Synthesis of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines as novel skin protecting and anti-aging agents

Article abstract of DOI:10.3329/bjp.v12i2.32023

A series of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines 6a-6h were prepared by using the one-pot three component synthetic method. The target compounds 6a-6h were synthesized by reacting two molar equivalents of ketone functionality and one mole of aromatic aldehydes in ammonium acetate to obtain the desired products. The structures of newly synthesized compounds were characterized by FT-IR, ¹H-NMR, ¹³C-NMR, and elemental analysis. All the synthesized compounds were screened for their elastase inhibition and antioxidant activity. Almost all of the compounds 6a-h showed good to excellent activities against elastase enzyme more than the reference drug. Compounds 6d and 6b at 0.2 ± 0.0 μM and 0.2 ± 0.0 μM were found to most potent derivatives against elastase enzyme. Compound 6a exhibited prominent free radical scavenging activity. From the results of the biological activity, we infer that some derivatives can serve as lead molecules in pharmacology.

Full text of DOI:10.3329/bjp.v12i2.32023

BJP
Bangladesh Journal of Pharmacology
Research Article
Synthesis of 4-aryl-2,6-dimethyl-
3,5-bis-N-(aryl)-carbamoyl-1,4-
dihydropyridines as novel skin pro-
tecting and anti-aging agents

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ISSN: 1991-0088
Synthesis of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-
dihydropyridines as novel skin protecting and anti-aging agents
Aamer Saeed1, Danish Shahzad1, Fayaz Ali Larik1, Pervaiz Ali Channar1, Haroon
Mehfooz1, Qamar Abbas2, Mubashir Hassan2, Hussain Raza2, Sung-Yum Seo2
and Ghulam Shabbir1
1Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; 2Department of Biological
Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju, Chungnam 314-
701, Republic of Korea.
Article Info
Abstract
Received:
Accepted:
Available Online:
8 April 2017 A series of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyri-
28 May 2017
25 June 2017
dines 6a-6h were prepared by using the one-pot three component synthetic
method. The target compounds 6a-6h were synthesized by reacting two molar
equivalents of ketone functionality and one mole of aromatic aldehydes in
ammonium acetate to obtain the desired products. The structures of newly
synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR,
and elemental analysis. All the synthesized compounds were screened for
their elastase inhibition and antioxidant activity. Almost all of the com-
pounds 6a-h showed good to excellent activities against elastase enzyme
more than the reference drug. Compounds 6d and 6b at 0.2 ± 0.0 µM and 0.2 ±
0.0 µM were found to most potent derivatives against elastase enzyme.
Compound 6a exhibited prominent free radical scavenging activity. From the
results of the biological activity, we infer that some derivatives can serve as
lead molecules in pharmacology.
DOI: 10.3329/bjp.v12i2.32023
Cite this article:
Saeed A, Shahzad D, Larik FA, Chan-
nar PA, Mehfooz H, Abbas Q, Hassan
M, Raza H, Seo SY, Shabbir G. Synthe-
sis of 4-aryl-2,6-dimethyl-3,5-bis-N-
(aryl)-carbamoyl-1,4-dihydropyri-
dines as novel skin protecting and
anti-aging agents. Bangladesh J Phar-
macol. 2017; 12: 210-15.
and it is responsible for the cleavage of elastin
(Macdonald et al., 1998). Elastin is a protein present in
Introduction
The dazzling and fresh appearance of skin does not last
for very long. The physiological changes in the skin are
inevitable and dermatologists are keenly involved in
exploring the potent inhibitors for skin protection. Pre-
mature aging occurs mainly due to prolonged exposure
of skin to ultraviolet radiations (Kim et al., 2009). Photo-
induced skin results in the wrinkle formation and is
also linked with oxidative stress and inflammatory
response.
the skin and is responsible for the skin elasticity. Elastin
forms the elastic fiber which furnishes elasticity to
connective tissues. The abrasion of elastic fibers impe-
des the elasticity of the skin. Elastase enzyme degrades
the elastin, hence inhibition of elastase activity can
serve as an efficient way to protect skin aging.
