Antifungal Activity of Chemical Constituents from Piper pesaresanum C. DC. and Derivatives against Phytopathogen Fungi of Cocoa

In this study, the antifungal potential of chemical constituents from Piper pesaresanum and some synthesized derivatives was determined against three phytopathogenic fungi associated with the cocoa crop. The methodology included the phytochemical study on the aerial part of P. pesaresanum, the synthesis of some derivatives and the evaluation of the antifungal activity against the fungi Moniliophthora roreri, Fusarium solani and Phytophthora sp. The chemical study allowed the isolation of three benzoic acid derivatives (1–3), one dihydrochalcone (4) and a mixture of sterols (5–7). Seven derivatives (8–14) were synthesized from the main constituents, of which compounds 9, 10, 12 and 14 are reported for the first time. Benzoic acid derivatives showed strong antifungal activity against M. roreri, of which 11 (3.0 ± 0.8 µM) was the most active compound with an IC₅₀ lower compared with positive control Mancozeb^® (4.9 ± 0.4 µM). Dihydrochalcones and acid derivatives were active against F. solani and Phytophthora sp., of which 3 (32.5 ± 3.3 µM) and 4 (26.7 ± 5.3 µM) were the most active compounds, respectively. The preliminary structure–activity relationship allowed us to establish that prenylated chains and the carboxyl group are important in the antifungal activity of benzoic acid derivatives. Likewise, a positive influence of the carbonyl group on the antifungal activity for dihydrochalcones was deduced.     

Synthesis,Identification, Computer-Aided Docking Studies,and ADMET Prediction of Novel Benzimidazo-1,2,3-triazole Based Molecules as Potential Antimicrobial Agents

2-azido-1H-benzo[d]imidazole derivatives 1a,b were reacted with a β-ketoester such as acetylacetone in the presence of sodium ethoxide to obtain the desired molecules 2a,b. The latter acted as a key molecule for the synthesis of new carbazone derivatives 4a,b that were submitted to react with 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride to obtain the target thiadiazole derivatives 6a,b. The structures of the newly synthesized compounds were inferred from correct spectral and microanalytical data. Moreover, the newly prepared compounds were subjected to molecular docking studies with DNA gyrase B and exhibited binding energy that extended from −9.8 to −6.4 kcal/mol, which confirmed their excellent potency. The compounds 6a,b were found to be with the minimum binding energy (−9.7 and −9.8 kcal/mol) as compared to the standard drug ciprofloxacin (−7.4 kcal/mol) against the target enzyme DNA gyrase B. In addition, the newly synthesized compounds were also examined and screened for their in vitro antimicrobial activity against pathogenic microorganisms Staphylococcus aureus, E. coli, Pseudomonas aeruginosa, Aspergillus niger, and Candida albicans. Among the newly synthesized molecules, significant antimicrobial activity against all the tested microorganisms was obtained for the compounds 6a,b. The in silico and in vitro findings showed that compounds 6a,b were the most active against bacterial strains, and could serve as potential antimicrobial agents.     

Synthesis,Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives

Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2^® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.     

Synthesis and Evaluation of Thymol-Based Synthetic Derivatives as Dual-Action Inhibitors against Different Strains of H. pylori and AGS Cell Line

Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and ¹H/¹³C/¹⁹F NMR spectra. The analysis of structure–activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.     

Antimicrobial Constituents from Machaerium Pers.: Inhibitory Activities and Synergism of Machaeriols and Machaeridiols against Methicillin-Resistant Staphylococcus aureus,Vancomycin-Resistant Enterococcus faecium,and Permeabilized Gram-Negative Pathogens

