Chlorokojic Acid Research Articles

Nature-inspired innovation: Alginic-kojic acid material for sustainable antibacterial and carbon dioxide fixation

The current environmental consciousness of the world's population encourages researchers to work on new materials that are environmentally benign and able to display the appropriate features for the needed application. To develop high-performing, inexpensive eco-materials, scientists have frequently turned to nature, attempting to mimic its processes' excellent performance at a reasonable price. In this regard, we decided to focus on alginic acid (AA), a polysaccharide widely found in brown algae, and kojic acid (KA), a chelating agent fungi produces. This study proposes rapidly synthesizing a sustainable, biocompatible material (AK) based on AA and KA, employing chlorokojic acid (CKA). The material has a dual function: antibacterial activity on both Gram-positive and Gram-negative bacteria, without any cytotoxic action on human cells in vitro, and catalytic ability to convert CO2 into cyclic carbonates at atmospheric pressure, without solvents, with high yields, and without the use of metals. Furthermore, the material's insolubility in organic solvents allows it to be easily separated from the reaction product and reused for other catalytic cycles. Both applications have a key role in the medical and environmental fields, combating the outbreak of infections and providing an innovative methodology to fix the CO2 on specific substrates.

Design and synthesis of ferrocene‐based magnetic nanoparticle and investigation of its catalytic ability in the synthesis of novel 6‐[(morpholin‐4‐yl)methyl] substituted pyrano[3,2‐b]pyran derivatives

In this work, we designed and synthesized the Fe3O4@SiO2@(CH2)3‐Im‐bisethylFc (CH3CO2) as a new catalyst for three‐multicomponent reaction (t‐MCR), which is a silica‐coated Fe3O4 nanoparticle supported with bisethylferrocene‐containing IL. All of the prepared nanoparticles were specified using FT‐IR spectroscopy, FE‐SEM, XRD, TEM, and EDX techniques. The activity of the final modified nanoparticle as MCR catalyst was tested in the one‐pot procurement of novel pyran derivatives through a t‐MCR between 2‐[(morpholin‐4‐yl)methyl]‐5‐hydroxy‐4H‐pyran‐4‐one, malononitrile, and diversity of aromatic aldehydes. The compound 2‐[(morpholin‐4‐yl)methyl]‐5‐hydroxy‐4H‐pyran‐4‐one as a precursor, was prepared via nucleophilic substitution reaction of morpholine with chlorokojic acid. The FT‐IR, 1H, and 13C NMR spectroscopies were used for the identification of newly synthesized compounds.

Synthesis and Some Properties of New 5-Hydroxy-2-[(hetarylthio)methyl]-4H-pyran-4-ones

The reaction of 2-thioxoazines with chlorokojic acid in the presence of KOH in DMF led to the formation of new hybrid molecules containing fragments of kojic acid and azaheterocycle linked by the SCH2 spacer. In silico prediction of bioavailability parameters was carried out, possible protein targets were predicted by the protein ligand docking method.

The clean and mild synthesis, crystal structure, and intra-molecular hydrogen bond study of substituted new 4,8-dihydropyrano[3,2-b]-pyrans containing chlorokojic acid moiety

A safe, green and convenient process was developed for the synthesis of a novel group of 4,8-dihydropyrano[3,2-b]-pyrans by dialkyl acetylenedicarboxylates and alkyl isocyanides being trapped by chlorokojic acid in good to excellent yields at ambient temperature. Characterization of all structures was carried out by FT-IR and 1H and 13C NMR spectrometers, and two compounds were analyzed using X-ray diffraction technique. Crystal structures showed an intramolecular hydrogen bond and stacking of the dimeric (RS) molecules with the unit cell along the a-axis.

Synthesis, computational molecular docking analysis and effectiveness on tyrosinase inhibition of kojic acid derivatives

Tyrosinase inhibitors have become increasingly important as whitening agents and for the treatment of pigmentary disorders. In this study, the synthesis of kojic acid derivatives having 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/methyl/morpholinomethylpiperidinyl- methyl/pyrrolidinylmethyl-4H-pyran-4-one structure (compounds 1–30) with inhibitory effects on tyrosinase enzyme were described. One-pot Mannich reaction was carried out by using kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. Subsequently, cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid were obtained with nucleophilic substitutions in basic medium. The structures of new compounds were identified by FT-IR, 1H- and 13C NMR, ESI-MS and elemental analysis data. The potential mushroom tyrosinase inhibitory activity of the compounds were evaluated by the spectrophotometric method using l-DOPA as a substrate and kojic acid as the control agent. The potential inhibitory activity was also investigated in silico using molecular docking simulation method. Tyrosinase inhibitory action was significantly more efficacious for several compounds (IC50: 86.2–362.1 µM) than kojic acid (IC50: 418.2). Compound 3 bearing 3,4-dichlorobenzyl piperazine moiety was proven to have the highest inhibitory activity. The results of docking studies showed that according to the predicted conformation of compound 3 in the enzyme binding site, hydroxymethyl group provides a metal complex with copper ions and enzyme. Thus, this interaction explain the high inhibitory activities of the compounds 1, 3 and 4 possessing hydroxymethyl substituent supporting the mushroom assay results with docking studies. In accordance with the results, it is suggested that Mannich bases of kojic acid bearing substituted benzyl piperazine groups (compounds 1, 3, 4, 11, 13, 14, 23, 24, 28, and 29) could be promising antityrosinase agents. Additionally, considering the relationship between tyrosinase inhibitory activity results and molecular docking, a new tyrosinase inhibition mechanism can be proposed.

