The first efficient biocatalytic route for the synthesis of Kojic acid derivatives in aqueous media

Article abstract of DOI:10.1016/j.catcom.2021.106289

The first efficient biocatalytic route for the synthesis of kojic acid derivatives was developed in presence of an enzyme. In this process, benzaldehydes, malononitrile and kojic acid were used as starting materials while lipase from Aspergillus niger was

Full text of DOI:10.1016/j.catcom.2021.106289

Catalysis Communications 152 (2021) 106289
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Catalysis Communications
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Short communication
The first efficient biocatalytic route for the synthesis of Kojic acid
derivatives in aqueous media
,
,*
Kiran S. Dalala, Mangal A. Chaudharia, Dipak S. Dalalb *, Bhushan L. Chaudharia
a School of Life Sciences, Kavayitri Bahinabai Chaudhari North Maharashtra University, Jalgaon 425 001, Maharashtra, India
b School of Chemical Sciences, Kavayitri Bahinabai Chaudhari North Maharashtra University, Jalgaon 425 001, Maharashtra, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
The first efficient biocatalytic route for the synthesis of kojic acid derivatives was developed in presence of an
enzyme. In this process, benzaldehydes, malononitrile and kojic acid were used as starting materials while lipase
from Aspergillus niger was the promiscuous biocatalyst giving high conversion (82–95%) of kojic acid derivatives
in aqueous medium. The probable enzymatic mechanism is proposed here. The lipase was reused till three
consecutive cycles without a significant loss of activity. This efficient bioprocess has potential to replace the
existing chemical catalytic processes to produce heterocyclic anti-tyrosinase compounds that prevents
hyperpigmentation.
Aspergillus niger
Lipase
Biocatalysis
Kojic acid derivatives
1. Introduction
Pfizer and Compancy, USA in 1955 . Rapid growth of various industries
due to the potential uses of kojic acid and its derivatives generated great
Kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, KA) is a
natural product synthesized by many fungi and bacteria such as Asper-
gillus, Penicillium and Acetobacterium sp. [1]. It is a polyfunctional het-
erocycle, with several important reaction centers, used in many types of
reactions, involving addition, alkylation, acylation, oxidation, ring
opening, and nucleophilic and electrophilic substitution reactions [2].
KA is generally used as an antioxidant in food to act as a preservative, an
additive for preventing enzymatic discoloration of vegetables, crabs,
shrimps and as a skin lightening or bleaching agent in cosmetic prepa-
rations [3]. The melanin pigment is an important molecule which is
generally found in the microorganisms, plants and animals. Despite of
high importance, the overproduction of melanin is observed in several
hyperpigmentation disorders, such as freckles, senile lentigines and
melasma [4]. KAand its derivatives are used to inhibit tyrosinase activity
in synthesis of melanin or block the formation of pigment by melano-
cytes that prove to be the most popular lighteners among the cosmetic
product [5]. Besides its role as a whitening agent, kojic acid shows a
wide range of biological activities such as antibacterial and antifungal
activities [6], anti-inflammatory [7], antineoplastic [8], depigmenting
agents [9], anticonvulsant, antiviral [10] and anti-HIV activities [11].
Due to the importance of KA in industry, the synthesis of its derivatives
is of great importance to organic chemists.
demands for this product. According to FDA, kojic acid derivatives are
used in a about 16 products [12]. The kojic acid is the most studied
inhibitor of the tyrosinase enzyme. The synthesis of kojic acid de-
rivatives has become a challenge for academic and industrial researchers
due to its wide range of biological, industrial, and synthetic applications.
Many biocatalysts (enzymes/whole cells) can replace chemo-catalysts in
synthetic routes which are more efficient and more sustainable [13,14].
In this perspective, lipases were used in several important chemical
transformations that works well in aqueous medium as well as non-
conventional medium [15]. Lipases have gained attention due to their
general ease of handling, being inexpensive, broad substrate tolerance,
high stability towards a wide range of temperatures and solvents while
the most important aspect is its commercial availability [16]. Bora et al.
reported the synthesis of dihydropyrano(2,3-c)pyrazoles using lipase
from Aspergillus niger as a biocatalyst [17]. It catalyzed the Henry
–
(nitroaldol) reaction, which is an important C C bond formation re-
action between aromatic aldehydes and nitroalkanes in organic/
aqueous medium [18]. Recently, this lipase was used in the synthesis of
butyl butyrate [19]. But, this enzyme has not been studied in depth in
organic synthesis.
