Targeted potent antimicrobial and antitumor oxygen-heterocyclic-based pyran analogues: synthesis and computational studies.

The process of creating a series of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-q) involved reacting 6-methoxynaphthalen-2-ol (1), the appropriate aromatic aldehydes (2a-q), and malononitrile (3) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1H-benzo[f]chromene-2,8-dicarbonitrile (6a, d, e) was unsuccessful when 6-cyanonaphthalen-2-ol (5) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives (4 m, i, k) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br (4c, e) and a double bromine at 3,5-positions with a single methoxy group at 2-position (4n), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated (4a, b, d, f), dihalogenated (4 g, h, j, l) or trisubstituent phenyl ring (4o, p, q). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives (4a-f, g-q) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g, revealing bactericidal effects. Lastly, SAR and molecular docking were studied.

Iron/Copper/Phosphate nanocomposite as antimicrobial, antisnail, and wheat growth-promoting agent.

BACKGROUND: One of the current challenges is to secure wheat crop production to meet the increasing global food demand and to face the increase in its purchasing power. Therefore, the current study aimed to exploit a new synthesized nanocomposite to enhance wheat growth under both normal and drought regime. The effectiveness of this nanocomposite in improving the microbiological quality of irrigation water and inhibiting the snail's growth was also assessed. RESULTS: Upon the employed one-step synthesis process, a spherical Fe/Cu/P nanocomposite was obtained with a mean particle size of 4.35 ± 1.524 nm. Cu2+, Fe2+, and P4+ were detected in the dried nanocomposite at 14.533 ± 0.176, 5.200 ± 0.208, and 34.167 ± 0.203 mg/ml concentration, respectively. This nanocomposite was found to exert antibacterial activity against Escherichia coli and Salmonella typhi. It caused good inhibition percent against Fusarium oxysporum (43.5 ± 1.47%) and reduced both its germination rate and germination efficiency. The lethal concentration 50 (LC50) of this nanocomposite against Lanistes carinatus snails was 76 ppm. The treated snails showed disturbance in their feeding habit and reached the prevention state. Significant histological changes were observed in snail digestive tract and male and female gonads. Drought stress on wheat's growth was mitigated in response to 100 and 300 ppm treatments. An increase in all assessed growth parameters was reported, mainly in the case of 100 ppm treatment under both standard and drought regimes. Compared to control plants, this stimulative effect was accompanied by a 2.12-fold rise in mitotic index and a 3.2-fold increase in total chromosomal abnormalities. CONCLUSION: The finding of the current study could be employed to mitigate the effect of drought stress on wheat growth and to enhance the microbiological quality of irrigation water. This is due to the increased efficacy of the newly synthesized Fe/Cu/P nanocomposite against bacteria, fungi, and snails. This methodology exhibits potential for promoting sustainable wheat growth and water resource conservation.

Effect of germanium oxide on the structural aspects and bioactivity of bioactive silicate glass.

Ternary silicate glass (69SiO2-27CaO-4P2O5) was synthesized with the sol-gel route, and different percentages of germanium oxide GeO2 (6.25, 12.5, and 25%) and polyacrylic acid (PAA) were added. DFT calculations were performed at the B3LYP/LanL2DZ level of theory for molecular modelling. X-ray powder diffraction (XRPD) was used to study the effect of GeO2/PAA on the structural properties. The samples were further characterized using DSC, ART-FTIR, and mechanical tests. Bioactivity and antibacterial tests were assessed to trace the influence of GeO2 on biocompatibility with biological systems. Modelling results demonstrate that molecular electrostatic potential (MESP) indicated an enhancement of the electronegativity of the studied models. While both the total dipole moment and HOMO/LUMO energy reflect the increased reactivity of the P4O10 molecule. XRPD results confirmed the samples formation and revealed the correlation between the crystallinity and the properties, showing that crystalline hydroxyapatite (HA) is clearly formed in the highest percentages of GeO2, proposing 25% as a strong candidate for medical applications, consistent with the results of mechanical properties and the rest of the characterization results. Simulated body fluid (SBF) in vitro experiments showed promising biocompatibility. The samples showed remarkable antimicrobial and bioactivity, with the strongest effect at 25%. The experimental findings of this study revealed that the incorporation of GeO2 into the glass in terms of structural characteristics, bioactivity, antimicrobial properties, and mechanical properties is advantageous for biomedical fields and especially for dental applications.

Biostimulation of tomato growth and biocontrol of Fusarium wilt disease using certain endophytic fungi.