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are widely
recognized as Ca2+ channel blockers and have emerged
as the exquisite class of drugs for the treatment of
cardiac-related disorders and hypertension (Spedding
and Paoletti, 1992). The DHP heterocyclic ring is a
common feature of various bioactive compounds such
as vasodilator, bronchodilator (Tanabe et al., 1998),
antiatherosclerotic, antitumor, neuroprotective, hepato-
protective (Davis and Davis, 1979) and antidiabetic
The physiological damage to the skin can be either
extrinsic or intrinsic and storage of reactive oxygen
species (ROS) in human skin can lead to activation of
skin disease causing enzymes such as tyrosinase and
elastase enzymes (Popoola et al., 2015). Elastase is an
enzyme which belongs to the family of chymotrypsin
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Bangladesh J Pharmacol 2017; 12: 210-215
agents (Baraldi et al., 1989). 1,4-DHPs are capable of leum ether-chloroform (3:1) as eluent.
211
exhibiting extended medicinal utilities including
protection of nerve cells, prevent blood aggregation and
recently, it has observed that they can also show
bioactive effects against Alzheimer’s disease (Pastan
and Gottesman, 1987). These fascinating bioactive
features reveal the promising role of 1,4-DHPs as potent
and valuable drug candidates (Sridhar and Perumal,
2005; Kumar and Maurya, 2008).
4-(4-Chloro-3-nitrophenyl)-2,6-dimethyl-N3,N5-
diphenyl-1,4-dihydropyridine-3,5-dicarboxamide (6a)
Dark orange crystalline solid, m.p.=248-250ºC, Yield
93%, Rf=0.44 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.45 (s, 2H, 2×CO-NH),
9.52 (s, 1H, NH-DHP), 8.28 (s, 1H,=C-OH), 7.84 (d, 1H,
Ar-H, J= 1.8Hz), 7.64-7.22 (m, 13H, Ar-H), 7.02-6.97 (m,
2H, Ar-H), 5.22 (s, 1H, H4-DHP), 2.10 (s, 6H, 2×-
CH3),13C-NMR (75 MHz DMSO-d6) δ (ppm)167.51
(C=O), 148.51, 147.88, 139.78, 138.99, 133.09, 131.75,
129.23, 128.93, 124.49, 123.43, 122.82, 120.19, 105.33,
41.83, 17.95,Anal. Calcd. for C27H23ClN4O4 : C, 64.48; H,
4.61; N, 11.14; found: C, 64.43; H, 4.59; N, 11.11.
Based on the sound applications of 1,4-DHPs, herein,
we report the one pot-three component synthesis of 4-
Aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-
dihydropyridines as novel elastase inhibitors and free
radical scavenging agents. All the synthesized mole-
cules showed elastase inhibition better than the
standard drug.
4-(4-Isopropylphenyl)-2,6-dimethyl-N3,N5-diphenyl-
1,4-dihydropyridine-3,5-dicarboxamide (6b)
Dark orange crystalline solid, m.p.=248-250ºC, Yield
79%, Rf=0.64 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.42 (s, 2H, 2×CO-NH),
9.51 (s, 1H, NH-DHP), 8.26(s, 1H,=C-OH), 7.22-7.14 (m,
6H, Ar-H), 7.59-7.43 (m, 8H, Ar-H), 5.21 (s, 1H, H4-
DHP), 2.09 (s, 6H, 2×-CH3), 13C-NMR (75 MHz DMSO-
d6) δ (ppm) 167.50, 149.49, 145.32, 141.21, 138.63, 128.91,
128.62, 128.12, 126.31, 121.81, 105.29, 41.37, 32.32, 23.41,
17.91, Anal. Calcd. for C30H31N3O2: C, 77.39; H, 6.71; N,
9.03; found: C, 77.36; H, 6.65; N, 8.97.
Materials and Methods
The Rf-values were determined using aluminum preco-
ated silica gel plates Kiesel 60 F254 from Merck
(Germany). Melting points of the compounds were
measured in open capillaries using Stuart melting point
apparatus (SMP3) and are uncorrected. 1H-NMR
spectra were determined as DMSO solutions at 300
MHz using a Bruker AM-300 spectrophotometer using
TMS as an internal reference. The 13C-NMR spectra
were determined at 75 MHz using a Bruker 75 MHz
NMR in DMSO-d6 solution using TMS as an internal
standard. The elemental analysis was performed on
Leco CHNS-932 Elemental Analyzer (Leco Corporation,
USA). For the synthesis of compounds, all chemicals
were commercially obtained and used without additio-
nal purification.
