Table of Contents Author Guidelines Submit a Manuscript
Journal of Chemistry
Volume 2018, Article ID 1245712, 7 pages
https://doi.org/10.1155/2018/1245712
Research Article

Synthesis of Kojic Ester Derivatives as Potential Antibacterial Agent

Faculty of Resource Science and Technology, Universiti Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia

Correspondence should be addressed to Zainab Ngaini; ym.saminu@baniazn

Received 13 January 2018; Revised 9 March 2018; Accepted 19 March 2018; Published 6 May 2018

Academic Editor: Gabriel Navarrete-Vazquez

Copyright © 2018 Carolynne Zie Wei Sie et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The search for lead product with beneficial pharmacological properties has become a great challenge and costly. Extraction and synthetic modification of bioactive compounds from natural resources has gained great attention and is cost effective. In this study, kojic acid was produced from fungal fermentation, using sago waste as substrate, and chemically incorporated with chalcones and azobenzene to form a series of kojic ester derivatives and evaluated for antibacterial activities. Kojic ester bearing halogenated chalcone demonstrated active inhibition against Staphylococcus aureus compared to that of standard ampicillin. The inhibition increased as the electronegativity of halogens decreased, while incorporation of azobenzene derivatives on kojic acid backbone demonstrated fair antibacterial activity against Escherichia coli with minimum inhibitory concentration (MIC) of 190–330 ppm. The presence of C=C and N=N reactive moieties in both chalcone and azo molecules contributed to the potential biological activities of the kojic acid ester.

1. Introduction

Kojic acid is a natural pyrone produced from fungal fermentation from various types of carbon substrates in the presence of fungi [1, 2]. Kojic acid and its derivatives have drawn attention and were studied intensively due to its significant biological activities in medicine and pharmacological field such as antifungal, antibiotic [3, 4], anti-inflammatory and analgesic [5], and antibacterial [6] properties.

Many recent studies reported on chemical modification of kojic acid for various applications such as antibacterial activity [7] and dye sensitized solar cell (DSSC) [8]. Synthesis of bioactive molecules employing kojic acid as a precursor via esterification of available hydroxyl groups has been widely reported to overcome the drawbacks of its hydrophilic properties in various applications [912]. Esterification of kojic acid, for instance, is able to enhance the hydrophobic properties which in turn improved its performance as tyrosinase inhibitor and antioxidant [13, 14].

Incorporation of kojic acid into other biological active compounds has also been reported with enhanced biological activities [15, 16]. Chalcones are an example of biological active compound which is derived from natural sources such as fruits, vegetables, spices, tea, and soy-based foodstuff [17, 18] and used as an intermediate precursor of flavonoids and isoflavonoids [19]. Chalcone is also commonly prepared via Claisen Schmidt condensation. The synthesis of chalcone has drawn much attentions due to the presence of its α,β-unsaturated ketone moieties which contributes to various biological activities such as antimalaria [20], anticancer [21], antiprotozoal, anti-inflammatory, antibacterial, antifilarial, anticonvulsant [22], antifungal, insect antifeedant, antimutagenic [23], and antioxidant [24, 25]. The presence of halogen substituents particularly at the para position of chalcone backbone has been reported with excellent biological activities such as antibacterial [26] and anti-inflammatory [27], while azobenzene bearing aryl/alkyl and N=N reactive moieties have been extensively reported due to its excellent antibacterial [28, 29], antioxidant [30], anti-inflammatory [31], antifungal [32], and antitumor [33] properties. Azobenzene is also recognized for its medicinal properties such as antineoplastic [34], antidiabetic [35], and antiseptic [36].

Herein, we report on the isolation of kojic acid from sago waste and utilized it as a precursor for the synthesis of kojic acid ester bearing chalcone 3a–c and azobenzene 5a–d moieties. These compounds were screened for potential antibacterial activities against E. coli and S. aureus, and the effect of different moieties towards biological activities of kojic acid was studied.

2. Experimental

All the reagents were used as received without any further purification. Melting points were determined in open capillary tubes and are uncorrected. The IR spectra were recorded with KBr on Perkin Elmer 1605 FTIR spectrophotometer. The 1H NMR were recorded in CDCl3 or DMSO-d6 on JEOL ECA 500 spectrometer at 500 MHz using TMS as internal standard. The elemental carbon hydrogen nitrogen sulphur (CHNS) elemental analyses were performed using Thermo Scientific™ FLASH 2000 CHNS/O Analyzer.