Two new epimeric bibenzylated monoterpenes machaerifurogerol (1a) and 5-epi-machaerifurogerol (1b), and four known isoflavonoids (+)-vestitol (2), 7-O-methylvestitol (3), (+)-medicarpin (4), and 3,8-dihydroxy-9-methoxypterocarpan (5) were isolated from Machaerium Pers. This plant was previously assigned as Machaerium multiflorum Spruce, from which machaeriols A-D (6–9) and machaeridiols A-C (10–12) were reported, and all were then re-isolated, except the minor compound 9, for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture 10 + 11 was the most active with an MIC value of 1.25 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA) strains BAA 1696, −1708, −1717, −33591, and vancomycin-resistant Enterococcus faecium (VRE 700221) and E. faecalis (VRE 51299) and vancomycin-sensitive E. faecalis (VSE 29212). Compounds 6–8 and 10–12 were found to be more potent against MRSA 1708, and 6, 11, and 12 against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriols (7 or 8) and machaeridiols (11 or 12), which exhibited a strong synergistic activity of 12 + 8 (MIC 0.156 and 0.625 µg/mL), with >32- and >8-fold reduction of MIC’s, compared to 12, against MRSA 1708 and −1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds 10 + 11, 11, 12, and 8 showed activity in the range of 0.5–8 µg/mL for two strains of Acinetobacter baumannii, 2–16 µg/mL against Pseudomonas aeruginosa PAO1, and 2 µg/mL against Escherichia coli NCTC 12923, but were inactive (MIC > 64 µg/mL) against the two isolates of Klebsiella pneumoniae.     

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread^®) and tenofovir alafenamide (Vemlidy^®) against HIV and HBV infections and adefovir dipivoxil (Hepsera^®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex^®) against HSV-1 and VZV infections and stavudine (Zerit^®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex^®, Zelitrex^®) against HSV and VZV and rabacfosadine (Tanovea^®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide^®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.     

Synthesis and evaluation of novel O-functionalized aminated chitosan derivatives as antibacterial,antioxidant and anticorrosion for 316L stainless steel in simulated body fluid

Chitosan’s Schiff base derivatives are taking the attention of scientists as a promising biomaterial for various applications. In this study, O-functionalized aminated chitosan (O-F-Am-Ch) was coupled with 4,4-dimethyl amino-benzaldehyde and N-methyl-2-pyrrolidone to produce Schiff bases (I) and (II), respectively. The chemical and physical properties of the new derivatives were investigated by Fourier transform infrared (FT-IR) that show a significant band for C=C between 1400 and 1600 cm⁻¹, thermal gravimetric analysis (TGA), which demonstrate an increase in the thermal stability of new derivatives than O-F-Am-Ch and scanning electron microscope (SEM) that indicates a slight increase in the rough structure of the surface. In addition, 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assays that examined the antioxidant properties of the new Schiff bases. The biocidal activity against four different bacterial strains [two gram-negative (Pseudomonas aeruginosa and Escherichia coli) and two gram-positive (Bacillus cereus and Staphylococcus aureus)] demonstrates significant improvement of the inhibition activity compare to O-F-Am-Ch with more activity against Gram-negative bacteria than that against gram-positive bacteria.As an implanted alloy, 316L stainless steel is used as a temporary biomaterial in different countries without any pretreatment. Our study focused on further improving the alloy features by investigating the protection efficiency of O-F-Am-Ch and the synthesized Schiff bases for the 316L stainless steel surface against corrosion in simulated body fluid (SBF). The corrosion inhibition of these compounds was investigated using two electrochemical methods (potentiodynamic polarization technique and electrochemical impedance spectroscopy). The results suggested the formation of self-assembled monolayers (SAMs) of the compounds under investigation. Furthermore, they demonstrated a considerable dose-dependent inhibiting corrosion of 316L stainless steel in SBF, whereas the inhibition efficiency exceeds 77% at 1000 ppm for the Schiff bases II. In conclusion, the tested derivatives show promising properties to refine stainless steel for implant applications.     

Three New Acrylic Acid Derivatives from Achillea mellifolium as Potential Inhibitors of Urease from Jack Bean and α-Glucosidase from Saccharomyces cerevisiae

