Fluconazole Analogs and Derivatives: An Overview of Synthesis, Chemical Transformations, and Biological Activity.

Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol), which was patented in 1981 and introduced for commercial use in 1988, is a widely utilized antifungal drug whose mechanism of action involves inhibition of the activity of 14-α lanosterol demethylase. Its safety and effectiveness have established it as one of the most frequently employed antifungal agents. Resistance to azole antifungal drugs is becoming more common. It may be related to a mutation of the gene encoding the enzyme. To address this issue, molecules with modifications in three main regions of fluconazole, namely the hydroxyl group, the aromatic ring, and the 1,2,4-triazole rings, have been synthesized in an attempt to create more potent antifungal drugs. These modifications aim at enhancing the effectiveness against microorganisms and improving pharmacokinetic parameters and safety profiles of the synthesized compounds. The present review explores the synthesis of fluconazole derivatives, accompanied by insights into the results of biological studies evaluating the therapeutic effects of these compounds.

Arylcyanomethylenequinone Oximes: An Overview of Synthesis, Chemical Transformations, and Biological Activity.

Quinone methides are a class of biologically active compounds that can be used in medicine as antibacterial, antifungal, antiviral, antioxidant, and anti-inflammatory agents. In addition, quinone methides have the potential to be used as pesticides, dyes, and additives for rubber and plastics. In this paper, we discuss a subclass of quinone methides: methylenequinone oximes. Although the first representatives of the subgroup were synthesized in the distant past, they still need to be additionally studied, while their chemistry, biological properties, and perspective of practical applications require to be comprehensively summarised. Based on the analysis of the literature, it can be concluded that methylenequinone oximes exhibit a diversified profile of properties and outstanding potential as new drug candidates and reagents in organic synthesis, both of electrophilic and nucleophilic nature, worthy of wide-ranging further research.

Full Regio- and Stereoselective Protocol for the Synthesis of New Nicotinoids via Cycloaddition Processes with the Participation of Trans-Substituted Nitroethenes: Comprehensive Experimental and MEDT Study.

[3 + 2] Cycloaddition reactions with the participation of Z-C-(3-pyridyl)-N-methylnitrone and series of E-2-R-nitroethenes were both experimentally and theoretically explored in the framework of Molecular Electron Density Theory. It was found that all considered processes are realized under mild conditions and in full regio- and stereocontrol. The ELF analysis additionally showed that the studied reaction proceeds by a two-stage, one-step mechanism.

Silver Is Not Equal to Silver: Synthesis and Evaluation of Silver Nanoparticles with Low Biological Activity, and Their Incorporation into C12Alanine-Based Hydrogel.

A new type of silver nanoparticles (AgNPs) was prepared and comprehensively studied. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) analyses indicated that 24 nm AgNPs with narrow size distribution were obtained while Z-potential confirms their good stability. The composites of the obtained AgNPs with nontoxic-nature-inspired hydrogel were formed upon cooling of the aqueous solution AgNPs and C12Ala. The thermal gravimetric analysis (TGA) and the differential scanning calorimetry (DSC) do not show significant shifts in the characteristic temperature peaks for pure and silver-enriched gels, which indicates that AgNPs do not strongly interact with C12Ala fibers, which was also confirmed by SEM. Both AgNPs alone and in the assembly with the gelator C12Ala were almost biologically passive against bacteria, fungus, cancer, and nontumor human cells, as well as zebra-fish embryos. These studies proved that the new inactive AgNPs-doped hydrogels have potential for the application in therapy as drug delivery media.

Low-Molecular-Weight Organogelators Based on N-dodecanoyl-L-amino Acids-Energy Frameworks and Supramolecular Synthons.

Lauric acid was used to synthesize the low-molecular-weight organogelators (LMOGs), derivatives of two endogenous (L)-alanine, (L)-leucine, and three exogenous (L)-valine, (L)-phenylalanine, and (L)-proline amino acids. The nature of processes responsible for the gel formation both in polar and in apolar solvents of such compounds is still under investigation. Knowing that the organization of surfactant molecules affects the properties of nano scale materials and gels, we decided to elucidate this problem using crystallographic diffraction and energy frameworks analysis. The single crystals of the mentioned compounds were produced successfully from heptane/tBuOMe mixture. The compounds form lamellar self-assemblies in crystals. The energetic landscapes of single crystals of a series of studied amphiphilic gelators have been analyzed to explore the gelling properties. The presented results may be used as model systems to understand which supramolecular interactions observed in the solid state and what energy contributions are desired in the designing of new low-molecular-weight organic gelators.