2.1. Fermentation of Kojic Acid (1)

Sago waste was used as the substrate for kojic acid fermentation. Prior to fermentation, sago waste (5 g) was dried, ground, and sieved. The medium was supplemented with 3% (w/v) urea and 10% (w/v) mineral salts solution containing KH2PO4, (w/v) MgSO4·7H2O, and yeast extract. Mixed strains of Aspergillus flavus NSH9 and A. flavus Link 44-1 were added for fermentation process. The culture was incubated at °C in static condition for 20 days. The slurry suspension culture (40 mL) was extracted with ethyl acetate (2 × 15 mL). The organic layer was evaporated in vacuo to form crude brown solid and recrystallized from ethanol to afford 1 (0.15 g, 30%) as a yellowish needle like solid; m.p. 149-150°C [Reported 151–154°C [37]]; (KBr/cm−1) 3173 (OH), 2919 (C=C), 1661 (C=O), 1228 (C-O); 1H NMR (500 MHz, DMSO-d6): δ 9.04 (1H, s, OH-5), 8.02 (s, 1H, H-6), 6.34 (1H, s, H-3), 5.67 (1H, s, OH-7), 4.29 (1H, s, H-7); 13C NMR (125 MHz, DMSO-d6): δ 174.4 (C-4), 168.6 (C-2), 146.2 (C-5), 139.8 (C-6), 110.4 (C-3), 60.0 (C-7).

2.2. General Method for Synthesis of 4-Carboxyl Chalcone (2a–c)

Acetophenone (1.2 g, 0.1 mmol) was added to 4-carboxybenzaldehyde derivatives (0.15 g, 0.1 mmol) in methanol (50 mL). KOH (1.7 g, 0.3 mmol) in methanol was added and the mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The precipitate formed was filtered and recrystalized from ethanol to afford title compound.

4-[(E)-3-Oxo-3-phenyl-prop-1-enyl]benzoic Acid (2a). Compound 2a (2.32 g, 92%) as a yellowish powder. m.p. 223-224°C; (Found: C, 76.61; H, 4.37%. C16H12O3 Requires C, 76.2; H, 4.8%); (KBr/cm−1) 3059 (C=CH), 1677 (C=O), 1608 (COO), 1578 (aromatic); 1H NMR (500 MHz, DMSO-d6): δ 8.17 (2H, d, = 7.45 Hz, H-3), 8.05 (1H, d, = 16.05 Hz, H-β), 8.02 (2H, d, = 8.06 Hz, H-8), 7.99 (2H, d, = 8.00 Hz, H-2), 7.78 (1H, d, = 15.45 Hz, H-α); 7.69 (1H, t, = 7.73 Hz, H-10), 7.59 (2H, t, = 7.75 Hz, H-9).

4-[(E)-3-(4-Bromophenyl)-3-oxo-prop-1-enyl]benzoic Acid (2b). Compound 2b (2.65 g, 88%) as a yellowish powder; m.p. 246-247°C; (Found: C, 58.44; H, 3.65%. C16H11BrO3 Requires C, 58.0; H, 3.3%); (KBr/cm−1) 3064 (C=CH), 1663 (C=O), 1607 (COO), 1583 (aromatic); 1H NMR (500 MHz, DMSO-d6): δ 8.13 (2H, d, = 8.00 Hz, H-8), 8.05 (1H, d, = 15.45 Hz, H-β), 8.02 (2H, d, = 8.00 Hz, H-3), 7.98 (2H, d, = 8.60 Hz, H-9), 7.79 (1H, d, = 15.45 Hz, H-α), 7.79 (2H, d, = 8.00 Hz, H-2).

4-[(E)-3-(4-Chlorophenyl)-3-oxo-prop-1-enyl]benzoic Acid (2c). Compound 2c (2.12 g, 74%) as a yellowish powder. m.p. 259-260°C; (Found: C, 67.09; H, 3.27%. C16H11ClO3 Requires C, 67.0; H, 3.9%); (KBr/cm−1) 2943 (C=CH), 1678 (C=O), 1612 (COO), 1577 (aromatic); 1H NMR (500 MHz, DMSO-d6): δ 8.20 (2H, d, = 8.40 Hz, H-8), 8.00 (1H, d, = 16.05 Hz, H-β), 7.93 (2H, d, = 8.40 Hz, H-3), 7.90 (2H, d, = 8.40 Hz, H-9), 7.78 (1H, d, = 16.05 Hz, H-α), 7.65 (2H, d, = 7.65 Hz, H-2).

2.3. General Method for Synthesis of Kojic Acid-Chalcone Derivatives (3a–c)

Chalcone 2a–c (1.26 g, 0.05 mmol) was added to a solution of 1 (0.71 g, 0.05 mmol), DMAP (0.12 g, 1 mmol), and DCC (1.03 g, 0.05 mmol) in DCM (30 mL). The reaction mixture was stirred at 0°C for 4 h, washed with acetic acid (1 M, 2 × 20 mL), followed by Na2CO3 solution (1 M, 2 × 20 mL), and dried over magnesium sulphate. The crude product obtained was purified by column chromatography over silica gel (eluting with 1 : 2 EA/Hex) to afford title compound.

