Synthesis of N-arylindazole-3-carboxamide and N-benzoylindazole derivatives and their evaluation against α-MSH-stimulated melanogenesis

Article abstract of DOI:10.1016/j.bmcl.2019.07.055

We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-stimulated melanogenesis. In the bio evaluation studies of these compounds,

Full text of DOI:10.1016/j.bmcl.2019.07.055

Journal Pre-Proof
Synthesis of N-arylindazole-3-carboxamide and N-benzoylindazole derivatives
and their evaluation against α-MSH-stimulated melanogenesis
Sateesh Kumar Arepalli, Chaerim Lee, Jae-Kyung Jung, Youngsoo Kim, Kiho
Lee, Heesoon Lee
PII:
S0960-894X(19)30526-8
https://doi.org/10.1016/j.bmcl.2019.07.055
BMCL 26596
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
24 June 2019
29 July 2019
31 July 2019
Please cite this article as: Kumar Arepalli, S., Lee, C., Jung, J-K., Kim, Y., Lee, K., Lee, H., Synthesis of N-
arylindazole-3-carboxamide and N-benzoylindazole derivatives and their evaluation against α-MSH-stimulated
melanogenesis, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.07.055
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis of N-arylindazole-3-carboxamide and N-benzoylindazole derivatives
and their evaluation against α-MSH-stimulated melanogenesis
Sateesh Kumar Arepallia, Chaerim Leea, Jae-Kyung Junga, Youngsoo Kima, Kiho Leeb and Heesoon Leea, 
aCollege of pharmacy, Chungbuk National University, Chungbuk 28160, Republic of Korea
bCollege of pharmacy, Korea University, Sejong 30019, Republic of Korea
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +82 43 261 2811; fax: +82 43 268 2732; e-mail: medchem@chungbuk.ac.kr (H. Lee)
Article history:
Received
Revised
Accepted
Available online
We have designed and synthesized twenty-six N-arylindazole-3-carboxamide (3a-p) and N-
benzoylindazole (6a-j) derivatives to discover with excellent inhibition activities of α-MSH-
stimulated melanogenesis. In the bio evaluation studies of these compounds, we discovered
eighteen compounds, out of twenty-six exhibited more potent inhibition than the positive control
arbutin. From the SAR studies, we identified 3k and 6g as lead compounds which displayed
almost 5 and 9 times more potent inhibition of α-MSH-stimulated melanogenesis respectively
than the reference arbutin. It is also evident the presence of electron withdrawing group at para
position (R3) for the compounds (3a-p) and presence of +M group at ortho position (R5) for the
compounds (6a-j) were crucial for their excellent inhibition activities of α-MSH-stimulated
melanogenesis.
Keywords:
Melanogenesis
α-MSH
Arbutin
N-arylindazole-3-carboxamides
N-benzoylindazoles
2009 Elsevier Ltd. All rights reserved.
OH
Melanin is the key source and responsible for the
pigmentation of human skin, eyes and hair which is produced
from epidermis melanocytes with basal keratinocytes.1 Upon
ultraviolet B (UVB)-irradiation, melanocyte synthesizes the
melanin through melanogenesis process.2 Melanogenesis is a
complex process involves the combination of biochemical and
enzymatic reactions in which melanocytes produce two kinds of
melanin pigments such as eumelanin (brown-black) and
pheomelanin (red-yellow) formed by the conjugation of cysteine
or glutathione.3-5 At normal physiological conditions, melanin
protects the skin against harmful UV irradiation and acts a vital
evolutionary role in camouflage and animal mimicry.6 But
irregular production of melanin that leads to pigmented acne
scars, age spots, melasma, postinflammatory melanoderma, and
freckles,7-11 as well as cancer.12 It is also reported that abnormal
melanogenesis associated with Parkinson’s, Alzheimer’s, and
Huntington’s diseases.13-17 Thus, this area has been extensively
focused by the researchers to control the abnormal production of
melanin as well as the development of skin whitening agents
including skin medication. Around the globe, approximately 15%
world population is anticipated to invest for skin whitening
products and by 2020; the global market is expected to reach
around U.S. $23 billion.18 Most of the marketed skin whitening
products inhibit the melanin synthesis by overactive melanocytes.