Various chemical methods have been reported in the literature to-
wards the synthesis of kojic acid derivatives. Generally, these de-
rivatives were synthesized by multi-component reaction of kojic acid,
The kojic acid was commercially produced and marketed by Charles
* Corresponding authors.
E-mail addresses: dsdalal2007@gmail.com (D.S. Dalal), blchaudhari@nmu.ac.in (B.L. Chaudhari).
https://doi.org/10.1016/j.catcom.2021.106289
Received 8 September 2020; Received in revised form 30 January 2021; Accepted 31 January 2021
Available online 3 February 2021
1566-7367/© 2021 The Author(s).
Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
aldehydes and malononitrile. Recently, some environment compatible
catalyst like MCM-41-SO3H [20], Cobalt nanoparticles [21], Cuprous
oxide-Zeolite clinoptilolite nanoparticles [22], Fe3O4@SiO2-BenzIm-Fc
(Cl)/ZnCl2 [23], nano Fe3 O4@SiO2-IL-Fc [24], NH4Cl [25], Fe3O4@-
SiO2-s-triazinium chloride [26], Ultrasonic irradiation [27] and
β-Cyclodextrin [28] were also used to achieve this transformation. Lajis
et al. reported the enzymatic method for the synthesis of kojic acid based
KAD (7-O-kojic acid monopalmitate) using immobilized lipase N435 at
80 ◦C for 4 h in bioreactors (reaction volume 0.12 L) using palmitic acid
and kojic acid as a substrate [29]. Although these methods show good
results, exhibit some limitations such as low conversion rate, high
temperature, toxic reagents and use of strong catalysts. Therefore, it is
important to explore newer biocatalyst with good activity to avoid toxic
chemical catalysts and reagents in the reaction. In continuation of our
work for the synthesis and characterization of promising heterocyclic
compounds [30], we recently developed a new methodology for the
synthesis of ortho-aminocarbonitriles using lipase as a biocatalyst [31].
To the best of our knowledge, there is no report on enzyme-catalyzed
synthesis of kojic acid derivatives using multicomponent reaction of
aromatic aldehydes, malononitrile and kojic acid.
off and washed with acetone. Isolated products were further recrystal-
lized from ethanol to achieve the pure products. The structures of the
products were confirmed by IR, 1H NMR, 13C NMR, Mass Spectrometry.
3. Results and discussion
3.1. Screening of enzymes
In initial phase, the kojic acid (1.0 mmol), malononitrile (1.0 mmol)
and 4-chloro benzaldehyde (1.0 mmol) were used as the model sub-
strates to optimize the reaction conditions (Scheme 1). In order to carry
out the model reaction, different enzymes were tested for the synthesis
of 2-amino-4,8-dihydropyrano [3,2-b]pyran-3‑carbonitrile and the re-
sults are shown in Table 1. The results showed that only 20% yield of
product was obtained when the reaction was carried out in the control
with absence of catalyst (entry 1, Table 1). When lipase from Porcine
pancreas and Candida rugosa were used, the target compound 4b was
obtained with 63% and 69%, yields respectively (entry 2 and 3,
Table 1). The best yield of 95% was achieved using lipase from Asper-
gillus niger (entry 4, Table 1). Under the same condition, the Acylase I
from Aspergillus melleus was used as a catalyst which resulted in low yield
of 50% (entry 5, Table 1). To determine the catalytic effects coming from
enzyme, the control experiments were performed using denatured lipase
that obtained the yield of 21% (entry 6, Table 1). In next experiment,
lipase samples pretreated with urea and PMSF were tested to confirm its
role as enzyme in overall reaction system (entry 7–8, Table 1). The
results indicated that the active ANL is the only enzymatic preparation
capable of performing this reaction with good yield.
2. Experimental section
2.1. General information
Lipase from Aspergillus niger (200 U/g), Lipase from Candida rugosa
(2 U/mg), Lipase from porcine pancreas Type II (100–500 U/mg) and
Acylase I from Aspergillus melleus (0.5 U/mg) were purchased from
Sigma-Aldrich. All other chemicals including aldehydes, kojic acid and
malononitrile were purchased from Spectrochem and Sigma-Aldrich,
India and used without further purification. The reactions were moni-
tored by thin-layer chromatography (Hexane: Ethyl acetate, 3:7) using
silica gel-coated plates and EtOAc/hexane solution as the mobile phase.
