Comparative study of antioxidant and antimicrobial activity of berberine-derived Schiff bases, nitro-berberine and amino-berberine.

In recent years, the scientific community has focused on traditional natural products and their potential therapeutic benefits. Berberine is a plant-derived isoquinoline alkaloid with a variety of biological properties and identified as a promising pharmacophore for discovering new therapeutic agents against various diseases. However, unfavorable pharmacokinetic properties of berberine have limited its clinical application so much that researchers pursue its structure modification to overcome this problem. This study focuses on the synthesis of new berberine derivatives to improve its antioxidant and antimicrobial potentials, which were characterized using CHNO and NMR instruments. Berberine extracted from barberry root was nitrated, reduced to amine and condensed with benzaldehyde derivatives to produce berberine-based Schiff bases. The H atom donating ability of all compounds was measured against DPPH free radicals, with IC50 values ranging from 18.28 to 108.20 µg ml-1. All berberine-based Schiff bases exhibited stronger antioxidant activity than nitro-berberine and amino-berberine. Only Schiff base derived from 4-hydroxybenzaldehyde showed slightly better antioxidant effects than original berberine. The inhibitory effects of the synthesized compounds were evaluated against important pathogenic fungal and bacterial strains using disk diffusion assays, with inhibition zone diameters ranging from 8.36 to 25.48 µg ml-1. Berberine itself only affected Candida albicans fungus. Nitrated berberine was effective against all microorganisms except Gram-negative Acinetobacter baumannii. The results suggest that structural modifications and functionalization can enhance the antimicrobial and antioxidant properties of berberine.

Loading of green-synthesized cu nanoparticles on Ag complex containing 1,3,5-triazine Schiff base with enhanced antimicrobial activities.

The physicochemical properties of materials change significantly in nanometer dimensions. Therefore, several methods have been proposed for the synthesis of nanoparticles. Plant extracts and essential oils are applied as natural and economic resources to prepare nanomaterials especially metal nanoparticles. In this project, a green, simple and efficient method has been designed for the synthesis of Cu nanoparticles using Purple cabbage extract as a reducing and stabilizing agent. They were successfully loaded onto a new Ag complex containing 1,3,5-triazine Schiff base as ligand to form Cu@Ag-CPX nanocomposite. Phytochemical contents of extract were identified by standard qualitative analyses. The chemical structure of all synthesized compounds was characterized using spectral data. In FT-IR, coordination of C=N bond of Schiff base ligand to Ag+ ions shifted the absorption band from 1641 to 1632 cm-1. The UV-Vis spectrum of Cu@Ag-CPX nanocomposite shown the peak related to Cu nanoparticles in the region of around 251 nm. 5:7 molar ratio of Cu to Ag in Cu@Ag-CPX was determined using ICP-OES. The FESEM, TEM, and DLS techniques provided valuable insights into the morphology and size distribution of the nanocomposite, revealing the presence of rods and monodispersed particles with specific diameter ranges. These analyses of the nanocomposite displayed rods with diameters from 40 to 62 nm as well as monodispersed and uniform particles with average diameter of 45 nm, respectively. The presence of elements including carbon, nitrogen, oxygen, Cu and Ag was proved by EDX-EDS analysis. The XRD pattern of Cu@Ag-CPX shown the diffraction peaks of Cu and Ag particles at 2θ values of 10°-80°, and confirmed its crystalline nature. The inhibitory properties of the synthesized compounds were evaluated in vitro against four Gram-negative and two Gram-positive bacteria, as well as two fungal strains. The MIC, MBC and MFC values obtained from microdilution and streak plate sensitivity tests were ranged from 128 to 4096 µg ml-1. While Cu nanoparticles and Ag complexes were effective against some pathogens, they were not effective against all them. However, the growth of all tested microbial strains was inhibited by Cu@Ag-CPX nanocomposite, and makes it as a new promising antimicrobial agent. Modification of nanocomposite in terms of nanoparticle and complex can improve its blocking activities.

A study of the interaction space of two lactate dehydrogenase isoforms (LDHA and LDHB) and some of their inhibitors using proteochemometrics modeling.