[6-(Hydroxymethyl)-4-oxo-pyran-3-yl] 4-[(E)-3-oxo-3-phenyl-prop-1-enyl] Benzoate (3a). Compound 3a (0.4 g, 23%) as a white powder. m.p. 162-163°C; (Found: C, 69.56; H, 4.25%. C22H16O6 Requires C, 70.2; H, 4.3%); (KBr/cm−1) 2987 (C=CH), 1730 (C=O ester), 1665 (C=O), 1644 (C=O), 1605 (aromatic), 1201 (C-O); 1H NMR (500 MHz, DMSO-d6): δ 8.69 (1H, s, H-6), 8.11 (7H, m, H-9, H-10, H-15, H-β), 7.79 (2H, d, = 16.05 Hz, H-α), 7.67 (1H, m, H-17), 7.59 (2H, m, H-16), 6.65 (1H, s, H-3), 5.02 (2H, s, H-7).

[6-(Hydroxymethyl)-4-oxo-pyran-3-yl]4-[(E)-3-(4-bromophenyl)-3-oxo-prop-1-enyl] Benzoate (3b). Compound 3b (0.4 g, 19%) as a white powder. m.p. 194-195°C; (Found: C, 58.37; H, 3.24%. C22H15BrO6 Requires C, 58.0; H, 3.3%); (KBr/cm−1) 2926 (C=CH), 1697 (C=O ester), 1651 (C=O), 1623 (C=O), 1570 (aromatic), 1242 (C-O); 1H NMR (500 MHz, DMSO-d6): δ 8.67 (1H, s, H-6), 8.13 (2H, d, = 8.6 Hz, H-15), 8.12 (2H, d, 8.00 Hz, H-10), 8.04 (1H, d, = 15.45 Hz, H-β), 7.99 (2H, d, = 8.00 Hz, H-16), 8.00 (1H, d, = 12.6 Hz, H-α), 7.80 (2H, d, = 8.55 Hz, H-9), 6.50 (1H, s, H-3), 4.40 (2H, s, H-7).

[6-(Hydroxymethyl)-4-oxo-pyran-3-yl]4-[(E)-3-(4-chlorophenyl)-3-oxo-prop-1-enyl]benzoate (3c). Compound 3c (0.5 g, 25%) as a white powder. m.p. 202-203°C; (Found: C, 63.54; H, 3.31%. C22H15ClO6 Requires C, 64.3; H, 3.7%); (KBr/cm−1) 2927 (C=CH), 1731 (C=O ester), 1666 (C=O), 1643 (C=O), 1607 (aromatic), 1239 (C-O); 1H NMR (500 MHz, DMSO-d6): δ 8.67 (1H, s, H-6), 8.13 (4H, t, = 7.73 Hz, H-15, H-10), 8.04 (1H, d, = 14.9 Hz, H-β), 7.99 (2H, d, = 8.0 Hz, H-16), 7.86 (1H, d, = 11.45 Hz, H-α), 7.79 (2H, d, = 7.45 Hz, H-9), 6.50 (1H, s, H-3), 4.39 (2H, s, H-7).

2.4. Synthesis of Azobenzene Derivatives (4a–d)

HCl (8 M, 100 mL) was added drop wise to a solution of 4-aminoethylbenzoate (5 g, 30.0 mmol) in methanol (50 mL) in an ice bath at 0–5°C. Sodium nitrite (3.1 g, 45.0 mmol) in distilled water (10 mL) and phenol (3.4 g, 36 mmol) in methanol (50 mL) were added drop wise to the reaction mixture. NaOH solution (1 M, 100 mL) was then added drop wise to pH 8.5–9.5. The reaction mixture was stirred for 4 hr under nitrogen atmosphere. Methanol (50 mL) was added and acidified with HCl (8 M, 50 mL) to form precipitate. The solid was filtered, washed, and recrystallized from ethanol. KOH (0.13 g, 2.4 mmol) was added to the solid (0.2 g, 0.8 mmol) in methanol (50 mL) and heated under reflux for 4 h under nitrogen atmosphere. Cold water (30 mL) was added to the reaction mixture, acidified with acetic acid (8 M), and filtered and recrystallized from ethanol to give azobenzene intermediate. Azobenzene (1.5 g, 5 mmol) was added to a solution of bromoalkene derivatives, t- BuOK (0.62 g, 5.0 mmol) and KI (20 mg) in acetone (100 mL), and heated at reflux for 48 h under nitrogen atmosphere. DCM (50 mL) and water (30 mL) were added and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL) and the combined organic layers were dried and evaporated under reduced pressure and recrystallized from ethanol to give title compound 4a–d as colorless crystals. FTIR and NMR data were consistent with the reported literature [8].