The spots were visualized under UV light. Melting points of compounds
were recorded in open glass capillary method and were uncorrected. The
NMR spectra were recorded on Bruker Avance-II spectrophotometer
operating at 500, 400 MHz and 125, 100 MHz. Infrared (IR) spectra were
obtained on Shimadzu IR-Affinity spectrometer using KBr pellets.
3.2. Influence of solvents
The reaction medium has always been one of the important influ-
encing factors. The solvents are known to affect the configuration of the
enzyme and hence the enzyme promiscuity also. Several solvents were
screened in this reaction using kojic acid, 4-chlorobenzaldehyde and
malononitrile as a model reaction. As shown in Table 2, the experi-
mental results demonstrate that this reaction went smoothly in the
presence of various proportions of water and ethanol. When the reaction
was carried out in acetonitrile, the yield was just 10% (entry 1, Table 2)
while in ethanol it was 60% (entry 2, Table 2). Methanol gave lesser
yield of 15% (entry 3, Table 2). When the reaction was performed in
pure water, only 42% of yield was obtained. We speculated that the low
yield might be due to poor solubility of the aldehyde in water and the
corresponding Knoevenagel product. (entry 4, Table 2). Therefore, the
model reaction was tested in a 50% aqueous ethanol, so that the solu-
bility could be enhanced. Interestingly, when water and ethanol were
used in equal concentration (1:1) for the reaction, the yield of the
product enhanced dramatically up to 95% (entry 5, Table 2). Many
2.2. General procedure for the synthesis of kojic acid derivatives (4a-4 k)
In a 25 ml round bottom flask containing aromatic aldehyde (1.0
mmol), malononitrile (66 mg, 1.0 mmol), kojic acid (142 mg, 1.0 mmol)
and enzyme (50 mg, 10 U) were added in the mixture of H2O (5 ml) and
ethanol (5 ml) and then stirred at room temperature (RT). Completion of
reaction was confirmed by TLC and the crude solid products were
extracted by adding 10 ml of ethyl acetate to the reaction mixture, fol-
lowed by filtration and evaporation of solvent. The enzyme was filtered
Scheme 1. Model reaction to prepare derivatives of kojic acid
2

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
Table 1
Influence of water content
Screening of enzyme for synthesis of kojic acid derivativesa.
100
80
60
40
20
0
Entry
Enzyme
Yieldb (%)
95
77
1
2
3
4
5
6
7
8
Blank (without enzyme)
20
63
69
95
50
21
18
20
71
Lipase from Porcine pancreasc (PPL)
Lipase from Candida rugosad (CRL)
Lipase from Aspergillus niger (ANL)
Acylase I from Aspergillus melleuse
Denatured lipase from Aspergillus nigerf
ANL denatured with ureag
67
60
58
52
ANL pretreated with PMSFh
a
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), malononitrile (1.0
mmol), Kojic acid (1.0 mmol), enzyme ANL (10 U, 50 mg), in H2O (5 ml),
ethanol (5 ml) at RT, 10 h,
0
20
30
40
50
60
70
b
Isolated yield of product.
% Water content
c
d
Lipase from porcine pancreas (100–500 U, 20 mg).
Lipase from Candida rugosa (20 U, 10 mg).
Fig. 1. Effect of concentration of ethanol: water binary mixture on lipase
catalyzed kojic acid derivative (4b).
e
Acylase from Aspergillus melleus (15 U, 30 mg).
f
ANL denatured by heating it to 100 ◦C for 6 h in water.
aReaction conditions: 4-chlorobenzaldehyde (1.0 mmol), malononitrile (1.0
mmol), kojic acid (1.0 mmol), enzyme ANL (10 U, 50 mg), H2O /+ ethanol =
10 ml at RT, 10 h, bIsolated yield.
g
h
ANL denatured with 50 mg urea in 2 ml water (0.83 M) at 100 ◦C for 24 h.
ANL pretreated with 50 mg PMSF in 2 ml THF (0.29 M) at 25 ◦C for 24 h.