Lactate dehydrogenase (LDH) is a tetramer enzyme that converts pyruvate to lactate reversibly. This enzyme becomes important because it is associated with diseases such as cancers, heart disease, liver problems, and most importantly, corona disease. As a system-based method, proteochemometrics does not require knowledge of the protein's three-dimensional structure, but rather depends on the amino acid sequence and protein descriptors. Here, we applied this methodology to model a set of LDHA and LDHB isoenzyme inhibitors. To implement the proteochemetrics method, the camb package in the R Studio Server programming environment was used. The activity of 312 compounds of LDHA and LDHB isoenzyme inhibitors from the valid Binding DB database was retrieved. The proteochemometrics method was applied to three machine learning algorithms gradient amplification model, random forest, and support vector machine as regression methods to find the best model. Through the combination of different models into an ensemble (greedy and stacking optimization), we explored the possibility of improving the performance of models. For the RF best ensemble model of inhibitors of LDHA and LDHB isoenzymes, and were 0.66 and 0.62, respectively. LDH inhibitory activation is influenced by Morgan fingerprints and topological structure descriptors.

Lipid-Based Delivery Systems for Flavonoids and Flavonolignans: Liposomes, Nanoemulsions, and Solid Lipid Nanoparticles.

Herbal chemicals with a long history in medicine have attracted a lot of attention. Flavonolignans and flavonoids are considered as two classes of the above-mentioned compounds with different functional groups which exhibit several therapeutic capabilities such as antimicrobial, anti-inflammatory, antioxidant, antidiabetic, and anticancer activities. Based on the studies, high hydrophobic properties of the aforementioned compounds limit their bioavailability inside the human body and restrict their wide application. Nanoscale formulations such as solid lipid nanoparticles, liposomes, and other types of lipid-based delivery systems have been introduced to overcome the above-mentioned challenges. This approach allows the aforementioned hydrophobic therapeutic compounds to be encapsulated between hydrophobic structures, resulting in improving their bioavailability. The above-mentioned enhanced delivery system improves delivery to the targeted sites and reduces the daily required dosage. Lowering the required daily dose improves the performance of the drug by diminishing its side effects on non-targeted tissues. The present study aims to highlight the recent improvements in implementing lipid-based nanocarriers to deliver flavonolignans and flavonoids.

Domino protocol for the synthesis of diversely functionalized derivatives of a novel fused pentacyclic antioxidant/anticancer fluorescent scaffold: Pyrazolo[5'',1'':2',3']pyrimido[4',5':5,6][1,4]thiazino[2,3-b]quinoxaline.

Rising to the challenge of formidable multi-step reaction needed for the synthesis of polycyclic compounds, an efficient one-pot two-step procedure for the synthesis of densely functionalized novel pyrazolo[5″,1'':2',3']pyrimido[4',5':5,6] [1,4]thiazino[2,3-b]quinoxalines from synthetically accessible starting materials 6-bromo-7-chloro-3-cyano-2-(ethylthio)-5-methylpyrazolo[1,5-a]pyrimidine, 3-aminoquinoxaline-2-thiol and some readily accessible alkyl halides was established. The domino reaction pathway involves cyclocondensation/N-alkylation sequence in K2CO3/N,N-dimethyl formamide under heating condition. DPPH free radical scavenging activity of all synthesized pyrazolo[5″,1'':2',3']pyrimido[4',5':5,6][1,4]thiazino[2,3-b]quinoxalines was evaluated to determine their antioxidant potentials. IC50 values were recorded in the range of 29-71 µM. N-benzyl substituted derivative represented the most effective antioxidant activity as well as antiproliferative activity against MCF-7 cells. Moreover, fluorescence in solution for these compounds exhibited strong red emission in the visible region (λflu. = 536-558 nm) with good to excellent quantum yields (61-95%). Due to their interesting fluorescence properties, these novel pentacyclic fluorophores can be used as fluorescent markers and probes for studies in biochemistry and pharmacology.

BioMOF-Mn: An Antimicrobial Agent and an Efficient Nanocatalyst for Domino One-Pot Preparation of Xanthene Derivatives.

In this paper, a new Mn-based metal-organic framework [UoB-6] was obtained via a one-step ultrasonic irradiation method with the ligand (H2bdda: 4,4'-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))dibenzoic acid. The structural integrity of the synthesized BioMOF-Mn was corroborated by FT-IR, EDX, ICP, XRD, TEM, DLS, FESEM, and BET-BJH analyses. The aerobic oxidative domino reaction of benzyl alcohols or aldehydes with dimedone derivatives was performed in the presence of the UoB-6 catalyst to produce xanthene derivatives in good yields. Hot filtration and Hg poisoning tests proved the heterogeneous nature of the catalyst. Novel synthesized xanthene-based bis-aldehydes were introduced as potent HDAC1 inhibitors according to molecular docking calculations. Finally, the inhibitory activities of Mn-MOF nanoparticles were evaluated on Escherichia coli and Candida albicans. The MIC, MBC, and MFC values were determined from 2048 to 4096 µg·mL-1 according to antimicrobial susceptibility testing methods. The inhibitory effects of antimicrobial agents can be exacerbated when loaded on BioMOFs.