In that process several inhibitors such as arbutin, kojic acid (Fig.
1) and various herbal extracts have been developed.19-20
R
S
R3
R2
O
NH
OH
HO
HO
HO
HO
O
O
N
N
HO
H
O
O
R1
HO
HO
OH
OH
MSH inhibitors (Ref 21, 22)
Kojic acid
Arbutin
NH
N
O
OH
NH
O
I
O
O
N
N
HO
F
N
O
N
3HCl
N
H
N
O
N
OH
H
Tyrosinase inhibitors (Ref 23, 24)
DRD4A antagonist (Ref 25)
Figure 1. The representative potent inhibitors of melanogenesis.
Recently Jung, J-K et al have reported the caffeic acid and
chlorogenic acid derivatives (Fig. 1) as potent α-MSH induced
melanogenesis inhibitors.21-22 Different heterocycles (Fig. 1) such
as indoles,23 aurones24 and pyrrolo[2,3-b]pyridines25 were also
found to be acts as inhibitors of tyrosinase, melanin in B16, and
human melanocytes25 respectively. To the best of our knowledge,
this is the first report on N-benzoylindazoles and N-arylindazole-
3-carboxamides as potent inhibitors of α-MSH-stimulated
melanogenesis. As a part of our exploration of the synthesis of
novel heterocyclic systems as medicinally and pharmaceutically
important scaffolds, 26-29 in this report we disclosed the design

JOURNAL PRE-PROOF
This work
o
HOBt.H2O, DMF, 100 C, Overnight. Isolated yields of (3a-
p): 19% to quantitative.
R3
NH
R4
R5
N
O
R2
R1
NH
O
Cl
O
O
O
R1
O
NH
R5
R6
N
R2
O2N
X
O2N
X
R
N
b
N
R5
N
N
N
R8
Caffeamide analogs
R6
R7
N
N
H
R
F
R7
5a-d
R5
R6
O
O
S
4a, b
X = H, Br; R = H
R7
N
N
6a-j
R1
NH
N
R8
R9
R8
N
R
R5=R6=R7=R8= H; X = Br ;
N
O
6a, 47%
H
5
6
7
8
6b,
6c,
6d,
6e,
6f,
R =R =R =H; R = CH3; X = Br ;
R6=R7=R8=H; R5= Cl; X = Br ;
R5=R6=R8=H; R7= Cl; X = Br ;
R5=R6=R7=R8= X =H;
R5=R6=R7=H; R8= CH3; X = H ;
R6=R7=R8=H; R5= Cl; X = H ;
51%
46%
35%
61%
62%
63%
R10
Indazole analogs
Thiazole analogs
Indole analogs
Figure 2. Design of our target molecules by using molecular modification.
6g,
R5=R6=R8=H; R7= Cl; X = H ;
X = Br; R = COCH2-2-Thiophenyl;
63%
61%
6h,
6i,
(Fig. 2) and synthesis of total twenty-six N-benzoylindazole and
N-arylindazole-3-carboxamide derivatives and tested their
inhibitory activities against α-MSH-stimulated melanogenesis.
The assay determined the inhibitory activity of melanin
formation in B16 melanoma cells in the presence of α-MSH
(100nM) during three-day incubation. The quantity of melanin
produced into the culture media was determined by measuring
sample absorbance against synthetic melanin standard. 30-31
6j,
X = H; R = COCH2-2-Thiophenyl;
62%
Scheme 2. Synthesis of N-benzoylindazole derivatives (6a-j).