3.5. Influence of substrate
polar aprotic solvents such as DMSO, DMF, and THF failed to show good
yields (entries 6–8, Table 2). The combination of polar protic solvents
such as water and ethanol gave best yield (entry 5, Table 2). The po-
larization of the solvent creates a field that polarizes the solute in the
direction to enhance its dipole moment. Hence, the water and ethanol
(1:1) was chosen as the most suitable medium for the said
transformation.
After optimizing all parameters, the scope and generality of the
method was explored with respect to various aromatic aldehydes under
the optimal conditions of which the results are summarized in Table 3,
4a–k. The electron-rich aromatic aldehydes such as benzaldehyde, 4-
chloro, 4-methyl, and 3-methoxy benzaldehydes reacted efficiently
with kojic acid and malononitrile to bring good yields of 94, 95, 94 and
90% respectively within 4 h. The aromatic aldehydes with electron
withdrawing groups such as 2-nitro, 4-nitro, and 3-nitro benzaldehydes
reacted efficiently to give 82, 84, and 86% yield respectively within 5 h.
The -NO2 group shows strong electron withdrawing effect (i.e., negative
effect) when substituted at ortho and para position that affects the yield.
Again, 2-nitrobenzaldehyde is insoluble in water whereas 4-nitrobenzal-
dehyde is slightly soluble in water that perhaps decreases the yield of
product. The 4-chlorobenzaldehyde gave highest yield 95% whereas 4-
fluorobenzaldehyde required the highest reaction time of 5 h among
other tested halides. The substituents present on the aromatic ring as
well as solubility of reactants had shown some effect on the conversion.
In all cases, the conversion was completed within 2–5 h with good to
excellent yields of desired products without forming any by-products.
3.3. Influence of water content
The effect of water molecule in presence of ethanol solvent was
examined and the results are plotted in Fig. 1. When addition of water
molecule was raised from 0 to 70%, the yield was increased from 60 to
95% while in ethanol it was 60%. When we added the water in the re-
action (20, 30, 40, 50%), the yields of 67, 71, 77, 95% were obtained
respectively. However, addition of water above 50%, the yield of reac-
tion was decreased probably due to the insolubility of reactants/in-
termediates. The results showed that water was crucial for synthesis of
kojic acid derivatives in organic medium. The performance of enzyme
improved when binary mixture of ethanol and water was used in reac-
tion medium possibly due to essential conformational flexibility of
enzyme obtained in ethanol-water mixture necessary for catalytic ac-
tivity of enzyme.
4. Proposed mechanism
Based on literature studies [32–35], the promiscuous reactions by
hydrolases are known to proceed through the activation of the Michael
acceptor through binding of its heteroatom functionality with the oxy-
anion hole of the enzyme. The proposed plausible mechanism is stated in
Fig. 2. The intermediate (I) forms promptly by condensation of benzal-
dehyde and malononitrile, bound with the oxyanion hole of the lipase.
Then kojic acid bound with lipase undergoes activation to form complex
(II). The complex (II) possibly undergoes Michael type addition with the
activated enzyme intermediate (I). Then a lipase catalyzed cyclization
results in the formation of kojic acid derivative 4a.
3.4. Reusability of enzyme
To investigate the reusability of lipase, the model reaction of 4-chlor-
obenzaldehyde, malononitrile and kojic acid were stirred in ethanol:
water (1:1) solvent at room temperature for four hours. After completion
of reaction, the lipase was separated via centrifugation. Even after three
runs, the product isolated was good enough (95, 92 and 80% respec-
tively) where the yield of the isolated compound was not affected in the
second run but, in the third run the reactivity of lipase reduced
considerably to obtain 80% yield of product.
3

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
Fig. 2. Proposed mechanism of synthesis of kojic acid derivative 4a.
4

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
Table 3
Synthesis of kojic acid derivativesa.
5

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
6

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
aReaction conditions: aldehydes (1.0 mmol), malononitrile (1.0 mmol), kojic acid (1.0 mmol), enzyme (10 U, 50 mg), in H2O (5 ml) + ethanol (5 ml) at RT.
bIsolated yield.