On the Question of the Formation of Nitro-Functionalized 2,4-Pyrazole Analogs on the Basis of Nitrylimine Molecular Systems and 3,3,3-Trichloro-1-Nitroprop-1-Ene.

Experimental and theoretical studies on the reaction between (E)-3,3,3-trichloro-1-nitroprop-1-ene and N-(4-bromophenyl)-C-arylnitrylimine were performed. It was found that the title process unexpectedly led to 1-(4-bromophenyl)-3-phenyl-5-nitropyrazole instead of the expected Δ2-pyrazoline molecular system. This was the result of a unique CHCl3 elimination process. The observed mechanism of transformation was explained in the framework of the molecular electron density theory (MEDT). The theoretical results showed that both of the possible channels of [3 + 2] cycloaddition were favorable from a kinetic point of view, due to which the creation of 1-(4-bromophenyl)-3-aryl-4-tricholomethyl-5-nitro-Δ2-pyrazoline was more probable. On the other hand, according to the experimental data, the presented reactions occurred with full regioselectivity.

A Modular Approach to Atropisomeric Bisphosphines of Diversified Electronic Density on Phosphorus Atoms.

The series of C2-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6'-diiodo-2,2',4,4'-tetramethylbiphenyl-3,3'-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity.

Experimental and theoretical study of adsorption of synthesized amino acid core derived surfactants at an air/water interface.

The adsorption characteristics of amino acid surfactants, synthesized as substances with different volumes and hydrophilic head properties, have been previously described experimentally, without robust theoretical explanation. A theoretical model enabling the characterization of the adsorption behavior and physicochemical properties of this type of biodegradable surfactants, based on molecular structure, would be beneficial for assessment of their usefulness in colloids and interface science in comparison with typical surface-active substances. In this paper, the adsorption behaviour of synthesized amino acid surfactants at the liquid/gas interface was analyzed experimentally (by surface tension measurements using two independent techniques) and theoretically by means of an elaborate model, considering the volume of the surfactant hydrophilic "head" and its ionization degree. It was shown that the adsorption behavior of the synthesized compounds can be successfully described by the proposed model, including the Helfand-Frisch-Lebowitz isotherm based on the equation of state of 2D hard disk-like particles, with molecular properties of surfactant particles obtained using molecular dynamics simulations (MDS). Model parameters allow for direct comparison of physicochemical properties of synthesized amino acid surfactants with other ionic and non-ionic surface-active substances. Furthermore, it was revealed that intermolecular hydrogen bonds allow the formation of surfactant dimers with high surface activity.

New Supramolecular Drug Carriers: The Study of Organogel Conjugated Gold Nanoparticles.

An aqueous solution of sodium citrate stabilized gold nanoparticles (AuNP) in the presence of N-lauroyl-L-alanine (C12ALA) forms a stable gel. The structure of the gel and the distribution profile of AuNP in it were analyzed. Will nanoparticles separated from each other with sodium citrate behave in the same way in solution and trapped in the gel matrix? Will the spatial limitation of solvent molecules aggregate nanoparticles and destroy their homogeneity? These questions are very important from the point of view of the use of gold nanoparticles, trapped in the gel structure as carriers of drugs in the slow-release process. The lack of homogeneity of this distribution will have a major impact on the rate of release of the appropriate amount of therapeutic drug from the matrix. In this work, we attempt to answer these questions. The performed biological assays revealed that both C12ALA and C12ALA-AuNP show an excellent level of biological neutrality. They might be used as a transporting medium for a drug delivery without affecting the drug's activity.

A straightforward, environmentally beneficial synthesis of spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12-triones mediated by a nano-ordered reusable catalyst.

A library of new spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12-trione derivatives has been prepared in an efficient, one-pot pseudo four-component method mediated by a reusable heterogeneous nano-ordered mesoporous SO3H functionalized-silica (MCM-41-SO3H) catalyst. Excellent yields, short reaction times, as well as convenient non-chromatographic purification of the products and environmental benefits such as green and metal-free conditions constitute the main advantages of the developed synthetic methodology. The obtained fused indole-indenone dyes would be of interest to pharmaceutical and medicinal chemistry. Furthermore, due to their sensitivity to pH changes, they could be used as novel pH indicators.

Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells.