2.5. Synthesis of Kojic Acid-Azobenzene (5a–d)

Thionyl chloride (0.036 g, 0.3 mmol) was added to a solution of 1 (0.014 g, 0.1 mmol) in DMF (20 mL) and heated under reflux for 4 h. The reaction mixture was extracted with DCM (2 × 15 mL). The organic layer was dried, filtered, and concentrated under reduced pressure to give kojyl chloride as yellowish needle solid (0.012 g, 70%). Azo intermediate was added to a solution of kojyl chloride prepared (0.1 g, 0.6 mmol) in DMF (30 mL) with TEA (0.015 g, 0.15 mmol) in dried acetone (20 mL) and heated under refluxed for 24 h. The reaction mixture was washed with dilute HCl (1 M, 2 × 20 mL). The organic layer was dried, filtered, and concentrated under reduced pressure. Crude product was recrystallized from ethanol to afford 5b–e as colorless crystals. FTIR and NMR data were consistent with the reported literature [8].

2.6. Antibacterial Screening
2.6.1. Turbidimetric Kinetic Method

The antibacterial activities of synthesized 4a–d and 5a–d were screened against Escherichia coli using turbidimetric kinetic method. Escherichia coli were cultured on LB plate agar for 24 h at 37°C and a single colony was transferred to the media containing nutrient broth prepared. The inoculum was allowed to grow at 37°C with 250 rpm stirring overnight. Inoculum (0.2 mL) was added to 10 mL of culture medium which had been added with different concentrations (50 ppm, 80 ppm, and 100 ppm) of respective compounds in DMSO. Three replicates of each concentration were prepared. The control used was the medium broth of inoculums added with DMSO with no active compound. The mixture was shaken at 230 rpm at 37°C. The transmittances (T) of the aliquots were taken every 1 h interval for six continuous hours using UV-Visible Spectrophotometer Optima SP-300. The antibacterial activity was determined from the graph of In Nt versus time plotted. The In Nt values represent the number of colony forming units (units/mL) which follows the equation of In Nt = 27.1 − 8.56 T [38, 39]

2.6.2. Via Kirby Bauer Disc Diffusion Method

The antibacterial activities of the synthesized 2a–c and 3a–c were evaluated against Escherichia coli and Staphylococcus aureus using Kirby Bauer Disc Diffusion method. E. coli and S. aureus were used as inoculums and cultured in Mueller-Hinton Broth (MHB) and incubated at 37.5°C with constant shaking at 150 rpm for 18 h. The bacteria suspension prepared was inoculated onto the entire surface of a Mueller-Hinton Agar (MHA) plate with sterilised cotton tipped swab to form an even lawn. Sterilised filter paper disc impregnated with 10 μL of the compound in DMSO was placed on the bacteria surface of MHA plate using a sterilised forcep. The plates were incubated at 37.5°C for 24 h. The zone of inhibition was measured in millimetres (mm) to estimate the potency of the tested compound.

3. Results and Discussion

3.1. Preparation of Kojic Acid via Fermentation

Kojic acid 1 was prepared via fermentation of sago hampas employing mixed strains of Aspergillus flavus NSH9 and Aspergillus flavus Link 44-1. Aspergillus flavus was used for a higher yield of 1[15]. The optimum parameters were from a combination of 3% (w/v) urea and 10% mineral salts solution containing KH2PO4, (w/v) MgSO4·7H2O and yeast. KH2PO4 and MgSO4 supported the growth of bacteria strain and boosted the production of kojic acid [40]. Yeast is a nitrogen source for metabolic activation to enhance kojic acid production. Its high levels of essential components such as vitamins and oligoelements support growth of bacteria and fermentation process [3].

3.2. Synthesis of Kojic Acid Ester Derivatives

Kojic ester 2a–c was prepared via Claisen Schmidt condensation followed by Steglich esterification with isolated kojic acid to yield 3a–c, whereas kojic ester (5a–d) was prepared via kojyl chloride [11] followed by addition of 4a–d to afford 5a–d (70–87%). The overall synthesis is shown in Scheme 1. Structures of the compounds synthesized were confirmed by elemental analysis, IR spectra, and 1H NMR spectra.

Scheme 1: Synthesis of kojic esters (3a–c) and (5a–d).

The IR spectra for 2a–c showed absorptions band at 3064–2943 cm−1 and 1678–1663 cm−1 attributed to C=C and C=O group of chalcone linkage. A sharp band at 1612–1607 cm−1 indicated the presence of carboxyl group. Absorption peaks at 1583–1577 cm−1 revealed the presence of aromatic group. The 1H NMR showed aromatic protons of 2a at δ 8.17–7.59 ppm as doublet and triplet while aromatic protons of 2b-c appeared at δ 8.20–7.65 ppm as four doublets with coupling constant 8–8.6 Hz. The peaks of = were observed at δ 7.79–7.78 and 8.05–8.00 ppm as two doublets with 15.5–16.1 Hz, which indicated trans configuration.