Reagents and conditions: (b) Aroyl chlorides, Et3N, DCM, 0
oC to RT, Overnight. Isolated yields of (6a-j): 35-63%.
of various indazole analogs (3a-p & 6a-j), we focused to
examine their inhibitory activities against α-MSH-induced
melanogenesis in B16 melanoma cells as shown in Table 1. As
shown in Table 1, a total sixteen compounds of N-arylindazole-3-
carboxamide derivatives (3a-p) were evaluated for inhibitory
activities of α-MSH-induced melanogenesis with positive control
arbutin which is used as reference compound in this studies.5, 19-20,
21-22 Among all examined sixteen compounds; when compared to
positive control arbutin (IC50: 64±9 μM), eleven compounds such
as 3a (IC50: 40±2 μM), 3b (IC50: 20±1 μM), 3c (IC50: 16±1 μM),
3d (IC50: 36±1 μM), 3e (IC50: 38±6 μM), 3f (IC50: 15±2 μM), 3h
(IC50: 15±1 μM), 3k (IC50: 13±1 μM), 3l (IC50: 21±2 μM), 3m
(IC50: 35±5 μM), and 3n (IC50: 18±1 μM), exhibited strong
inhibitory activities against α-MSH-induced melanogenesis in
B16 melanoma cells. The compounds 3p (IC50: 69±4 μM) and 3o
(IC50: 93±4 μM) also displayed comparable activities with
reference compound. In particular, the compound 3k (IC50: 13±1
μM) shown excellent inhibitory activity which is almost 5 times
more potent inhibition than the positive control arbutin (IC50:
Our studies commenced toward the synthesis of various N-
arylindazole-3-carboxamide (3a-p) and N-benzoylindazole
derivatives (6a-j) as shown in Schemes 1 and 2. The synthesis of
N-arylindazole-3-carboxamide (3a-p) derivatives was achieved
by the addition of 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide
hydrochloride
(EDC.HCl)
and
1-
hydroxybenzotriazole hydrate (HOBt.H2O) to a solution of
indazole-3-carboxylic acid (1) in DMF and aniline derivatives
(2a-p). The resulting mixture was stirred at 100oC for overnight
provided the desired compounds 3a-p (Scheme 1). As depicted in
scheme 2, the N-benzoylindazole derivatives (6a-j) were
synthesized by the treatment of 5-nitroindazole derivatives (4a-b)
in DCM with mixture of triethylamine and benzoyl chloride
derivatives (5a-d) at 0 ℃ and then stirred at room temperature for
overnight furnished the corresponding N-benzoylindazole
derivatives (6a-j). All the synthesized products 3a-p & 6a-j were
confirmed by 1H, 13C NMR and mass spectra. After the synthesis
64±9 μM). It is also noted that the compounds 3h (IC50: 15±1 μM)
and 3f (IC50: 15±2 μM) exhibited almost 4 times more potent
inhibition than the reference compound arbutin (IC50: 64±9 μM)
against α-MSH-induced melanogenesis. Next, we turned our
attention to screen the inhibitory activities of N-benzoylindazole
derivatives (6a-j) against α-MSH-induced melanogenesis with
reference compound arbutin. As depicted in Table 1, among all
ten synthesized compounds (6a-j); seven compounds 6a (IC50:
32±1 μM), 6b (IC50: 28±5 μM), 6c (IC50: 25±1 μM), 6e (IC50:
51±5 μM), 6g (IC50: 7±1 μM), 6h (IC50: 60±3 μM), and 6j (IC50:
55±1 μM) displayed potent inhibition than the reference arbutin
(IC50: 64±9 μM). The compound 6f also shown comparable
activity (IC50: 77±13 μM). Especially, the compound 6g (IC50:
7±1 μM) exhibited excellent inhibition which is almost 9 times
more potent inhibition than the positive control against α-MSH-
induced melanogenesis.
R3
R4
R2
R5
O
R1
R1
OH
O
H2N
NH
R2
R2
+
a
N
N
N
N
H
R4
2a-p
H
1
3a-p
R1=R2=R3=R4= R5= H
3a,
3b,
3c,
3d,
3e,
3f,
;
81%
68%
R1=R2=R4=R5=H ; R3= OCH3;
R2=R3=R4=R5= H ; R1= OCH3;
R1=R3=R4=R5= H ; R2= OCH3;
R1=R2=R4=R5= H ; R3= CH3;
70%
65%
Quant.