In the light of the increasing occurrence of antifungal resistance, there is an urgent need to search for new therapeutic strategies to overcome this phenomenon. One of the applied approaches is the synthesis of small-molecule compounds showing antifungal properties. Here we present a continuation of the research on the recently discovered anti-Candida albicans agent 4-AN. Using next generation sequencing and transcriptional analysis, we revealed that the treatment of C. albicans with 4-AN can change the expression profile of a large number of genes. The highest upregulation was observed in the case of genes involved in cell stress, while the highest downregulation was shown for genes coding sugar transporters. Real-time PCR analysis revealed 4-AN mediated reduction of the relative expression of genes engaged in fungal virulence (ALS1, ALS3, BCR1, CPH1, ECE1, EFG1, HWP1, HYR1 and SAP1). The determination of the fractional inhibitory concentration index (FICI) showed that the combination of 4-AN with amphotericin B is synergistic. Finally, flow cytometry analysis revealed that the compound induces mainly necrosis in C. albicans cells.

New Perspectives for Fisetin.

Fisetin is a flavonol that shares distinct antioxidant properties with a plethora of other plant polyphenols. Additionally, it exhibits a specific biological activity of considerable interest as regards the protection of functional macromolecules against stress which results in the sustenance of normal cells cytoprotection. Moreover, it shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and recently also senotherapeutic agent. In view of its prospective applications in healthcare and likely demand for fisetin, methods for its preparation and their suitability for pharmaceutical use are discussed herein.

Novel functionalized ß-nitrostyrenes: Promising candidates for new antibacterial drugs.

The process of searching for new antibacterial agents is more and more challenging due to the increasing drug resistance which has become a major concern in the field of infection management. Our study presents a synthesis and characterization by IR, UV, 1H NMR and 13C NMR spectra of a homogenous series of 1-EWG functionalized 2-aryl-1-nitroethenes which could prove good candidates for the replacement of traditional antibacterial drugs In vitro screening against a panel of the reference strains of bacteria and fungi and their cytotoxicity towards cultured human HepG2 and HaCaT cells was performed. Antimicrobial results indicated that four of the synthesized compounds exhibited a significant antimicrobial activity against all tested reference bacteria and fungi belonging to yeasts with a specific and strong activity towards B. subtilis ATCC 6633. Two of these compounds had no detectable cytotoxicity towards the cultured human cell lines, making them promising candidates for new antibacterial drugs.

New Rigid Polycyclic Bis(phosphane) for Asymmetric Catalysis.

A simple, highly efficient synthesis of a series of novel chiral non-racemic rigid tetracyclic phosphorus ligands, applicable in important chemical asymmetric transformations, was performed. In a tandem cross-coupling/C-H bond activation reaction, a well-recognised and readily available ligand (R,R)-NORPHOS was used as the starting material. The palladium complexes of new ligands were obtained and characterised on the example of a crystalline dichloropalladium complex of [(1R,2R,9S,10S,11R,12R)-4-phenyltetracyclo[8.2.1.02,9.03,8]trideca-3,5,7-triene-11,12-diyl]bis(diphenylphosphane). A notably high activity and stereoselectivity of the palladium catalysts based on the new ligands were confirmed in a model asymmetric allylic substitution reaction. Herein, we discuss the geometry of the palladium complexes formed and its impact on the efficiency of the catalysts. A comparison of their geometric features with other bis(phosphane) ligand complexes found in the Cambridge Structural Database and built density functional theory (DFT) commutated models is also presented and rationalised.

The Anti-Candida albicans Agent 4-AN Inhibits Multiple Protein Kinases.

Small molecules containing quinone and/or oxime moieties have been found as promising anti-fungal agents. One of them is 4-AN, a recently reported potent anti-Candida compound, which inhibits the formation of hyphae, decreases the level of cellular phosphoproteome, and finally shows no toxicity towards human erythrocytes and zebrafish embryos. Here, further research on 4-AN is presented. The results revealed that the compound: (i) Kills Candida clinical isolates, including these with developed antibiotic resistance, (ii) affects mature biofilm, and (iii) moderately disrupts membrane permeability. Atomic force microscopy studies revealed a slight influence of 4-AN on the cell surface architecture. 4-AN was also shown to inhibit multiple various protein kinases, a characteristic shared by most of the ATP-competitive inhibitors. The presented compound can be used in novel strategies in the fight against candidiasis, and reversible protein phosphorylation should be taken into consideration as a target in designing these strategies.

Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 + 2] cycloaddition.

ABSTRACT: 5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole was obtained as a product of a high-yielding [3 + 2] cycloaddition reaction of in situ-generated benzonitrile N-oxide and 3-nitroprop-1-ene. For the first time, the regiochemistry of this reaction was unambiguously proven by X-ray structural analysis. The quantum-chemical calculation performed at the M06-2X/6-31G(d) (PCM) theoretical level affords a basis for explaining the course of reaction as well as the nature of transition states. Next, further DFT calculations together with spectral data shed light on structural aspects of the product.