Formation of 3a–c was confirmed by FTIR and 1H NMR spectroscopies. The IR spectrum for 3a–c showed appearance of C=O ester absorption band at 1731–1697 cm−1. The IR spectrum revealed two strong bands at 1666–1651 cm−1 and 1644–1623 cm−1 attributed to (C=O) of chalcone and kojic acid, respectively. The absorption frequency at 1605–1570 cm−1 was attributed to aromatic group while (C-O) was represented by absorption band at 1242–1201 cm−1. The 1H NMR showed that all corresponding peaks indicated the formation of 3a–c. The existence of kojic acid moieties in 3a–c was proven by appearance of two kojic acid olefinic proton at δ 8.69–8.67 and 6.65–6.50 ppm as singlet. The oxymethyl protons of kojic acid were represented by peaks at δ 5.02–4.39 ppm.

The NMR spectra of kojic ester (5a–d) via formation of kojyl chloride revealed the presence of peak attributed to oxymethyl proton (OCH2) at δ 5.26–5.24 ppm as singlet, which indicated 7-O-substituent 1 [41]. In comparison to 5-O-substituted 3a–c, 7-O-substituted 5a–d showed shifted H-6 olefinic proton signals to upfield and oxymethyl proton signals to downfield. Carbonyl group of ketone is more deshielded than carbonyl group of ester due to deshielding effect of pyrone ring [42].

3.3. Antibacterial Activities of Kojic Ester Derivatives

The kojic ester derivatives 3a–c and 5a–d were evaluated for antibacterial activities against gram negative strain E. coli at 37°C via turbidimetric method at three different concentrations, 50 ppm, 80 ppm, and 100 ppm, and compared to chalcones (2a–c) and azobenzene (4a–d) derivatives. Due to solubility limitation of 2a–c and 3a–d in organic solvent, turbidimetric method was only applied on 4a–d and 5a–d. Negative control, which is comprised of solvent and inoculums, showed significant increase in growth of E. coli. The antibacterial assay was expressed by plotting graph of In  versus time. The In  value indicated number of colony forming (growth of E. coli) units/mL which followed the expression of In  = 27.1 − 8.56 T [39].

Kojic ester 4a–d exhibited weak inhibition while 5a–d exhibited good inhibition against E. coli. The inhibition of 5a–d is concentration dependent where 100 ppm > 80 ppm > 50 ppm. The minimum inhibitory concentration (MIC) of 4a–d and 5a–d was determined by extrapolating the concentration to zero growth rate of E. coli. The MIC of 4a–d and 5a–d is summarized in Table 1. Kojic ester moieties in azobenzene are envisaged to increase the lipophilic properties in 5a–d to interact and destruct the bacterial cell membrane [43]. The presence of C=O and N=N moieties in kojic ester offers more reactive sites that easily protonated under acidic condition and reacted with the bacterial surfaces which further enhance the biological activity [44]. Compound 5a-b showed better activity than 5c-d due to the increase of chain length after the cutoff effect associated with decrease in solubility.

Table 1: MIC for 4a–d and 5a–d.

Antibacterial activity of kojic esters 2a–c and 3a–c bearing chalcone moieties was conducted by measuring the zone of inhibition on agar plates (Kirby Bauer Disc Diffusion method) against S. aureus and E. coli bacterial strain due to solubility limitation in DMSO. Ampicillin was used as reference standard and DMSO as negative control.

The zone inhibition of 2a–c and 3a–c is shown in Table 2. Kojic acid showed no inhibition against both S. aureus and E. coli, while both series of 2a–c and 3a–c showed no inhibition against E. coli compared to standard ampicillin. Compounds 2a–c and 3a–c, however, showed active inhibition against S. aureus with 2c and 3a-b being inhibited better than ampicillin. The selective antibacterial activity of 2a–c and 3a–c against gram positive bacterial strain is due to the significance different in the membrane composition and architecture of gram positive and gram negative organism [45]. S. aureus has simpler mesh like cell membrane compared to E. coli which eases the penetration of compound [46].

Table 2: Inhibition zones of 2a–c and 3a–c.

Antibacterial activities of 2a–c increased with the decrease in electronegativity of substituent on chalcone. Electronegativity in decreasing order is as follows: Cl (8 mm) > Br (13 mm) > H (16 mm). Polarized ability of antibacterial agent increases with the decreased in electronegativity which reasoned to enhance activity of acting antibacterial agent [47].

The antibacterial activities of 3a–c, however, showed an opposite trend. The inhibition was increased with the increased in electronegativity. The incorporation of kojic acid transformed the lipophilic properties of the compound. A good balance between hydrophilic and hydrophobic properties of compound makes good antibacterial agent [48]. Compound 3c with chlorine substituents showed the biggest zone of inhibition with 13 mm while 3a with hydrogen showed the least zone of inhibition (8 mm).