Adamantyl pyran-4-one derivatives and their in vitro antiproliferative activity.

Pyran-4-one (maltol, kojic acid and chlorokojic acid 1) esters of adamantan-1-ylacetic acid were prepared through efficient synthetic routes in good yields and evaluated for their in vitro antiproliferative activity on four cancer cell lines: K562 (chronic myelogenous leukemia), HeLa (cervical cancer), Caco-2 (colorectal adenocarcinoma) and NCI-H358 (bronchioalveolar carcinoma). The results indicate that the presence and the position of the adamantyl acyl group or chlorine atom are the necessary requirement for antitumor activity of pyranone systems. Derivatives of kojic acid with either free (compounds 1 and 8) or acylated 5-OH group (compounds 2 and 9) have shown good-to-moderate activity (IC50 values ranging from 13.1 to 43.0μM) on all cell lines. Adamantyl kojic acid derivative 5 with a free OH group on the position 2 showed activity only on the K562 cell line. It seems that removal of halogen or adamantyl unit from position 2 elicits antileukemic activity, as observed in compound 5. The positive influence of the adamantyl unit was also observed on a 3-OH acylated derivative of maltol I which was also selectively active on the same cell line. 5-O-benzylated adamantyl compounds 6 and 7 and unmodified starting pyranones were found to be inactive. Antibacterial activity of compounds was also evaluated on S. aureus ATCC 13709, M. catarrhalis ATCC 23246, E. faecalis ATCC29212 and E. coli TolC-Tn10, but no activity was observed (MIC values 128-256µg/mL).

Efficient synthesis of new pyrano[3,2-b]pyran derivatives via Fe3O4@SiO2-IL-Fc catalyzed three-component reaction

Abstract Ferrocene-containing ionic liquid supported on silica-coated Fe3O4 magnetic nanoparticles (nano Fe3O4@SiO2-IL-Fc), a novel heterogeneous nanocatalyst, was synthesized. The structure of the catalyst was characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction patterns (XRD), energy-dispersive X-ray spectroscopy (EDX) and field emission scanning electron microscopy (FE-SEM). The novel nanomagnetic catalyst was used in the one-pot synthesis of pyrano[3,2-b]pyran derivatives by the three-component reaction of various aldehydes, malononitrile and kojic acid or chlorokojic acid at room temperature under ultrasonic irradiation. This new method has many advantages such as simplicity, short reaction times, high yields, easy workup and easy purification. Also, the nanocatalyst can be separated on an external magnet and reused for at least six consecutive runs without any significant loss of its catalytic activity.

Synthesis, Characterization, and Antimicrobial Activity of Kojic Acid Grafted Chitosan Oligosaccharide

A novel water-soluble chitosan oligosaccharide (COS) derivative, chitosan oligosaccharide/kojic acid grafts assigned as COS/KA, was prepared by using the selective partial alkylation of N-benzylidene COS and chlorokojic acid in the presence of dimethyl sulfoxide (DMSO) and pyridine (Py). The derivative was characterized by UV-vis spectroscopy, FTIR, (1)H NMR, TGA, SEM, and XRD techniques, which showed that the alkylation reaction took place at the C-6 and C-3 positions of COS. The results showed that the degree of substitution (DS) for COS/KA was from 0.38 to 1.21, and the product exhibited an excellent solubility in organic solvents and distilled water. The antibacterial results indicated that the antibacterial activity of COS/KA was strengthened relative to COS with the increase of DS for Staphylococcus aureus , Escherichia coli , Aspergillus niger and Saccharomyces cerevisiae . These findings provide important supports for developing new antibacterial agents and expand the scope of application of COS in the food industry.