Synergistic effects of dual antimicrobial combinations of synthesized N-heterocycles or MgO nanoparticles with nisin against the growth of Aspergillus fumigatus: In vitro study.

Introduction of new inhibitory agents such as peptides, heterocyclic derivatives and nanoparticles (NPs) along with preventive proceedings are effective ways to deal with standard and drug-resistant strains of microorganisms. In this regard, inhibitory activities of some recently synthesized 4-thiazolylpyrazoles, imidazolidine- and tetrahydropyrimidine-2-thiones and magnesium oxide (MgO) NPs alone and in combination with nisin have been assessed against Aspergillus fumigatus. Antimicrobial susceptibility tests were done via broth microdilution, disk diffusion and streak plate methods according to the modified Clinical and Laboratory Standards Institute (CLSI) guidelines. Synergistic effects were also determined as fractional inhibitory concentration (FIC) and fractional fungicidal concentration (FFC) values. Inhibitory potentials of all heterocycles and NPs against A. fumigatus were proved based on inhibition zone diameter (IZD) values in the range of 7.72 - 16.85 mm, minimum inhibitory concentration (MIC) values in the range of 64.00 - 512 µg mL-1 and minimum fungicidal concentration (MFC) values in the range of 256 - 2048 µg mL-1. Tetrahydropyrimidine derivative 3f showed the best inhibitory properties. Inhibitory activity was not significant with nisin. While antifungal effects of major derivatives were improved by combination with it. The results indicated that the combined treatment of heterocycles used in the present study with nisin might be efficient for mold prevention and removal in foodstuffs or other products.

Ultrasound-Assisted Synthesis, Antioxidant Activity and Computational Study of 1,3,4-Oxadiazol-2-amines.

Development of synthetic procedures for the preparation of 1,3,4-oxadiazole derivatives has always been in the interest of researchers as a result of their widespread biological activities. In this study, an ultrasound-assisted procedure was proposed for the synthesis of 1,3,4-oxadiazol-2-amines form the reaction of hydrazides and cyanogen bromide. They were efficiently produced in 81-93% yields in the presence of ethanol and potassium bicarbonate as the reaction media and the base, respectively. Their antioxidant properties were determined via DPPH free radical scavenging method as one of the most basic steps in identifying other related biological effects. IC50 values were in the range of from 0.237 to 0.863 mM. The synthesized 1,3,4-oxadiazoles are protective agents against oxidative stress, and can be used in the treatment of cancer, candidiasis, diabetes, neurodegenerative and inflammatory diseases. Furthermore, bond dissociation energies (BDEs) and electron densities based NCI (non-covalent interactions) were calculated using density-functional theory (DFT) to understand the observed reactivities. It was found that reversible dipole-dipole forces play a key role in most interactions.

Quercetin-loaded F127 nanomicelles: Antioxidant activity and protection against renal injury induced by gentamicin in rats.