R1=R3=R4=R5= H ; R2= CH3
R1=R3=R5=CH3; R2=R4=H;
R1=R2=R4=R5= H ; R3= CF3;
R1=R3=R4=R5= H ; R2= CF3;
R2=R3=R4=R5= H ; R1= CF3;
R1=R2=R4=R5= H ; R3= OCF3;
R2=R3=R4=R5= H ; R1= OH;
R1=R3=R4=R5= H ; R2= OH;
R1=R2=R4=R5= H ; R3= OH;
R1=R2=R4=R5= H ; R3= Cl;
R1=R2=R4=R5= H ; R3= COOCH3;
;
57%
70%
76%
57%
69%
3g,
3h,
3i,
3j,
3k,
3l,
72%
19%
To develop the structure-activity relationship (SAR), initially
we modified the indazole core unit at 1st and 3rd positions which
resulted the two sets of 3a-p and 6a-j compounds. In the first set
3m,
3n,
3o,
3p,
49%
41%
Quant
Quant
of
N-arylindazole-3-carboxamide
derivatives
(3a-p),
substitutions were performed at the N-phenyl ring (R1, R2, R3, R4,
and R5). Subsequently R1= R2= R3= R4= R5 =H (3a, IC50: 40±2
μM) was prepared to study the effect of core motif of N-phenyl-
1H-indazole-3-carboxamide. We also examined the electronic
influence of different groups at R1, R2, R3, R4, and R5 including
Scheme 1. Synthesis of N-arylindazole-3-carboxamide
derivatives (3a-p). Reagents and conditions: (a) 1-ethyl-3-(3-
dimethylaminopropyl)
carbodiimide
hydrochloride,

JOURNAL PRE-PROOF
electron withdrawing (–CF3 –OCF3 and –COOCH3) and electron
donating groups (–OCH3 and –OH).
Table 1. Inhibitory activities of N-arylindazole-3-carboxamide (3a-p) and N-benzoyl indazole (6a-j) derivatives
R3
R4
R2
R5
O2N
R1
O
R6
N
NH
R7
R8
N
X
N
O
N
H
R9
3a-p
6a-j
Compounds
R1
R2
R3
R4
R5
IC50
Compounds
R
X
R6
R7
R8
R9
IC50 (μM)a
(μM)a
Arbutin
3a
64±9
40±2
20±1
16±1
36±1
38±6
15±2
--
6a
6b
6c
6d
6e
6f
Br
Br
Br
Br
H
H
H
Cl
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Cl
H
CH3
H
32±1
28±5
25±1
--
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
3b
3c
OCH3
H
H
H
H
3d
OCH3
H
H
H
H
51±5
77±13
7±1
3e
H
CH3
H
H
H
CH3
H
3f
H
CH3
H
H
6g
6h
6i
H
3g
CH3
H
CH3
CF3
CH3
H
H
H
60±3
--
3h
H
15±1
COCH2-2-
Thiophenyl
Br
3i
3j
H
CF3
H
H
H
H
H
H
H
--
--
6j
COCH2-2-
Thiophenyl
H
55±1
CF3
3k
3l
H
OH
H
H
H
OCF3
H
H
H
H
H
H
H
H
H
H
H
H
13±1
21±2
35±5
18±1
93±4
69±4
H
H
3m
3n
3o
3p
OH
H
H
OH
H
H
Cl
H
H
COOCH3
a Data taken as a mean from three independent experiments.