BACKGROUND: Tomato plant (Solanum lycopersicum L.) suffers from numerous fungal pathogens that cause damage to yeild production qualitatively and quantitatively. One of the most destructive disease of tomato is Fusarium wilt that caused by soil borne fungus called F. oxysporum. METHODS: In this study, the anti-Fusarium capabilities of the foliar application of fungal endophytes extracts have been investigated on tomato under Fusarium challenges. Antifungal assay, inhibition of conidial germination, disease severity, photosynthetic pigments, osmolytes, secondary metabolites, oxidative stress, peroxidase (POD) and polyphenol oxidases (PPO) isozymes were tested for potential resistance of tomato growing under Fusarium infection. RESULTS: Ethyl acetate extracts of A. flavus MZ045563, A. fumigatus MZ045562 and A. nidulans MZ045561 exhibited antifungal activity toward F. oxysporum where inhibition zone diameters were 15, 12 and 20 mm, respectively. Moreover, extracts of all fungal isolates at concentration 7.5 mg/mL reduced conidia germination from 94.4 to 100%. Fusarium infection caused a destructive effects on tomato plant, high severity desiese index 84.37%, reduction in growth parameters, photosynthetic pigments, and soluble protein. However, contents of proline, total phenol, malondialdehyde (MDA), hydrogen peroxide (H2O2) and antioxidant enzymes activity were increased in tomato plants grown under Fusarium wilt. Treatment of healthy or infected tomato plants by ethyl acetate fungal extracts showed improvements in morphological traits, photosynthetic pigments, osmolytes, total phenol and antioxidant enzymes activity. Besides, the harmful impacts of Fusarium wilt disease on tomato plants have also been reduced by lowering MDA and H2O2 levels. Also, treated tomato plants showed different responses in number and density of POD and PPO isozymes. CONCLUSION: It could be suggested that application of ethyl acetate extracts of tested fungal endophytes especially combination of A. flavus, A. nidulans and A. fumigatus could be commercially used as safe biostimulation of tomato plants as well as biofungicide against tomato Fusarium wilt disease.

First report on isolation of Mucor bainieri from honeybees, Apis mellifera: Characterization and biological activities.

Fungi are potential biocontrol agents and rich sources of secondary metabolites with demonstrated biological activities. This study aimed to isolate and identify fungi from surface-sterilized honeybees (Apis mellifera), as well as to evaluate their biological activities. One fungal isolate was obtained and identified morphologically and genetically as Mucor bainieri MK-Bee-2. Gas chromatography-mass spectroscopy (GC-MS) analysis of fungus crude extract, showed the existence of six major metabolites representing 92.48% of the total peak area. The crude extract of Mucor bainieri MK-Bee-2 was tested for antimicrobial, antioxidant, and antitumor activities. It demonstrated wide antimicrobial activities against human pathogenic Gram-positive and Gram-negative bacterial strains, as well as Candida albicans, with MIC values ranged from 62.5 to 250 µg/ml. The results revealed that the extract exhibited considerable antioxidant activities indicated by strong inhibition of both DPPH and ABTS free radicals. Additionally, the extract exhibited greater potential anticancer activity against both adenocarcinomic human non-small cell lung cancer cells (A549) [IC50 = 6.45 µg/ml], and immortal cell line hepatoma G2 (HepG2) human liver cancer cells [IC50 = 27.48 µg/ml] and higher selectivity in cancer cells than normal cell lines. Furthermore, the extract showed less cytotoxic activity against normal cells with higher IC50 values of 106.99 and 132.57 µg/ml against human lung fibroblast Wistar-38 (Wi-38) and oral epithelial cells (OEC), respectively. Taken together, the Mucor bainieri MK-Bee-2 extract comprises bioactive compounds as promising potential therapeutic candidates for the treatment of lung cancer. Strikingly, the extract sensitizes the lung cancer cells A549  to the ionizing radiation through the pro-apoptotic pathway as indicated by the annexin V flow cytometry analysis which showed that the extract reduced the apoptosis of lung cancer cells.

Antifungal and antibiofilm activities of bee venom loaded on chitosan nanoparticles: a novel approach for combating fungal human pathogens.