A representative of arylcyanomethylenequinone oximes effectively inhibits growth and formation of hyphae in Candida albicans and influences the activity of protein kinases in vitro.

In this study, we applied various assays to reveal new activities of phenylcyanomethylenequinone oxime-4-(hydroxyimino) cyclohexa-2,5-dien-1-ylidene](phenyl)ethanenitrile (4-AN) for potential anti-microbial applications. These assays demonstrated (a) the antimicrobial effect on bacterial and fungal cultures, (b) the effect on the in vitro activity of the kinase CK2, (c) toxicity towards human erythrocytes, the Caco-2 cancer cell line, and embryonic development of Zebrafish. We demonstrated the activity of 4-AN against selected bacteria and Candida spp. The MIC ranging from 4 µg/ml to 125 µg/ml proved effective in inhibition of formation of hyphae and cell aggregation in Candida, which was demonstrated at the cytological level. Noteworthy, 4-AN was found to inhibit the CK2 kinase with moderate potency. Moreover, at low concentrations, it did not exert any evident toxic effects on human erythrocytes, Caco-2 cells, or Zebrafish embryos. 4-AN can be a potential candidate as a novel drug against Candida infections.

Green in water sonochemical synthesis of tetrazolopyrimidine derivatives by a novel core-shell magnetic nanostructure catalyst.

A green approach for the one-pot four-component sonochemical synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic esters from the reaction of 2-cyano-guanidine, sodium azide, various aromatic aldehydes and methyl or ethyl acetoacetate in the presence of a catalytic amount of Fe2O3@SiO2-(CH2)3NHC(O)(CH2)2PPh2 as a new hybrid organic-inorganic core-shell nanomagnetic catalyst is described. This is the first design, preparation, characterization and application of the present nanomaterial and also the first ultrasound irradiated synthesis of the biologically and pharmaceutically important heterocyclic compounds in water as a green solvent. This novel sonocatalysis/nanocatalysis protocol offers several advantages such as high yields, short reaction times, environmentally-friendly reaction media, easily isolation of the products, simple preparation, full characterization and recoverability of the nanocatalyst by an external magnet and reusing several times without significant loss of activity.

1,4-Naphthoquinone derivatives potently suppress Candida albicans growth, inhibit formation of hyphae and show no toxicity toward zebrafish embryos.

PURPOSE: In this study, we applied various assays to find new activities of 1,4-naphthoquinone derivatives for potential anti-Candida albicans applications. METHODOLOGY: These assays determined (a) the antimicrobial effect on growth/cell multiplication in fungal cultures, (b) the effect on formation of hyphae and biofilm, (c) the influence on cell membrane integrity, (d) the effect on cell morphology using atomic force microscopy, and (e) toxicity against zebrafish embryos. We have demonstrated the activity of these compounds against different Candida species and clinical isolates of C. albicans. KEY FINDINGS: 1,4-Naphthoquinones significantly affected fungal strains at 8-250 mg l-1 of MIC. Interestingly, at concentrations below MICs, the chemicals showed effectiveness in inhibition of hyphal formation and cell aggregation in Candida. Of note, atomic force microscopy (AFM) analysis revealed an influence of the compounds on cell morphological properties. However, at low concentrations (0.8-31.2 mg l-1), it did not exert any evident toxic effects on zebrafish embryos. CONCLUSIONS: Our research has evidenced the effectiveness of 1,4-naphthoquinones as potential anti-Candida agents.

New family of antimicrobial agents derived from 1,4-naphthoquinone.

Naphthalene-1,4-dione derivatives were synthesized and tested against selected bacterial strains. All the tested compounds were prepared by direct introduction of corresponding substituents into the naphthoquinone core in oxidative conditions. In this study, eight strains of bacteria (Proteus, Escherichia, Klebsiella, Staphylococcus, Enterobacter, Pseudomonas, Salmonella, Enterococcus) were used for determination of antimicrobial activity of synthesized compounds with the Minimal Inhibitory Concentration (MIC) method. Additionally, selected compounds were tested for haemolytic activity using human erythrocytes. All naphthalene-1,4-dione derivatives exhibited significant antimicrobial activity with MIC values between 7.8 and 500 µg/ml. A majority of the synthesized compounds showed the strongest antibacterial properties towards S. aureus, with a high level of selectivity. None of the tested naphthalene-1,4-dione derivatives exhibited haemolytic activity.