Mannich bases of 7-piperazinylquinolones and kojic acid derivatives: Synthesis, in vitro antibacterial activity and in silico study

Novel Mannich bases of 7-piperazinylquinolones with kojic acid and chlorokojic acid were designed as new quinolone antibacterials. All compounds showed significant in vitro antibacterial activity against both Gram-positive and Gram-negative bacteria. Particularly, chlorokojic derivative 2b was the most potent compound against Staphylococcus aureus and Pseudomonas aeruginosa (MIC values ≤0.19 μg/mL). Its activity was 4–8 times more than that of standard drug norfloxacin. The molecular docking study of compound 2b further supported the molecular basis of the designed compounds.

Evaluation of bioactivities of chlorokojic acid derivatives against dermatophytes couplet with cytotoxicity

In an attempt to find novel antifungal agents with improved activity, a series of compounds bearing 6-chloromethyl-3-hydroxy-2-substituted 4H-pyran-4-one moiety were synthesized and examined for their cytotoxic evaluation and antifungal activities against both standard and isolated dermatophytic fungal species Microsporum gypseum, Trichophyton mentagrophytes var. erinacei and Epidermophyton floccosum.

Experimental and Theoretical Charge Density Study of the Chemical Bonding in Chlorokojic Acid Crystal Structure

The experimental charge density in the chlorokojic acid crystal structure was investigated on the basis of high-resolution X-ray diffraction data collected at 80(2) K. The nature of chemical bonding and halogen interactions has been studied by means of deformation densities and by topological analysis using the Bader's quantum theory of atoms in molecules (QTAIM). A comparison between the experimental and theoretical results, from calculations concerning gas phase and periodic DFT/B3LYP, was performed. For the intermolecular hydrogen bonds of O-H···O, C-H···O, and C-H···Cl types, full characteristics of bond critical points (BCP's) were provided indicating closed-shell interactions. The topological analysis of charge density distribution revealed the presence of intermolecular C-Cl···O halogen bridge and halogen-halogen interactions of C-Cl···Cl-C type forming supramolecular Cl(3) synthons, crucial for three-dimensional structure formation of chlorokojic acid. The pronounced anisotropy of electrostatic potential at the Cl atom clarifies both electrophilic and nucleophilic properties of the substituent.

Design, synthesis and in vivo/in vitro screening of novel chlorokojic acid derivatives

A series of novel Mannich bases of chlorokojic acid (2-chloromethyl-5-hydroxy-4H-pyran-4-one) were synthesized and their biological activities were investigated. Anticonvulsant activity results according to phase-I tests of Antiepileptic Drug Development (ADD) Program revealed that compound 13 was the most effective one at 4 h against subcutaneous pentylenetetrazole (scPTZ)-induced seizure test. Antimicrobial activities were evaluated in vitro against bacteria and fungi by using broth microdilution method. The antitubercular activities against Mycobacterium tuberculosis and M. avium were discussed with Resazurin microplate assay (REMA). The antimicrobial activity results indicated that compounds 1 and 12 (MIC: 8–16 µg/mL) showed higher activity against Gram negative bacteria while compound 12 had MIC: 4–16 µg/mL against Gram positive bacteria. Compound 1 was the most active one with MIC values of 8–32 µg/mL against fungi. Mannich bases also exhibit significant antitubercular activity in a MIC range of 4 to 32 µg/mL, especially compound 18 against M. avium.

A study of cytotoxicity of novel chlorokojic acid derivatives with their antimicrobial and antiviral activities

A series of 6-chloromethyl-3-hydroxy-2-substituted 4 H-pyran-4-one derivatives were synthesized and tested for their antimicrobial and antiviral activities. Mannich base derivatives were prepared through the reaction of substituted piperazine or piperidine derivatives on chlorokojic acid and formaline. The structures of the synthesized compounds were confirmed by IR, 1H and 13C NMR, ESI-MS, and elemental analysis. According to the activity studies, compounds 2– 7 (MIC: 1–2 μg/mL) were found to be highly active against Bacillus subtilis and Staphylococcus aureus, while compounds 3, 5 and 6 showed significant activity against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Also, compounds 2– 7 were more remarkably active against Candida albicans and Candida parapsilosis (MIC: 4–8 μg/mL). Additionally, compound 2 was the most active one against RNA virus PI-3.

Synthesis and biological activities of new Mannich bases of chlorokojic acid derivatives

A novel series of 6-chloromethyl-3-hydroxy-2-substituted 4H-pyran-4-one derivatives were synthesized and tested for their antibacterial, antifungal and antiviral in vitro properties. In the view of activity results, compounds 8–11 (MIC: 8 μg/ml) were more remarkably active against Staphylococcus aureus and Enterococcus faecalis. Compounds 1–7 were highly active against Candida albicans and C. parapsilosis with MIC value of 8 μg/ml. Compound 9 bearing 3-chlorophenyl moiety was determined to be the most active compound against RNA virus PI-3.