(1) Background: Achillea mellifolium belongs to a highly reputed family of medicinal plants, with plant extract being used as medicine in indigenous system. However, limited data is available regarding the exploitation of the medicinal potential of isolated pure compounds from this family; (2) Methods: A whole plant extract was partitioned into fractions and on the basis of biological activity, an ethyl acetate fraction was selected for isolation of pure compounds. Isolated compounds were characterized using different spectroscopic techniques. The compounds isolated from this study were tested for their medicinal potential using in-vitro enzyme assay, coupled with in-silico studies; (3) Results: Three new acrylic acid derivatives (1–3) have been isolated from the ethyl acetate fraction of Achillea mellifolium. The characterization of these compounds (1–3) was carried out using UV/Vis, FT-IR, 1D and 2D-NMR spectroscopy (¹H-NMR, ¹³C-NMR, HMBC, NOESY) and mass spectrometry. These acrylic acid derivatives were further evaluated for their enzyme inhibition potential against urease from jack bean and α glucosidase from Saccharomyces cerevisiae, using both in-silico and in-vitro approaches. In-vitro studies showed that compound 3 has the highest inhibition against urease enzyme (IC₅₀ =10.46 ± 0.03 μΜ), followed by compound 1 and compound 2 with percent inhibition and IC₅₀ value of 16.87 ± 0.02 c and 13.71 ± 0.07 μΜ, respectively, compared to the standard (thiourea-IC₅₀ = 21.5 ± 0.01 μΜ). The investigated IC₅₀ value of compound 3 against the urease enzyme is two times lower compared to thiourea, suggesting that this compound is twice as active compared to the standard drug. On the other hand, all three compounds (1–3) revealed mild inhibition potential against α-glucosidase. In-silico molecular docking studies, in combination with MD simulations and free energy, calculations were also performed to rationalize their time evolved mode of interaction inside the active pocket. Binding energies were computed using a MMPBSA approach, and the role of individual residues to overall binding of the inhibitors inside the active pockets were also computed; (4) Conclusions: Together, these studies confirm the inhibitory potential of isolated acrylic acid derivatives against both urease and α-glucosidase enzymes; however, their inhibition potential is better for urease enzyme even when compared to the standard.     

In Vivo and In Vitro Assays Evaluating the Biological Activity of Taurine,Glucose and Energetic Beverages

Taurine is one of the main ingredients used in energy drinks which are highly consumed in adolescents for their sugary taste and stimulating effect. With energy drinks becoming a worldwide phenomenon, the biological effects of these beverages must be evaluated in order to fully comprehend the potential impact of these products on the health due to the fact nutrition is closely related to science since the population consumes food to prevent certain diseases. Therefore, the aim of this study was to evaluate the biological effects of taurine, glucose, classic Red Bull^® and sugar-free Red Bull^® in order to check the food safety and the nutraceutical potential of these compounds, characterising different endpoints: (i) Toxicology, antitoxicology, genotoxicology and life expectancy assays were performed in the Drosophila melanogaster model organism; (ii) The in vitro chemopreventive activity of testing compounds was determined by assessing their cytotoxicity, the proapoptotic DNA-damage capability to induce internucleosomal fragmentation, the strand breaks activity and the modulator role on the methylation status of genomic repetitive sequences of HL-60 promyelocytic cells. Whereas none tested compounds showed toxic or genotoxic effect, all tested compounds exerted antitoxic and antigenotoxic activity in Drosophila. Glucose, classic Red Bull^® and sugar-free Red Bull^® were cytotoxic in HL-60 cell line. Classic Red Bull^® induced DNA internucleosomal fragmentation although none of them exhibited DNA damage on human leukaemia cells. In conclusion, the tested compounds are safe on Drosophila melanogaster and classic Red Bull^® could overall possess nutraceutical potential in the in vivo and in vitro model used in this study. Besides, taurine could holistically be one of the bioactive compounds responsible for the biological activity of classic Red Bull^®.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Synthesis,characterization, antimicrobial activity, 3D-QSAR,DFT, and molecular docking of some ciprofloxacin derivatives and their copper(II) complexes

Six new derivatives of ciprofloxacin compounds and their copper(II) complexes were synthesized, characterized by spectroscopic methods (ultraviolet–visible [UV–vis], Fourier transform infrared [FTIR], nuclear magnetic resonance [NMR], mass spectrometry [MS], and electron paramagnetic resonance [EPR]), and tested for antibacterial activities against gram-negative and gram-positive bacteria. The data showed that ciprofloxacin derivatives act as bidentate ligands and the metal ions coordinate through the pyridone carbonyl and the carboxylate oxygen atoms. Tetragonally distorted octahedral ligand fields were assumed for all complexes based on their spectral studies. Copper(II) complexes of the synthesized ciprofloxacin derivatives revealed higher antibacterial activities against gram-positive and gram-negative bacterial species than the parent ciprofloxacin antibiotic. Furthermore, three-dimensional quantitative structure–activity relationship (3D-QSAR) models were evaluated by studying 30 antibiotic compounds of the quinolone class. Density function theory (DFT) calculations were applied to evaluate the optimized geometrical structures using the B3LYP method and 6-311G(d,p) basis set. The 3D-QSAR study revealed that there are eight optimum parameters that give the best predictive modulation with good reliability (R² = 0.996, F = 12.004, sigma = 0.426). In silico molecular docking was also performed on the derivatives, and the results revealed the presence of two types of interactions between the Escherichia coli and the derivatives, H-bonding and Van der Waals interactions, and an effective inhibition at the docked site.     