4-(4-(Dimethylamino)phenyl)-2,6-dimethyl-N3,N5-
diphenyl-1,4-dihydropyridine-3,5-dicarboxamide (6c)
Dark orange crystalline solid, m.p.=248-250ºC, Yield
83%, Rf=0.71 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.40 (s, 2H, 2×CO-NH),
9.52 (s, 1H, NH-DHP), 8.26 (s, 1H,=C-OH), 7.62-7.21
(m,10H, Ar-H), 6.62-6.973 (m, 4H, Ar-H), 5.20 (s,1H, H4-
DHP), 3.08 (s,6H, 2×N-CH3), 2.10 (s, 6H, 2×-CH3),13C-
NMR (75 MHz DMSO-d6) δ (ppm) 167.51 (C=O),
148.49, 147.91, 136.81, 133.72, 128.93, 122.61,112.28,
105.31, 41.34, 17.92, Anal. Calcd. forC29H30N4O2: C,
74.65; H, 6.48; N, 12.01; found: C, 74.61; H, 6.42; N,
11.07.
General procedure for the synthesis of N-arylaceto-
acetamides (3)
A mixture of ethyl acetoacetate (1, 1.3 g, 10 mmol/L),
an aniline (2, 10 mmol/L) and a catalytic amount of
potassium tert-butoxide was taken into a 250 mL round
bottom flask and dissolved in 25 mL of ethanol. The
reaction mixture was heated under reflux for 1 to 1.5
hours. The product was filtered and washed with small
portions of dry ether. Purification was effected by
recrystallization from ethanol to obtain colorless
crystalline solid.
2,6-Dimethyl-N3,N5-diphenyl-4-(p-tolyl)-1,4-dihydro-
pyridine-3,5-dicarboxamide (6d)
Dark orange crystalline solid, m.p.=248-250ºC, Yield
71%, Rf=0.76 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.43 (s, 2H, 2×CO-NH),
9.51 (s, 1H, NH-DHP), 8.26 (s, 1H,=C-OH)7.65- 7.21 (m,
10H, Ar-H), 7.10 (m, Ar-H), 5.21 (s, 1H, H4-DHP), 2.31
(s, 3H), 2.09 (s, 6H, 2×-CH3), 13C-NMR (75 MHz DMSO-
d6) δ (ppm) 167.49 (C=O), 148.49, 141.81, 137.23, 135.94,
128.95, 128.66, 128.37, 128.18, 127.91, 105.32, 41.36, 21.39,
17.94, Anal. Calcd. For C28H27N3O2: C, 76.86; H, 6.22; N,
9.60; found: C, 76.82; H, 6.18; N, 9.57.
General procedure for the synthesis of 4-aryl-2,6-
dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyri-
dines (6a-6h)
A mixture of N-arylacetoacetamide (3, 20 mmol/L), an
appropriate aldehyde (4, 10 mmol/L) and ammonium
acetate (5, 20 mmol/L) in ethanol (25 mL) was heated
under reflux, on a water-bath for 25-35 hours while
monitoring the reaction by TLC. Further purification
was effected by column chromatography using petro-
4-(2,4-Dichlorophenyl)-2,6-dimethyl-N3,N5-diphenyl-
1,4-dihydropyridine-3,5-dicarboxamide (6e)

212
Bangladesh J Pharmacol 2017; 12: 210-215
Dark orange crystalline solid, m.p.=248-250ºC, Yield
89%, Rf=0.66 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.44 (s, 2H, 2×CO-NH),
9.50 (s, 1H, NH-DHP), 8.26, (s, 1H,=C-OH) 7.71-7.15
(m,13H, Ar-H), 5.20 (s, 1H, H4-DHP), 2.09 (s, 6H, 2×-
CH3),13C-NMR (75 MHz DMSO-d6) δ (ppm) 167.51
(C=O), 148.49, 142.12, 136.99, 136.01, 132.03, 131.81,
130.30, 129.09, 128.0, 127.04, 121.67, 121.66, 105.30,
41.32, 17.90, Anal. Calcd. for C27H23Cl2N3O2: C, 65.86; H,
4.71; N, 8.53; found: C, 65.81; H, 4.72; N, 7.58.
quantified by calculating the absorbance at 410 nm. In
general, 0.2 M Tris-HCl buffer (pH 8.0) was prepared
and used for preparing substrate (0.8 mM) N-succinyl-
Ala-Ala-Ala-p-nitroanilide. After that 130 µL of buffer
and 10 µL of compounds was poured in the 96 well
microplate and pate was incubated at 25ºC for 10 min.