Crystal structure and vibrational spectra of 2-chloromethyl-5-hydroxy-4 H-pyran-4-one and 5-hydroxy-2-methyl-4 H-pyran-4-one as potential ligands for Fe(III) complexes

The title compounds form octahedral bidentate complexes with iron(III). Both the ligands and the complexes exhibit biological activity. The complexes may form isomers of fac or mer configuration. To predict the complex configuration, the structures of chlorokojic acid and allomaltol were determined and their vibrational spectra were analysed. The structure of chlorokojic acid, C 6H 5ClO 3, was solved in the polar space group Pna2 1 (ITC No. 33) and that of allomaltol, C 6H 6O 3, in centrosymmetric space group P 1 ¯ (ITC No. 2). The characteristic features of both structures are molecular ribbons but of different origin. In the case of chlorokojic acid, the ribbons are formed of molecules related by twofold screw axis and linked by H-bonds of O H⋯O type. In allomaltol, the ribbons are built of centrosymmetric dimers joined by the weak interactions of C H⋯O type. The normal modes of vibration have been calculated by means of the density functional theory method B3LYP and the 6-31+G ∗∗ basis set. The results were used for the vibrational analysis of both compounds. The theoretical spectra are in agreement with the experimental ones. The detailed inspection of the results obtained led to conclusion that allomaltol should form fac complexes with iron(III) in analogy to kojic acid, whereas for chlorokojic acid the mer isomer might be expected.

Conjugation of kojic acid with chitosan

Direct and non-direct conjugation of kojic acid with chitosan was carried out according to the following approaches: (a) covalent binding of chlorokojic acid to chitosan via free amino groups, and (b) complexation of kojic acid with iron(III) bound to chitosan. Obtained products were analysed by organic elemental analysis and spectroscopic methods. The maximal degree of substitution was ∼0.2 mol/mol for the chitosan–kojic acid conjugates. The triple chitosan–FeO(OH)–kojate complex contained these components in the molar ratio of 1:0.48:0.07. UV–vis absorption, FT-IR and Raman spectra of the obtained products showed characteristic bands of bound kojic acid and thus confirmed that both ways of kojic acid binding were efficient. Solution 1H NMR and solid state 13C CP-MAS NMR spectra of the chitosan–kojic acid conjugates supported the predicted way of 4-oxypyranone binding to chitosan. UV–vis absorption spectra of the chitosan films subsequently modified with ferric chloride and kojic acid indicated that the ligand molecules are bound to peripheral iron(III) cations of FeO(OH) subcolloidal particles arranged on the surfaces of a film.

Re-examination of Nucleophilic Substitutionin Chlorokojic Acid

Chlorokojic acid was reacted with S2O3 2−, NO3 −, N3 −, I−, and SCN−. Only the three latter nucleophiles substituted the chlorine atom in the 2-CH2Cl group of kojic acid. In none of the products nucleophilic substitution at position 6 of the 4-pyrone could be found. Regular substituion of chlorokojic acid with I− (iodokojic acid), N3 − (azidokojic acid), and SCN− (thiocyanato and isothiocyanato kojic acids) was accompanied by formation of allomaltol. Reaction pathways for the formation of allomaltol and 6-substituted allomaltol derivatives are proposed. The latter has been formerly discovered in the reaction of chlorokojic acid with secondary amines.

Chemistry of lanthanons—XLI. Isolation and characterisation of tris chelates of lanthanides with maltol, kojic acid and chloro-kojic acid

Chemistry of lanthanons—XLI. Isolation and characterisation of tris chelates of lanthanides with maltol, kojic acid and chloro-kojic acid

Chemistry of lanthanons—XXXV: Formation constants of rare-earth elements with a few oxygen donating ligands

Formation constants for lanthanon complexes of 2-isovaleryl cyclohexanone, 2-butyryl, 6-methyl cyclohexanone, kojic acid and chloro kojic acid are reported. The formation constants of kojates, chloro-kojates and maltolates are found to be higher than those of acetyl acetonates indicating greater stabilities of the γ-pyrone derivatives.

The formation of 2‐(dimethylamino)‐3‐hydroxy‐6‐methyl‐4H‐pyran‐4‐one from chlorokojic acid and dimethylamine. The preparation of 2,3,5‐trioxohexanoic acid N,N‐dimethylamide

AbstractThe reaction of chlorokojic acid with dimethylamine yields 2‐(dimethylamino)‐3‐hydroxy‐6‐methyl‐4H‐pyran‐4‐one in addition to the expected 2‐[(dimethylamino)methyl]‐5‐hydroxy‐4H‐pyran‐4‐one. Upon oxidation the former could be converted into 2,3,5‐trioxohexanoic acid N,N‐dimethylamide.