Synthesis and Antibacterial Activity of New Azole,Diazole and Triazole Derivatives Based on p-Aminobenzoic Acid

The p-aminobenzoic acid was applied for the synthesis of substituted 1-phenyl-5-oxopyrrolidine derivatives containing benzimidazole, azole, oxadiazole, triazole, dihydrazone, and dithiosemicarbazide moieties in the structure. All the obtained compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, and Pseudomonas aeruginosa by using MIC and MBC assays. This study showed a good bactericidal activity of γ-amino acid and benzimidazoles derivatives. The antimicrobial activity of the most promising compounds was higher than ampicillin. Furthermore, two benzimidazoles demonstrated good antimicrobial activity against L. monocytogenes (MIC 15.62 µg/mL) that was four times more potent than ampicillin (MIC 65 µg/mL). Further studies are needed to better understand the mechanism of the antimicrobial activity as well as to generate antimicrobial compounds based on the 1-phenyl-5-oxopyrrolidine scaffold.     

Prenylated Flavonoids and C-15 Isoprenoid Analogues with Antibacterial Properties from the Whole Plant of Imperata cylindrica (L.) Raeusch (Gramineae)

The local botanical Imperata cylindrica in Cameroon was investigated for its antibacterial potency. The methanol extract afforded a total of seven compounds, including five hitherto unreported compounds comprising three flavonoids (1–3) and two C-15 isoprenoid analogues (4 and 5) together with known derivatives (6 and 7). The novelty of the flavonoids was related to the presence of both methyl and prenyl groups. The potential origin of the methyl in the flavonoids is discussed, as well as the chemophenetic significance of our findings. Isolation was performed over repeated silica gel and Sephadex LH-20 column chromatography and the structures were elucidated by (NMR and MS). The crude methanol extract and isolated compounds showed considerable antibacterial potency against a panel of multi-drug resistant (MDR) bacterial strains. The best MIC values were obtained with compound (2) against S. aureus ATCC 25923 (32 µg/mL) and MRSA1 (16 µg/mL).     

Evaluation of Efficiency of Polymerization,Surface Roughness,Porosity and Adaptation of Flowable and Sculptable Bulk Fill Composite Resins

A new category of commercial bulk fill composite resins (CRs) enables the placement of 4-mm-thick layers as an alternative to the traditional time-consuming incremental technique. The purpose of the present study was to compare the efficiency of the polymerization, adaptation and porosity of two high-viscosity ‘sculptable’ bulk fill CRs (Filtek™ Bulk Fill (3M™ ESPE, St. Paul, MN, USA) and Tetric EvoCeram^® Bulk Fill (Ivoclar Vivadent AG, Schwan, Liechtenstein)) and two low-viscosity ‘flowable’ bulk fill CRs (SureFil^® SDR™ flow (Dentsply Sirona, Charlotte, NC, USA) and Tetric EvoFlow^® Bulk Fill (Ivoclar Vivadent AG, Schaan, Liechtenstein)). Cylindrical samples of the bulk fill CRs (4 mm height × 10 mm diameter) were analyzed by Fourier-transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Additionally, occlusal cavities were prepared in twelve extracted human molars and restored with the bulk fill CRs (n = 3 for each CR). The adaptation and porosity of the bulk fill CRs were evaluated by X-ray microcomputed tomography (µCT) with a 3D morphometric analysis, and the adaptation was also analyzed by scanning electron microscopy (SEM) on longitudinal vestibulo-oral sections of the restored teeth. The AFM analysis demonstrated that the surface roughness of the SureFil^® SDR™ flow was higher than that of the Tetric EvoFlow^® Bulk Fill and that the surface roughness of Filtek™ Bulk Fill was higher than that of Tetric EvoCeram^® Bulk Fill. µCT and SEM confirmed that the flowable bulk fill CRs had excellent adaptation to the cavity walls. The 3D morphometric analysis showed the highest and lowest degrees of porosity in Filtek™ Bulk Fill and Tetric EvoFlow^® Bulk Fill, respectively. In general, the flowable bulk fill CRs exhibited better adaptation, a higher efficiency of polymerization and lower porosity than the sculptable materials.     