5. Conclusion
Table 2
An efficient method has been developed for the synthesis of biolog-
ically relevant kojic acid derivatives using lipase from Aspergillus niger as
a catalyst in aqueous ethanol medium. A total of eleven derivatives were
prepared, where the highest 95% of yield was obtained for 4b and 4a, 4c
have 94% yield while the lowest yield of 82% was found for 4g after 5 h.
Based on the literature studies, the plausible mechanism is proposed for
the synthesis of kojic acid derivatives. This enzymatic route is new and
has potential to replace conventional chemical methods. This study
could be helpful in designing the new tyrosinase inhibitors for human
use. Furthermore, this bio-based methodology has advantages,
including short reaction time, high yields, recyclability of catalyst,
simplicity in operations and safe reaction conditions.
Selection of solvent for the model reaction for the formation of kojic acid de-
rivative.a
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Acetonitrile
Ethanol
Methanol
H2O
10
60
15
42
95
60
55
52
H2O: Ethanol (1:1)
DMSO
DMF
THF
a
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), malononitrile (1.0
mmol), kojic acid (1.0 mmol), enzyme ANL (10 U, 50 mg), in solvent (10 ml) at
RT, 10 h.
Credit author statement
b
Isolated yield.
The below stated authors contributed in multiple roles as follows,
7

K.S. Dalal et al.
Catalysis Communications 152 (2021) 106289
Sr No.
1.
Authors name
Author contribution
Author categories
First Author
Dr. Kiran Sharad Dalal
Mr. Mangal Arun Chaudhari
Dr. Dipak Sharadrao Dalal
Dr. Bhushan Liladhar Chaudhari
Methodology, formal analysis, validation
Methodology, formal analysis
2.
Second Author
3.
Conceptualization, project administration, supervision, writing original draft
Conceptualization, administration, Editing the draft
Corresponding Author
Corresponding Author
4.
[14] J.P. Adams, M.J. Brown, A. Diaz-Rodriguez, R.C. Lloyd, G.D. Roiban, Biocatalysis:
a pharma perspective, Adv. Synth. Catal. 361 (11) (2019) 2421–2432.
[15] B.P. Dwivedee, S. Soni, M. Sharma, J. Bhaumik, J.K. Laha, U.C. Banerjee,
Promiscuity of lipase-catalyzed reactions for organic synthesis: a recent update,
ChemistrySelect 3 (9) (2018) 2441–2466.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests.
[16] A.C.L.M. Carvalho, T.D.S. Fonseca, M.C. Mattos, M.D.C.F. Oliveira, T.L.G. Lemos,
F. Molinari, D. Romano, I. Serra, Recent advances in lipase-mediated preparation
of pharmaceuticals and their intermediates, Int. J. Mol. Sci. 16 (2015)
29682–29716.
Acknowledgments
[17] P.P. Bora, M. Bihani, G. Bez, Multicomponent synthesis of dihydropyrano [2, 3-c]
pyrazoles catalyzed by lipase from Aspergillus niger, J. Mol. Catal. B Enzym. 92
(2013) 24–33.
The authors are thankful to the Department of Science and Tech-
nology for infrastructural facilities under FIST Programme and Special
Assistance Programme (SAP) of University Grants Commission, New
Delhi to KBCNMU for financial support. BLC and DSD are thankful to
Rajiv Gandhi Science & Technology Commission, Government of
Maharashtra for financial support. Authors also thank SAIF-Punjab
University, Chandigarh for characterization support to this work.
[18] Z.G. Le, L.T. Guo, G.F. Jiang, X.B. Yang, H.Q. Liu, Henry reaction catalyzed by
lipase A from Aspergillus niger, Green Chem. Lett. Rev. 6 (4) (2013) 277–281.
[19] B.M. Travalia, M. Galvao, A.S. Lima, C.M.F. Soares, N. Narain, L.C.L. de Aquino
Santana, Effect of parameters on butyl butyrate synthesis using novel Aspergillus
niger lipase as biocatalyst, Acta Sci. Technol. 40 (1) (2018), e35999.
[20] Y. Sarrafi, E. Mehrasbi, S.Z. Mashalchi, MCM-41-SO3H: an efficient, reusable,
heterogeneous catalyst for the one-pot, three-component synthesis of pyrano [3, 2-
b] pyrans, Res. Chem. Intermediat. (2015) 1–13.