4. Conclusions

A series of kojic esters 2a–c and 3a–c has been successfully synthesized and exhibited good antibacterial activity towards gram positive S. aureus bacteria strain. Antibacterial activities of 2a–c increased with the decrease in electronegativity of halogen substituent on chalcone with 2c showing the highest inhibition, better than the ampicillin reference standard. Lipophilic properties of kojic ester bearing chalcone derivatives 3a-b inhibited better antibacterial activity. Kojic ester 5a–d bearing azobenzene derivatives showed good inhibition against E. Coli compared to 4a–d. The presence of C=O ester, N=N, and alkene chains has increased the lipophilic properties of of 5a–d and disrupts the bacteria cell walls.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

This work was supported by Universiti Malaysia Sarawak and Ministry of Education for Research Funds F07(DPP17)/1173/2014(17) and FRGS/ST01(02)/968/2013(09). The authors would also like to express special thanks to Professor Dr. Arbakariya Ariff from UPM for providing the A. flavus Link 44-1 strain.

References

  1. J. Chaudhary, A. N. Pathak, and S. Lakhawat, “Production technology and applications of kojic acid,” Annual Research & Review in Biology, vol. 4, no. 21, pp. 3165–3196, 2014. View at Publisher · View at Google Scholar
  2. A. F. B. Lajis, M. Basri, R. Mohamad et al., “Enzymatic synthesis of kojic acid esters and their potential industrial applications,” Chemical Papers, vol. 67, no. 6, pp. 573–585, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. S. A. El-Aasar, “Cultural conditions studies on kojic acid production by Aspergillus parasiticus,” nternational Journal of Agriculture & Biology, vol. 8, no. 4, pp. 468–473, 2006. View at Google Scholar
  4. M. D. Aytemir, D. D. Erol, R. C. Hider, and M. Özalp, “Synthesis and evaluation of antimicrobial activity of new 3-Hydroxy-6-methyl-4-oxo-4H-pyran-2-carboxamide derivatives,” Turkish Journal of Chemistry, vol. 26, no. 7, pp. 757–764, 2003. View at Google Scholar · View at Scopus
  5. H. Kayahara, N. Shibata, K. Tadasa, H. Maeda, T. Kotani, and I. Ichimoto, “Amino acid and peptide derivatives of kojic acid and their antifungal properties,” Agricultural and Biological Chemistry, vol. 54, no. 9, pp. 2441-2442, 1990. View at Publisher · View at Google Scholar · View at Scopus
  6. B. V. S. Reddy, M. R. Reddy, C. Madan, K. P. Kumar, and M. S. Rao, “Indium(III) chloride catalyzed three-component coupling reaction: a novel synthesis of 2-substituted aryl(indolyl)kojic acid derivatives as potent antifungal and antibacterial agents,” Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 24, pp. 7507–7511, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Emami, E. Ghafouri, M. A. Faramarzi, N. Samadi, H. Irannejad, and A. Foroumadi, “Mannich bases of 7-piperazinylquinolones and kojic acid derivatives: synthesis, in vitro antibacterial activity and in silico study,” European Journal of Medicinal Chemistry, vol. 68, pp. 185–191, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Z. Sie and Z. Ngaini, “Incorporation of kojic acid-azo dyes on TiO2 thin films for dye sensitized solar cells applications,” Journal of Solar Energy, vol. 2017, Article ID 2760301, pp. 1–10, 2017. View at Publisher · View at Google Scholar
  9. K.-J. Liu and J.-F. Shaw, “Lipase-catalyzed synthesis of kojic acid esters in organic solvents,” Journal of the American Oil Chemists’ Society, vol. 75, no. 11, pp. 1507–1511, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. N. El-Boulifi, S. E. Ashari, M. Serrano, J. Aracil, and M. Martínez, “Solvent-free lipase-catalyzed synthesis of a novel hydroxyl-fatty acid derivative of kojic acid,” Enzyme and Microbial Technology, vol. 55, pp. 128–132, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. S. R. Ho, S. B. Heung, M. A. Soo, H. K. Duck, and S. C. Ih, “Synthesis of new anti-melanogenic compounds containing two molecules of kojic acid,” Bulletin of the Korean Chemical Society, vol. 29, no. 8, pp. 1569–1571, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. T. Kobayashi, S. Adachi, K. Nakanishi, and R. Matsuno, “Semi-continuous production of lauroyl kojic acid through lipase-catalyzed condensation in acetonitrile,” Biochemical Engineering Journal, vol. 9, no. 2, pp. 85–89, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. H. S. Rho, M. Goh, J. Lee et al., “Ester derivatives of kojic acid and polyphenols containing adamantane moiety with tyrosinase inhibitory and anti-inflammatory properties,” Bulletin of the Korean Chemical Society, vol. 32, no. 4, pp. 1411–1414, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. C. M. Yang, J. Y. Hong, K. W. Lee, B. G. Lee, and D. I. Chang, “Kojic Acid Derivative,” United States Patent, Patent number: 5486624, 1996.