Enhancement of Antibiotic Activity by 1,8-Naphthyridine Derivatives against Multi-Resistant Bacterial Strains

The search for new antibacterial agents has become urgent due to the exponential growth of bacterial resistance to antibiotics. Nitrogen-containing heterocycles such as 1,8-naphthyridine derivatives have been shown to have excellent antimicrobial properties. Therefore, the purpose of this study was to evaluate the antibacterial and antibiotic-modulating activities of 1,8-naphthyridine derivatives against multi-resistant bacterial strains. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the following compounds: 7-acetamido-1,8-naphthyridin-4(1H)-one and 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide. The antibiotic-modulating activity was analyzed using subinhibitory concentrations (MIC/8) of these compounds in combination with norfloxacin, ofloxacin, and lomefloxacin. Multi-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were used in both tests. Although the compounds had no direct antibacterial activity (MIC ≥ 1.024 µg/mL), they could decrease the MIC of these fluoroquinolones, indicating synergism was obtained from the association of the compounds. These results suggest the existence of a structure–activity relationship in this group of compounds with regard to the modulation of antibiotic activity. Therefore, we conclude that 1,8-naphthyridine derivatives potentiate the activity of fluoroquinolone antibiotics against multi-resistant bacterial strains, and thereby interesting candidates for the development of drugs against bacterial infections caused by multidrug resistant strains.     

Fatty Acid Composition and Cytotoxic Activity of Lipid Extracts from Nannochloropsis gaditana Produced by Green Technologies

Microalgae are alternatives and sustainable sources of omega-3 long chain-polyunsaturated fatty acids (LC-PUFA). However, the eco-friendly extraction of these bioactives remains unexplored. In this work, the use of enzyme-based methods in combination with ultrasounds was evaluated as green approaches to extract the omega-3 lipids from Nannochloropsis gaditana. Three commercial enzymatic solutions (Viscozyme^® L, Celluclast^® 1.5 L, and Saczyme^®) were investigated, and results were compared with the traditional Folch method. A promising extraction approach was developed by using Saczyme^®, achieving a lipid yield of 25.7% ± 0.5, comparable to the traditional method (27.3% ± 0.7) (p > 0.05). Similar omega-3 content was found by GC–MS analysis for both lipid extracts (30.2% ± 2.4 and 29.3% ± 0.8 for the green and the traditional method, respectively), showing that the green approaches did not affect the fatty acid profile. Moreover, the cytotoxic activity of produced lipids was assessed by comparing human colon cancer cells (HCT-116) and epithelial nontumorigenic immortalized cells (HCEC-1CT). Results suggest that the lipid extracts have a selective effect, reducing the viability of the colon carcinoma cells but not the nontumorigenic cells. Thus, this study provides new eco-innovative approaches for extracting the omega-3 LC-PUFA from microalgae with promising biological properties.     

Synthesis,spectral characterization,and biological studies of 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-thione derivatives

The reaction of 3,4-dichlorophenyl-1,3,4-oxadiazole-2( 3H )-thione with piperidine derivatives via Mannich reaction was used to generate eleven novel compounds in moderate to good yields. Synthesized molecules were characterized according to their structure with ¹H NMR, ¹³C NMR and FT-IR spectral foundations, which were compatible with literature informations. Antimicrobial activity and cytotoxicity studies were done by disc diffusion and NCI-60 sulphordamine B assay methods. The antimicrobial test results revealed that synthesized compounds have better activity against gram-positive species than gram-negative ones. A total analysis of the antibacterial, antifungal, and antiyeast activity revealed that newly synthesized compounds were really active against Bacillus cereus , Bacillus ehimensis, and Bacillus thuringiensis species . For cytotoxicity, among three different cancer cell lines (HCT116, MCF7, HUH7) compounds 5c, 5d, 5e, 5f, 5g, 5i, 5j and 5k were seemed especially effective on HUH7 cancer cell line via moderate to good activity. More significantly, against liver carcinoma cell line (HUH7) most of the compounds of the series ( 5c-5g and 5i-5j ) have better IC₅₀ values (IC₅₀= 18.78 µM) than 5-Florouracil (5-FU) and also compound 5d possessed 10.1 µM value, which represents good druggable cytotoxic activity. Further, the molecules were also screened for in silico chemoinformatic and toxicity data to gather the predicted bioavailibity and safety measurements.     