The prevalence of opportunistic human fungal pathogens is increasing worldwide, and antimicrobial resistance is one of the greatest medical challenges the world faces. Therefore, this study aimed to develop a novel agent to control fungal pathogens. The honeybee products (honey, royal jelly, propolis, bee bread, and bee venom) were screened against unicellular fungal (UCF) pathogens (Cryptococcus neoformans, Kodamaea ohmeri, and Candida albicans) and the bee venom was only exhibited an inhibitory effect against them. The protein contents of crude bee venom were separated using the gel filtration technique into eight fractions which were visualized on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to confirm the presence of five bands with molecular weights of 65, 43, 21, 15, and 3 KDa. Bee venom (BV) of Apis mellifera loaded chitosan nanoparticles were prepared by the ionotropic gelation method. The encapsulation efficiency%, average size, zeta potentials, and surface appearance by Transmission electron microscope (TEM) were evaluated for the prepared nanoparticles. The minimum inhibitory concentration (MIC) of crude BV and BV loaded chitosan nanoparticles (BV-CNPs) was evaluated against the offer mentioned UCF where the MIC values of crude BV were 6.25, 3.12 & 6.25 while MIC values in the case of BV-CNPs were decreased to 3.12, 3.12 & 1.56 mg/ml against C. neoformans, K. ohmeri and C. albicans, respectively. Also, the results showed that BV-CNPs suppressed the biofilm formation as well as yeast to hyphal transition formed by the examined UCF. These results revealed that BV-CNPs are a promising natural compound for fungal pathogens treatment.

Antifungal Activity of Endophytic Aspergillus terreus Extract Against Some Fungi Causing Mucormycosis: Ultrastructural Study.

Endophytes fungi are applied as favorable safe antifungal agents as well as natural bioactive compounds reservoir. In the current study, the inhibitory effect of endophytic fungus was explained by direct antifungal activity against fungi causing mucormycosis, ultrastructural, and determination of active compounds in fungal extract. Endophytic Aspergillus terreus was isolated from healthy Moringa oleifera leaves and identified morphologically and genetically, and was recorded in gene bank with accession number MW444551.1. Phytochemical analysis and gas chromatography-mass spectroscopy (GC-MS) of ethyl acetate crude extract (EACE) of A. terreus were performed. GC-MS results of EACE of A. terreus revealed that fungal extract contains 16 major bioactive compounds with extensive pharmaceutical activities. Furthermore, EACE of A. terreus revealed a promising antifungal activity against fungi causing mucormycosis as Rhizopus oryzae, Mucor racemosus, and Syncephalastrum racemosum, where inhibition zones of EACE (10 mg/ml) were 20, 37, and 18 mm, respectively. Minimum inhibitory concentration (MIC) of EACE was 0.3125 toward M. racemosus, while 1.25 and 2.5 mg/ml against R. oryzae and S. racemosum, respectively. In the same context, treated R. oryzae, M. racemosus, and S. racemosum with EACE of A. terreus revealed elevation of membrane lipid peroxidation which approves membrane leakage. Furthermore, ultrastructure changes were observed which established alteration in both sporangium and hyphal structures; cell membrane and cytoplasm leakage. In conclusion, endophytic A. terreus has an outstanding antifungal activity against fungi causing mucormycosis.

New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation.

Background: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects. Purpose: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxaline-based derivatives was designed and synthesized on the basis of the pharmacophoric features of VEGFR-2 inhibitor drugs. Methods: The new candidates were evaluated against A549 lung cancer cells, HepG-2 hepatoma cells, Caco-2 colon cancer cells, MDA breast cancer cells, and VEGFR-2 kinase. Moreover, cell cycle kinetics and apoptosis rates were studied in HepG-2 cells treated with compound 11, which was the most promising candidate. Results: The new derivatives revealed better antitumor results (IC50 from 6.48 to 38.58 µM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC50 values ranging from 0.19 to 0.60 µM compared to 0.08 µM for sorafenib. Compound 11, meanwhile, showed IC50 values equal to 10.61, 9.52, 12.45, 11.52, and 0.19 µM against the cancer cell lines and VEGFR-2, respectively. Moreover, compound 11 raised the apoptosis rate in HepG-2 cells from 5% to 44% and caused 4, 2.3, and 3-fold increases in BAX/Bcl-2 ratio, caspase-3 level, and P53 expression, respectively, compared to control untreated cells. Finally, the new derivatives displayed the correct binding mode into VEGFR-2 kinase pocket, giving interactions with the essential residues. Conclusion: This work suggests that compound 11 is a very significant anticancer candidate, and piperazinylquinoxaline is an important scaffold in the development of new potential effective and safer VEGFR-2 inhibitor agents.

Antimicrobial, Antioxidant, Cytotoxic Activities and Phytochemical Analysis of Fungal Endophytes Isolated from Ocimum Basilicum.