  15. C. Balakrishna, N. Payili, S. Yennam, P. Uma Devi, and M. Behera, “Synthesis of new kojic acid based unnatural α-amino acid derivatives,” Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 21, pp. 4753–4756, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. K. Morisaki and S. Ozaki, “Design of novel hybrid vitamin C derivatives: Thermal stability and biological activity,” Chemical & Pharmaceutical Bulletin, vol. 44, no. 9, pp. 1647–1655, 1996. View at Publisher · View at Google Scholar · View at Scopus
  17. D. E. Okwu and N. Ukanwa, “Isolationand characterization of flavonoids chalcones and anthocynidines from bridelia ferruginea benth,” Der Chemica Sinica, vol. 1, no. 2, pp. 21–28, 2010. View at Google Scholar
  18. G. Di Carlo, N. Mascolo, A. A. Izzo, and F. Capasso, “Flavonoids: old and new aspects of a class of natural therapeutic drugs,” Life Sciences, vol. 65, no. 4, pp. 337–353, 1999. View at Publisher · View at Google Scholar · View at Scopus
  19. G. Achanta, A. Modzelewska, L. Feng, S. R. Khan, and P. Huang, “A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome,” Molecular Pharmacology, vol. 70, no. 1, pp. 426–433, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. R. Ferrer, G. Lobo, N. Gamboa et al., “Synthesis of [(7-chloroquinolin-4-yl)amino] chalcones: potential antimalarial and anticancer agents,” Scientia Pharmaceutica, vol. 77, no. 4, pp. 725–741, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Modzelewska, C. Pettit, G. Achanta, N. E. Davidson, P. Huang, and S. R. Khan, “Anticancer activities of novel chalcone and bis-chalcone derivatives,” Bioorganic & Medicinal Chemistry, vol. 14, no. 10, pp. 3491–3495, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Rahman, “Chalcone: a valuable insight into the recent advances and potential pharmacological activities,” Chemical Sciences Journal, vol. 29, 2011. View at Google Scholar
  23. A. H. Shridhar, J. Keshavayya, S. K. Peethambar, and H. Joy Hoskeri, “Synthesis and biological activities of Bis alkyl 1,3,4-oxadiazole incorporated azo dye derivatives,” Arabian Journal of Chemistry, vol. 9, pp. S1643–S1648, 2016. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Suksamrarn, P. Poomsing, N. Aroonrerk, T. Punjanon, S. Suksamrarn, and S. Kongkun, “Antimycobacterial and antioxidant flavones from Limnophila geoffrayi,” Archives of Pharmacal Research, vol. 26, no. 10, pp. 816–820, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. K. L. Ameta, N. S. Rathore, and B. Kumar, “Synthesis of some novel chalcones and their facile one-pot conversion to 2-aminobenzene-1, 3-dicarbonitriles using malononitrile,” Analele Universităţii din Bucuresti – Chimie (serie nouă), vol. 20, no. 1, pp. 15–24, 2011. View at Google Scholar
  26. A. N. Chaudhary and V. Juyal, “Synthesis of chalcone and their derivatives as antimicrobial agents,” International Journal of Pharmacy and Pharmaceutical Sciences, vol. 3, no. 3, pp. 125–128, 2011. View at Google Scholar
  27. M. A. El-Hashash, S. A. Rizk, and S. R. Atta-Allah, “Synthesis and regioselective reaction of some unsymmetrical heterocyclic chalcone derivatives and spiro heterocyclic compounds as antibacterial agents,” Molecules, vol. 20, no. 12, pp. 22069–22083, 2015. View at Publisher · View at Google Scholar · View at Scopus
  28. A. M. Khedr, M. Gaber, and E. H. Abd El-Zaher, “Synthesis, structural characterization, and antimicrobial activities of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes of triazole-based azodyes,” Chinese Journal of Chemistry, vol. 29, no. 6, pp. 1124–1132, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. P. K. Nikhil, M. P. Pratik, and R. Manoj, “Study on antibacterial activity for multidrug resistance stain by using phenyl pyrazolones substituted 3-amino 1H-pyrazolon(3, 4-b) quinoline derivative in vitro condition,” International Journal of Pharmtech Research, vol. 3, pp. 540–548, 2011. View at Google Scholar