The inhibitory effects of N-arylindazole-3-carboxamide
derivatives (3a-p) depended on the nature of the substitution at
the N-phenyl ring (R1, R2, R3, R4, and R5). For instance, the
electron withdrawing group such as –CF3 at para position (R3
substitution) exhibited (3h IC50: 15±1 μM) strong inhibitory
activities than the corresponding ortho (R1 substitution, 3i) and
meta position (R2 substitution, 3j) compounds respectively. It
is also important to note that the electron withdrawing group –
OCF3 at para position contained compound 3k (IC50: 13±1 μM)
exhibited 5 times more potent inhibition than the positive
control arbutin (IC50: 64±9 μM). Similarly, in the case of
electron donating groups; ortho substitution is vital for better
inhibitory activities. For instance, –OCH3 group ortho
substituted compound (3c, IC50: 16±1 μM) displayed more
potent inhibition than the corresponding meta (3d, IC50: 36±1
μM) and para (3b, IC50: 20±1 μM) substituted compounds
respectively. It is also explored that the compound 3c (IC50:
16±1 μM) displayed 4 times more potent inhibition than the
reference compound arbutin (IC50: 64±9 μM). In the case of N-
benzoylindazole (6a-j) derivatives, the structure-activity
relationship (SAR) development was initiated for the indazole
scaffold and it was modified at 1st, 5th and 6th positions of
indazole core unit which results the ten compounds (6a-j).
Significantly, we focused to perform different substitutions at
aromatic ring (R6, R7, R8, and R9) of N-benzoylindazole (6a-j)
derivatives. Consequently, R6= R7= R8= R9= H and X =Br (6a,
IC50: 32±1 μM) was prepared to study the effect of core motif
of (5-nitro-1H-indazol-1-yl)(phenyl)methanone. We also
screened different substitutions at R6, R7, R8, R9 and X.
Especially, when we tested +M substituents like –Cl at R6
position of aromatic ring exhibited strong inhibitory activities
than the remaining substitutions. For instance, the compounds
6c (IC50: 25±1 μM) and 6g (IC50: 7±1 μM) exhibited almost 4
and 9 times more potent inhibitory activities respectively than
the positive control arbutin (IC50: 64±9 μM). We also observed
that 2-thiophenyl substituted compound 6j (IC50: 55±1 μM)
also shown good inhibitory activity than the reference
compound.
In summary, a total twenty-six compounds of indazole
analogs (3a-p & 6a-j) were designed, synthesized and
evaluated their inhibitory effects on α-MSH-induced
melanogenesis. Structure-activity relationship (SAR) studies of
3a-p analogs revealed that the presence of electron
withdrawing groups at para position (R3) and electron donating
groups at ortho position (R1) were crucial for their inhibitory

JOURNAL PRE-PROOF
as potent tyrosinase inhibitors. Bioorg. Med. Chem. Lett.
2012;22:5523−5526.
effects on α-MSH-induced melanogenesis and also in the case
of 6a-j analogs +M groups at R6 position was most important
for their inhibitory activities. The screening starting from the
initial lead scaffold 3k directed to the discovery of 6g analog
which displayed 9 times more potent inhibition than the
reference compound against α-MSH-induced melanogenesis.
The remaining compounds also exhibited most potent
inhibitions. Thus, N-arylindazole-3-carboxamide (3a-p) and N-
benzoylindazole derivatives (6a-j) provided new chemical
tools for development of pathway-selective α-MSH-induced
melanogenesis inhibitors with excellent activity. Work on the
enrichment of potency and pharmacological profiles of the lead
molecules are underway.
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Acknowledgments
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIT) (NRF-2019R1F1A1057601), and Medical
Research Center Program (2017R1A5A2015541).
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Graphical Abstract

JOURNAL PRE-PROOF
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Synthesis of N-arylindazole-3-carboxamide and
N-benzoylindazole derivatives and their evaluation against
α-MSH-stimulated melanogenesis
Leave this area blank for abstract info.
Sateesh Kumar Arepalli, Chaerim Lee, Jae-Kyung Jung, Youngsoo Kim, Kiho Lee and Heesoon Lee*
altered.
Highlights:
 Twenty-six indazole analogs were
designed, synthesized and evaluated
as α-MSH inhibitors.
 Eighteen compounds exhibited more
potent inhibition than reference
arbutin.
 The compound (3k) displayed 5 times
more α-MSH inhibition than arbutin
 The compound (6g) displayed 9 times
more α-MSH inhibition than arbutin
 Structure-activity relationship was
developed