Fungal endophytes are living inside plants without any harmful effects; the prospecting about them is increased day by day because they can produce bioactive compounds which can be used in different applications. Herein, the current study was aimed to isolate the endophytic fungi from the Ocimum basilicum plant as safe microorganisms and evaluate their biological activities. The results illustrated that three endophytic fungal strains were isolated and identified morphologically and genetically as Aspergillus nidulans, Aspergillus fumigatus, and Aspergillus flavus and deposited in gene bank under accession numbers MZ045561, MZ045562, and MZ045563 respectively. Moreover, cell-free filtrates of endophytic fungal strains were extracted using ethyl acetate, where these crude extracts exhibited promising antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Bacillus subtilis, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumonia, and Candida albicans at a concentration of 1000 µg/mL. Furthermore, these endophytic strains exhibited a potential antioxidant activity where IC50 of the crude extract of A. nidulans, A. fumigatus, and A. flavus were (166.3, 68.4, and 347.1 µg/mL) and (151.2, 77.9, and 246.3 µg/mL) using DPPH and ABTS methods, respectively. Furthermore, the ethyl acetate crude extracts of these endophytic fungi did not exhibit any cytotoxic effect against Vero and Wi 38 normal cells. GC-MS analysis of the crude extract of A. nidulans, A. fumigatus, and A. flavus indicated the presence of 22, 22, and 20 active compounds, respectively. The major compounds in the fungal extracts are belonging to fatty acids, fatty acid esters, tetrahydrofurans, and sterols. In conclusion, the isolated endophytic A. nidulans, A. fumigatus, and A. flavus from Ocimum basilicum are promising sources for bioactive compounds.

Green Synthesized ZnO Nanoparticles Mediated by Streptomyces plicatus: Characterizations, Antimicrobial and Nematicidal Activities and Cytogenetic Effects.

Zinc oxide nanoparticles (ZnO-NPs) are regarded as one of the most promising kinds of materials in a variety of fields, including agriculture. Therefore, this study aimed to biosynthesize and characterize ZnO-NPs and evaluate their different biological activities. Seven isolates of actinomycetes were obtained and screened for ZnO-NPs synthesis. The isolate MK-104 was chosen and identified as the Streptomyces plicatus MK-104 strain. The biosynthesized ZnO-NPs exhibited an absorbance peak at 350 nm and were spherical in shape with an average size of 21.72 ± 4.27 nm under TEM. XRD and DLS methods confirmed these results. The biosynthesized ZnO-NPs demonstrated activity against plant pathogenic microbes such as Erwinia amylovora, Aspergillus flavus, Aspergillus niger, Fusarium oxysporum, Fusarium moniliform and Alternaria alternata, with MIC values ranging from 15.6 to 500 µg/mL. Furthermore, ZnO-NPs had a significant effect on Meloidogyne incognita, with death percentages of 88.2, 93.4 and 96.72% after 24, 48 and 72 h of exposure, respectively. Vicia faba seeds were treated with five concentrations of ZnO-NPs (12.5, 25, 50, 100 and 200 µg/mL). Low-moderate ZnO-NP concentrations (12.5-50 µg/mL) were shown to promote seed germination and seedling development, while the mitotic index (MI) decreased as the dosage of ZnO-NPs increased. Micronuclei (MNs) and the chromosomal abnormality index increased as well.

New combination approaches to combat methicillin-resistant Staphylococcus aureus (MRSA).

The herbal products proved to be more promising antimicrobials even though their antimicrobial activity is milder than commercially available antibiotics. Moreover, herbal drugs may act synergistically with antibiotics to kill microbes. In this study, we aimed to enhance the activity of penicillin against MRSA through combination with the active saponin fraction isolated from the Zygophyllum album plant. Three different types of metabolites (saponins, sterols, and phenolics) have been extracted from Zygophyllum album with ethanol and purified using different chromatographic techniques. The antibacterial activity of crude extract and the separated metabolites were checked against MRSA isolates, Saponin fraction (ZA-S) was only the active one followed by the crude extract. Therefore, the compounds in this fraction were identified using ultra-high-performance liquid chromatography connected to quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS) operated in positive and negative ionization modes. UHPLC/QTOF-MS revealed the presence of major six ursane-type tritepenoidal saponins (Quinovic acid, Quinovic acid 3ß-O-ß-D-quinovopyranoside, Zygophylloside C, Zygophylloside G, Zygophylloside K and Ursolic acid), in addition to Oleanolic acid. Interaction studies between saponin fraction and penicillin against MRSA were performed through the checkerboard method and time-kill assay. According to checkerboard results, only three combinations showed a fractional inhibitory concentration index less than 0.5 at concentrations of (62.5 + 312.5, 62.5 + 156.25, and 62.5 + 78.125 of penicillin and ZA-S, respectively). Time kill assay results showed that the highest reduction in log10 colony-forming unit (CFU)/ml of initial inoculum of MRSA after 24 h occurred by 3.7 at concentrations of 62.5 + 312.5 (µg/µg)/ml of penicillin and ZA-S, respectively. Thus, the combination between saponin fraction of Zygophyllum album and penicillin with these concentrations could be a potential agent against MRSA that can serve as possible model for new antibacterial drug.