  30. H. Yoo, H. K. Seung, J. Lee et al., “Synthesis and antioxidant activity of 3-methoxyflavones,” Bulletin of the Korean Chemical Society, vol. 26, no. 12, pp. 2057–2060, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. J.-S. Bae, H. S. Freeman, and A. El-Shafei, “Metallization of non-genotoxic direct dyes,” Dyes and Pigments, vol. 57, no. 2, pp. 121–129, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Xu and X. Zeng, “Synthesis of diaryl-azo derivatives as potential antifungal agents,” Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 14, pp. 4193–4195, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. T. A. Farghaly and Z. A. Abdallah, “Synthesis, azo-hydrazone tautomerism and antitumor screening of N-(3-ethoxycarbonyl-4,5,6,7-tetrahydro-benzo[b]thien-2-yl)-2-arylhydrazono-3- oxobutanamide derivatives,” Arkivoc, vol. 2008, no. 17, pp. 295–305, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. R. G. Child, R. G. Wilkinson, and A. Tomcu-Fucik, “Effect of substrate orientation of the adhesion of polymer joints,” Chemical Abstracts, vol. 87, article 6031, 1977. View at Google Scholar
  35. H. G. Garg and C. Praksh, “Preparation of 4-arylazo-3,5-disubstituted-(2H)-1,2,6-thiadiazine 1,1-dioxides,” Journal of Medicinal Chemistry, vol. 15, no. 4, pp. 435–439, 1972. View at Publisher · View at Google Scholar
  36. M. R. S. P. Piste, D. P. Indalkar, N. Z. Dnyandev, and S. M. Pankaj, “Synthesis and antimicrobial activity of substituted p-amino azobenzene with thymol moiety- a green protocol,” International Journal of Chemistry Research, vol. 3, no. 2, pp. 25–29, 2012. View at Google Scholar
  37. J.-M. Noh, S.-Y. Kwak, H.-S. Seo, J.-H. Seo, B.-G. Kim, and Y.-S. Lee, “Kojic acid-amino acid conjugates as tyrosinase inhibitors,” Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 19, pp. 5586–5589, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. Z. Ngaini, S. M. H. Fadzillah, and H. Hussain, “Synthesis and antimicrobial studies of hydroxylated chalcone derivatives with variable chain length,” Natural Product Research, vol. 26, no. 10, pp. 892–902, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. N. B. Pappano, O. P. Centorbi, and F. H. Ferretti, “Determination of minimum concentration inhibitory chalcone derivatives,” Revise Microbiology, vol. 2, no. 1, pp. 183–188, 1990. View at Google Scholar
  40. R. Mohamad, M. S. Mohameh, N. Suhaili, M. M. Salleh, and A. B. Ariff, “Kojic acid: applications and development of fermentation process for production,” Biotechnology and Molecular Biology Reviews, vol. 5, no. 2, pp. 24–37, 2010. View at Google Scholar
  41. H. Kaatz, K. Streffer, U. Wollenberger, and M. G. Peter, “Inhibition of mushroom tyrosinase by kojic acid octanoates,” Zeitschrift für Naturforschung, vol. 54c, pp. 70–74, 1999. View at Google Scholar
  42. D. L. Pavia, G. M. Lampman, G. S. Kriz, and J. A. Vyvyan, Introduction to Spectroscopy, Cengage Learning, Belmont, Calif, USA, 2008.
  43. R. Bartzatt and C. Malesa, “Synthesis, structural analysis and antibacterial activity of a butyl ester derivative of ampicillin,” Chemotherapy, vol. 49, no. 5, pp. 213–221, 2003. View at Publisher · View at Google Scholar · View at Scopus
  44. Z. Zhong, R. Xing, S. Liu, L. Wang, S. Cai, and P. Li, “Synthesis of acyl thiourea derivatives of chitosan and their antimicrobial activities in vitro,” Carbohydrate Research, vol. 343, no. 3, pp. 566–570, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. G. M. Morris, H. Ruth, W. Lindstrom et al., “Software news and updates AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility,” Journal of Computational Chemistry, vol. 30, no. 16, pp. 2785–2791, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. M. J. Alves, H. J. C. Froufe, A. F. T. Costa et al., “Docking studies in target proteins involved in antibacterial action mechanisms: Extending the knowledge on standard antibiotics to antimicrobial mushroom compounds,” Molecules, vol. 19, no. 2, pp. 1672–1684, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. I. A. El-Kady, A. N. Zohri, and S. R. Hamed, “Kojic acid production from agro-industrial by-products using fungi,” Biotechnology Research International, vol. 2014, Article ID 642385, pp. 1–10, 2014. View at Publisher · View at Google Scholar
  48. C. I. Wei, T. S. Huang, S. Y. Fernando, and K. T. Chung, “Mutagenicity studies of kojic acid,” Toxicology Letters, vol. 59, no. 1-3, pp. 213–220, 1991. View at Publisher · View at Google Scholar · View at Scopus