[21] S.H. Banitaba, A mild protocol for the preparation of 2-amino-dihydropyrano [3, 2-
b] pyran-3-carbonitriles via cobalt nanoparticles-catalyzed multi-component
reaction in water Iran, Chem. Commun. 6 (4) (2018) 389–401.
Appendix A. Supplementary data
[22] S.M. Baghbanian, Synthesis, characterization, and application of Cu2O and NiO
nanoparticles supported on natural nanozeolite clinoptilolite as a heterogeneous
catalyst for the synthesis of pyrano [3, 2-b] pyrans and pyrano [3, 2-c] pyridones,
RSC Adv. 4 (103) (2014) 59397–59404.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.catcom.2021.106289.
[23] M. Gholamhosseini-Nazari, S. Esmati, K.D. Safa, A. Khataee, R. Teimuri-Mofrad,
Fe3O4@ SiO 2-BenzIm-Fc [Cl]/ZnCl2: a novel and efficient nano-catalyst for the
one-pot three-component synthesis of pyran annulated bis-heterocyclic scaffolds
under ultrasound irradiation, Res. Chem. Intermediat. 45 (4) (2019) 1841–1862.
[24] R. Teimuri-Mofrad, S. Esmati, M. Rabiei, M. Gholamhosseini-Nazari, Efficient
synthesis of new pyrano [3, 2-b] pyran derivatives via Fe3O4@ SiO2-IL-Fc catalyzed
three-component reaction, Heterocycl. Commun. 23 (6) (2017) 439–444.
[25] K.O. Aghbash, N.N. Pesyan, B. Notash, The clean synthesis and confirmatory
structural characterization of new 2-amino-4, 8-dihydropyrano [3, 2-b] pyran-3-
cyano based on Kojic acid, Monatsh Chem. 149 (11) (2018) 2059–2067.
[26] D. Azarifar, H. Ebrahimiasl, R. Karamian, M. Ahmadi-Khoei, S-Triazinium-based
ionic liquid immobilized on silica-coated Fe3O4 magnetic nanoparticles: an
efficient and magnetically separable heterogeneous catalyst for synthesis of 2-
amino-4, 8-dihydropyrano [3, 2-b] pyran-3-carbonitrile derivatives for antioxidant
and antifungal evaluation studies, J. Iran. Chem. Soc. 16 (2) (2014) 341–354.
[27] S.H. Banitaba, J. Safari, S.D. Khalili, Ultrasound promoted one-pot synthesis of 2-
amino-4, 8-dihydropyrano [3, 2-b] pyran-3-carbonitrile scaffolds in aqueous
media: a complementary ‘green chemistry’ tool to organic synthesis, Ultrason.
Sonochem. 20 (1) (2013) 401–407.
References
[1] T. Yabuta, The constitution of kojic acid, a γ-pyrone derivative formed by
Aspergillus oryzae from carbohydrates, J. Chem. Soc. Trans. 125 (1924) 575–587.
[2] J. Brtko, L. Rondahl, M. Fickova, D. Hudecova, V. Eybl, M. Uher, Kojic acid and its
derivatives: history and present state of art, Cent. Eur. J. Public Health 12 (2004)
S16–S17.
[3] G.A. Burdock, M.G. Soni, I.G. Carabin, Evaluation of health aspects of kojic acid in
food, Regul. Toxicol. Pharmacol. 33 (1) (2001) 80–101.
[4] S. Kumari, S.T. Thng, N.K. Verma, H.K. Gautam, Melanogenesis inhibitors, Acta
Derm. Venereol. 98 (9–10) (2018) 924–931.
[5] Y.H. Cho, J.H. Kim, S.M. Park, B.C. Lee, H.B. Pyo, H.D. Park, New cosmetic agents
for skin whitening from Angelica dahurica, J. Cosmet. Sci. 57 (1) (2006) 11–21.
[6] B.S. Reddy, M.R. Reddy, C.H. Madan, K.P. Kumar, 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,
Bioorg. Med. Chem. Lett. 20 (24) (2010) 7507–7511.
[7] H.S. Rho, S.M. Ahn, D.S. Yoo, M.K. Kim, D.H. Cho, J.Y. Cho, Kojyl thioether
derivatives having both tyrosinase inhibitory and anti-inflammatory properties,
Bioorg. Med. Chem. Lett. 20 (22) (2010) 6569–6571.