Identification of the Impurities in Bopu Powder® and Sangrovit® by LC-MS Combined with a Screening Method

Bopu powder^® and Sangrovit^® were developed from Macleaya cordata and are widely used in agriculture and animal husbandry, but their impurities have been rarely reported in the literature. Impurity analysis is of great importance to the quality and safety of veterinary drugs. In this study, high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) combined with a screening method was used to screen and characterize the impurities in Bopu powder^® and Sangrovit^®. A total of 58 impurities were screened from Bopu powder^® and Sangrovit^® using the screening strategies, of which 39 were identified by their accurate m/z value, characteristic MS/MS data, and fragmentation pathways of references. This established method was used for impurity analysis for the first time and proved to be a useful and rapid tool to screen and identify the impurities of Bopu powder^® and Sangrovit^®, especially for those at trace levels in a complex sample. In addition, this study marks the first comprehensive research into impurities in these two products and has great significance for the systematic detection of impurities in other plant-derived drugs.     

Macrooxazoles A–D,New 2,5-Disubstituted Oxazole-4-Carboxylic Acid Derivatives from the Plant Pathogenic Fungus Phoma macrostoma

In our ongoing search for new bioactive fungal metabolites, four previously undescribed oxazole carboxylic acid derivatives (1–4) for which we proposed the trivial names macrooxazoles A–D together with two known tetramic acids (5–6) were isolated from the plant pathogenic fungus Phoma macrostoma. Their structures were elucidated based on high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The hitherto unclear structure of macrocidin Z (6) was also confirmed by its first total synthesis. The isolated compounds were evaluated for their antimicrobial activities against a panel of bacteria and fungi. Cytotoxic and anti-biofilm activities of the isolates are also reported herein. The new compound 3 exhibited weak-to-moderate antimicrobial activity as well as the known macrocidins 5 and 6. Only the mixture of compounds 2 and 4 (ratio 1:2) showed weak cytotoxic activity against the tested cancer cell lines with an IC₅₀ of 23 µg/mL. Moreover, the new compounds 2 and 3, as well as the known compounds 5 and 6, interfered with the biofilm formation of Staphylococcus aureus, inhibiting 65%, 75%, 79%, and 76% of biofilm at 250 µg/mL, respectively. Compounds 5 and 6 also exhibited moderate activity against S. aureus preformed biofilm with the highest inhibition percentage of 75% and 73% at 250 µg/mL, respectively.     

Activity of Compounds from Temperate Propolis against Trypanosoma brucei and Leishmania mexicana

Ethanolic extracts of samples of temperate zone propolis, four from the UK and one from Poland, were tested against three Trypanosoma brucei strains and displayed EC₅₀ values < 20 µg/mL. The extracts were fractionated, from which 12 compounds and one two-component mixture were isolated, and characterized by NMR and high-resolution mass spectrometry, as 3-acetoxypinobanksin, tectochrysin, kaempferol, pinocembrin, 4′-methoxykaempferol, galangin, chrysin, apigenin, pinostrobin, cinnamic acid, coumaric acid, cinnamyl ester/coumaric acid benzyl ester (mixture), 4′,7-dimethoxykaempferol, and naringenin 4′,7-dimethyl ether. The isolated compounds were tested against drug-sensitive and drug-resistant strains of T. brucei and Leishmania mexicana, with the highest activities ≤ 15 µM. The most active compounds against T. brucei were naringenin 4′,7 dimethyl ether and 4′methoxy kaempferol with activity of 15–20 µM against the three T. brucei strains. The most active compounds against L. mexicana were 4′,7-dimethoxykaempferol and the coumaric acid ester mixture, with EC₅₀ values of 12.9 ± 3.7 µM and 13.1 ± 1.0 µM. No loss of activity was found with the diamidine- and arsenical-resistant or phenanthridine-resistant T. brucei strains, or the miltefosine-resistant L. mexicana strain; no clear structure activity relationship was observed for the isolated compounds. Temperate propolis yields multiple compounds with anti-kinetoplastid activity.