration for investigating the growth-inhibition effect towards the Gram-positive and Gram-negative bacteria. The fractions were screened and the structure of the isolated compound was justified by interpretation of the spectroscopic data, mainly mass spectrometry (GC-MS). The structure was assigned as (5S)-3-[(3E,5S)-5-hydroxy-3-hepten-6-yn-1-yl]-5-methyl-2(5H)-furanone and was effective at concentrations as low as 0.20 mg/mL. The above findings, in the course of our ongoing research on marine products, may implicate that the profound anti-microbial activity of the S. trocheliophorum soft corals, inhabiting the red sea reefs, is attributed to the presence of growth-inhibiting secondary metabolites mainly terpenoids.