[28] E.A. Kataev, M.R. Reddy, G.N. Reddy, V.H. Reddy, C.S. Reddy, B.V. Reddy,
Supramolecular catalysis by β-cyclodextrin for the synthesis of kojic acid
derivatives in water, New J. Chem. 40 (2) (2016) 1693–1697.
[8] L. Novotný, P. Rauko, M. Abdel-Hamid, A. Vachalkova, Kojic acid–a new leading
molecule for a preparation of compounds with an anti-neoplastic potential,
Neoplasma 46 (2) (1999) 89–92.
[29] A.F.B. Lajis, M. Hamid, S. Ahmad, A.B. Ariff, Lipase-catalyzed synthesis of kojic
acid derivative in bioreactors and the analysis of its depigmenting and antioxidant
activities, Cosmetics 4 (3) (2017) 22.
[9] J.C. Cho, H.S. Rho, H.S. Baek, S.M. Ahn, B.Y. Woo, Y.D. Hong, J.W. Cheon, J.
M. Heo, S.S. Shin, Y.H. Park, K.D. Suh, Depigmenting activity of new kojic acid
derivative obtained as a side product in the synthesis of cinnamate of kojic acid,
Bioorg. Med. Chem. Lett. 22 (5) (2012) 2004–2007.
[30] K.S. Dalal, Y.A. Tayade, Y.B. Wagh, D.R. Trivedi, D.S. Dalal, B.L. Chaudhari, Bovine
serum albumin catalyzed one-pot, three-component synthesis of dihydropyrano [2,
3-c] pyrazole derivatives in aqueous ethanol, RSC Adv. 6 (18) (2016)
14868–14879.
[10] M.D. Aytemir, B. Ozçelik, A study of cytotoxicity of novel chlorokojic acid
derivatives with their antimicrobial and antiviral activities, Eur. J. Med. Chem. 45
(9) (2010) 4089–4095.
[31] K.S. Dalal, S.A. Padvi, Y.B. Wagh, D.S. Dalal, B.L. Chaudhari, Lipase from porcine
pancreas: an efficient biocatalyst for the synthesis of ortho-aminocarbonitriles,
ChemistrySelect 3 (37) (2018) 10378–10382.
[11] R. Tanaka, H. Tsujii, T. Yamada, T. Kajimoto, F. Amano, J. Hasegawa,
Y. Hamashima, M. Node, K. Katoh, Y. Takebe, Novel 3α-methoxyserrat-14-en-21β-
´
[32] M. Lopez-Iglesias, V. Gotor-Fernandez, Recent advances in biocatalytic
ol (PJ-1) and 3β-methoxyserrat-14-en-21β-ol (PJ-2)-curcumin, kojic acid,
quercetin, and baicalein conjugates as HIV agents, Bioorg. Med. Chem. Lett. 17
(14) (2009) 5238–5246.
promiscuity: hydrolase-catalyzed reactions for nonconventional transformations,
Chem. Rec. 15 (4) (2015) 743–759.
[33] M. Kapoor, M.N. Gupta, Lipase promiscuity and its biochemical applications,
Process Biochem. 47 (4) (2012) 555–569.
[12] C.L. Burnett, W.F. Bergfeld, D.V. Belsito, R.A. Hill, C.D. Klaassen, D.C. Liebler, J.
G. Marks, R.C. Shank, T.J. Slaga, P.W. Snyder, F.A. Andersen, Final report of the
safety assessment of kojic acid as used in cosmetics, Int. J. Toxicol. 29 (6) (2010)
244S–273S.
[34] C. Branneby, P. Carlqvist, A. Magnusson, K. Hult, T. Brinck, P. Berglund, Carbonꢀ
carbon bonds by hydrolytic enzymes, J. Am. Chem. Soc. 125 (4) (2003) 874–875.
[35] M. Svedendahl, K. Hult, P. Berglund, Fast carbon-carbon bond formation by a
promiscuous lipase, J. Am. Chem. Soc. 127 (51) (2005) 17988–17989.
[13] H. Bernhard, Embracing nature’s catalysts: a viewpoint on the future of
biocatalysis, ACS Catal. 10 (15) (2020) 8418–8427.
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