Quercetin (Q) is formulated into oil-in-water F127 microemulsions to improve its bioavailability. The size of the Q-loaded microemulsions system was about 8 nm by dynamic light scattering analysis. To compare antioxidant activity of bulk solution and microemulsion of Q, free radical scavenging activity was evaluated against 2,2-diphenyl-1-picrylhydrazyl (DPPH). The IC50 values were 56.77 and 187.68 µM, respectively. The drug in the bulk form released 16.34 times faster than microemulsion form. Although gentamicin (GM) has potent efficacy against gram-negative bacteria, it induces renal toxicity. Poor solubility and low bioavailability of Q as a bioflavonoid with potent antioxidant activity, limit its therapeutic application. We aimed to compare the effect of free Q and nanoencapsulated (NEQ) against GM-induced renal damage in Wistar rats. Forty-two animals were divided into six groups. Control and GM groups received apo-nanomicelles and GM (100 mg/kg) for 10 days. Two groups received Q (50 mg/kg, i.g.) and NEQ (50 mg/kg, i.g.) respectively for 10 days. Remaining two groups received Q and NEQ (50 mg/kg, i.g.) plus GM (100 mg/kg, i.p.) simultaneously for 10 days. After the experiments, serum and kidneys were used for biochemical, molecular and histological examinations. Immunohistochemical analysis was performed to explore kidney injury molecule-1 (KIM-1) expression as a specific protein biomarker of renal injury. Our findings indicated oxidative stress and altered histological features in renal tissue with deviated serum renal biomarkers in GM-treated rats. Although Q treatment in GM group tried to protect against GM-induced nephrotoxicity, but there were still differences compared to control rats. However, NEQ administration corrected elevations in the levels of urea, creatinine, uric acid and decrements in serum total proteins of GM group. Meanwhile, NEQ restored renal oxidative injury in GM rats through attenuation of lipid peroxidation and enhancement of antioxidant defense systems, glutathione, catalase and superoxide dismutase. NEQ could also normalize GM-induced abnormal renal histology features including fibrosis. Furthermore, the result of immunohistochemistry study confirmed these findings by undetecting KIM-1 expression in NEQ treated GM group, meanwhile showing this renal biomarker in GM and Q treated GM groups. Therefore, NEQ seems to be useful in protecting against renal oxidative stress and kidney damage in a rat model of GM nephrotoxicity which deserve further evaluations.

Ultrasound-assisted, low-solvent and acid/base-free synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols as potent antimicrobial and antioxidant agents.

One of the goals of green chemistry is to use environmentally friendly solvents or remove and reduce the volume of harmful spent solvents. In this study, a novel process for the synthesis of 5-substituted 1,3,4-oxadiazole-2-thiol derivatives was proposed via ultrasound-assisted reaction of aryl hydrazides with CS2 (1:1 molar ratio) in some drops of DMF in the absence of basic or acidic catalysts. They were produced in good to excellent yields under easy workup and purification conditions. In order to prove the usefulness of the prepared compounds, their antioxidant, antibacterial, and antifungal potentials were screened by DPPH free radical scavenging, serial twofold microdilution and streak plate methods. Acceptable to significant inhibitory activities were observed with synthesized heterocycles. The results showed that 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-thiol (3c) is an broad-spectrum antimicrobial agent. Many of them displayed remarkable antioxidant properties comparable to standard controls (ascorbic acid and α-tocopherol). Synthesized 1,3,4-oxadiazoles are also potent candidates to treat cancer, Parkinson, inflammatory, and diabetes diseases. Eighteen 5-substituted 1,3,4-oxadiazole-2-thiol derivatives as potent antimicrobial and antioxidant agents were prepared via a new, efficient and green procedure.

Expedient multicomponent synthesis of a small library of some novel highly substituted pyrido[2,3-d]pyrimidine derivatives mediated and promoted by deep eutectic solvent and in vitro and quantum mechanical study of their antibacterial and antifungal activities.

A facile and efficient catalyst- and oxidant-free multicomponent synthesis of a small library of highly substituted pyrido[2,3-d]pyrimidine derivatives is reported. The products were obtained within relatively short reaction times in good to excellent yields in the presence of deep eutectic solvents as media and promoters. Simple purification and reusability of the deep eutectic solvent were the other beneficial factors of the reported protocol. All of the synthesized derivatives were thoroughly screened for possible in vitro antibacterial and antifungal effects against twenty-two bacterial and three fungal pathogens. Some of the prepared pyrido[2,3-d]pyrimidine derivatives showed remarkable antibacterial and antifungal activities in comparison with some typical known antibacterial and antifungal agents. Finally, the derivatives possessing bioactivity effects were subjected to quantum chemical computational studies in order to reveal the probable structural and electronic effects governing the spotted bioactivities. It was found that the observed bioactivities could be best devoted to the HOMO-LUMO energy gap and para delocalization index of the corresponding derivatives.

Green multicomponent synthesis, antimicrobial and antioxidant evaluation of novel 5-amino-isoxazole-4-carbonitriles.

BACKGROUND: Design and synthesis of new inhibitor agents to deal with pathogenic microorganisms is expanding. In this project, an efficient, environmentally friendly, economical, rapid and mild procedure was developed for the synthesis of novel functionalized isoxazole derivatives as antimicrobial potentials. METHODS: Multicomponent reaction between malononitrile (1), hydroxylamine hydrochloride (2) and different aryl or heteroaryl aldehydes 3a-i afforded novel 5-amino-isoxazole-4-carbonitriles 4a-i in good product yields and short reaction times. Deep eutectic solvent K2CO3/glycerol was used as catalytic reaction media. Structure of all molecules were characterized by different analytical tools. In vitro inhibitory activity of all derivatives was evaluated against a variety of pathogenic bacteria including both Gram-negative and Gram-positive strains as well as some fungi. In addition, their free radical scavenging activities were assessed against DPPH. RESULTS: Broad-spectrum antimicrobial activities were observed with isoxazoles 4a, b, d. In addition, antioxidant activity of isoxazole 4i was proven on DPPH. CONCLUSIONS: In this project, compounds 4a, b, d could efficiently inhibit the growth of various bacterial and fungal pathogens. Antioxidant properties of derivative 4i were also significant. These biologically active compounds are suitable candidates to synthesize new prodrugs and drugs due to the presence of different functional groups on their rings.

Multicomponent Solvent-Free Synthesis, Antibacterial Evaluation and QSAR Study of 2-(Bis(benzylthio)methylene) malononitriles.

Multicomponent reaction of malononitrile, carbon disulphide and various benzyl halides was developed as an efficient strategy for the synthesis of 2-(bis(benzylthio)methylene)malononitrile derivatives via two different procedures: (a) in the presence of K2CO3 as a base in acetonitrile and (b) under solvent-free conditions in the presence of triethylamine. Higher yields with shorter reaction times were obtained from the latter procedure. Inhibitory activity of all derivatives was evaluated against 22 pathogenic bacteria including both Gram-negative and Gram-positive strains. Thioether 4b showed broad-spectrum antibacterial activities according to the antibiogram tests. DFT calculations (B3LYP/6-311++G**) were performed to determine the type of drug-receptor interactions. It was found that reversible dipole-dipole forces play a key role in most interactions.

MgO Nanoparticle-Catalyzed Synthesis and Broad-Spectrum Antibacterial Activity of Imidazolidine- and Tetrahydropyrimidine-2-Thione Derivatives.

The biological properties of imidazolidine- and tetrahydropyrimidine-2-thione derivatives such as antiviral, antitumor, anti-inflammatory, and analgesic activities increase the demand for mild and efficient synthetic routes. In this regard, methods such as reaction of diaminoalkanes with carbon disulfide have been developed. However, this method usually suffers from relatively long reaction times, using excess reagents, vigorous reaction conditions, and emission of pernicious hydrogen sulfide gas. In this project, MgO nanoparticle was used as an efficient, non-toxic, recyclable, and economic catalyst to synthesize cyclic five- or six-membered thioureas 3a-h via reaction of 1:1 molar ratios of 1,2- or 1,3-diaminoalkanes 1a-h and carbon disulfide in ethanol at ambient temperature. More interestingly, no hydrogen sulfide emission was detected during the reaction progress. The in vitro antimicrobial properties of synthesized compounds were investigated against 14 different Gram-positive and Gram-negative pathogenic bacteria according to CLSI (Clinical and Laboratory Standards Institute) broth microdilution and disk diffusion methods. The results were compared to those of penicillin, gentamicin, and ceftriaxone, and reported as inhibition zone diameter (IZD), the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC) values. The best inhibitory effects were observed with imidazolidine-2-thiones 3c and 3d. They were effective against 14 and 11 pathogens, respectively. The structure-activity relationships of the prepared heterocyclic compounds were also studied.

Green One-pot Synthesis of Novel Polysubstituted Pyrazole Derivatives as Potential Antimicrobial Agents.

Various biological properties of natural and synthetic pyrazole derivatives such as anti-inflammatory, antimicrobial, neuroprotective, anticonvulsant, antidepressant and anticancer activities encouraged us to propose a new, fast, green and eco-friendly procedure for the preparation of some novel 5-amino-3-(aryl substituted)-1-(2,4-dinitrophenyl)-1H-pyrazole-4-carbonitriles. They were efficiently synthesized via one-pot two-step process reaction of malononitrile, 2,4-dinitrophenylhydrazine and different benzaldehydes in deep eutectic solvent (DES) glycerol/potassium carbonate. The products yield and reaction times were considerably improved in the presence of applied DES. Antibacterial effects of all newly synthesized pyrazoles in comparison with several common antibiotics were evaluated against a variety of Gram-positive and Gram-negative pathogenic bacteria. In addition to, their inhibitory activities on three fungi were compared to some current antifungal agents. The moderate to good antimicrobial potentials particularly against fungi were observed in the major heterocyclic compounds according to the IZD, MIC, MBC and MFC results.