After pre-incubation, 10 µL elastase (0.0375 Unit/mL)
enzyme was added and the plate was further incubated
for 30 min at 25ºC. After the final incubation,
absorbance was recorded using microplate reader at
410 nm. The assay was performed in triplicate and % of
inhibition was calculated using following formula:
2,6-Dimethyl-4-(4-phenoxyphenyl)-N3,N5-diphenyl-
1,4-dihydropyridine-3,5-dicarboxamide (6f)
Ab Control - Ab Sample
Dark orange crystalline solid, m.p.=248-250ºC, Yield
88%, Rf= 0.67 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.44 (s, 2H, 2×CO-NH),
9.51 (s, 1H, NH-DHP), 8.26, (s, 1H,=C-OH) 7.63-7.16
(m,15H, Ar-H), 5.22 (s, 1H, H4-DHP), 2.10 (s, 6H, 2×-
CH3),13C-NMR (75 MHz DMSO-d6) δ (ppm) 167.51
(C=O), 156.98, 153.87, 149.23, 137.43, 137.55, 128.84,
128.77, 121.34, 136.99, 136.01, 132.03, 131.81, 130.30,
129.09, 128.0, 127.04, 121.67, 121.66, 105.30, 41.32,
17.90,Anal. Calcd. For C33H29N3O3: C, 76.87; H, 5.67; N,
8.15; found: C, 76.81; H, 5.63; N, 8.09.
Elastase inhibition (%) =
x 100
Ab Control
Oleanolic acid was used as the reference drug for
elastase.
Free radical scavenging assay
Radical scavenging potency of newly elastase inhibitors
was performed by following the already reported
protocol of Larik et al., 2016. The assay mixture
comprised of 100 µL of DPPH (150 µM), and 20 µL of
compounds with increasing doses and the amount of
mixture was fixed to 200 µL in each well with DMSO.
The assay plate was then incubated at room
temperature for 30 min. For comparison, ascorbic acid
(Vitamin C) was used as positive control. The absor-
bance’s were recorded at 517 nm using microplate
reader (OPTI Max, Tunable). The assay was performed
in triplicate and repeated three times.
4-(3-Chlorophenyl)-2,6-dimethyl-N3,N5-diphenyl-1,4-
dihydropyridine-3,5-dicarboxamide (6g)
Dark orange crystalline solid, m.p.=248-250ºC, Yield
84%, Rf=0.81 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.41 (s, 2H, 2×CO-NH),
9.52 (s, 1H, NH-DHP), 8.25 (s, 1H,=C-OH), 7.64-7.23 (m,
14H, Ar-H), 5.19 (s, 1H, H4-DHP),2.08 (s, 6H, 2×-CH3),
13C-NMR (75 MHz DMSO-d6) δ (ppm) 167.50 (C=O),
148.49, 143.63, 138.28, 134.29,130.03, 129.89, 129.39,
128.07, 126.23, 125.98, 121.63, 105.31, 41.29, 17.89, Anal.
Calcd. For C27H24ClN3O2 C, 70.81; H, 5.28; N, 9.18;
found: C, 70.75; H, 5.21; N, 9.13.
Results
The results of synthesized compounds 6a-6h are sum-
marized in Table I. The most derivatives in the series
were found to 6d and 6b. The IC50 value of 6d was 0.2 ±
4-(3-Methoxyphenyl)-2,6-dimethyl-N3,N5-diphenyl-
1,4-dihydropyridine-3,5-dicarboxamide (6h)
Table I
Dark orange crystalline solid, m.p.=248-250ºC, Yield
79%, Rf=0.69 (n-hexane: Ethyl acetate 6:4), 1H-NMR
(DMSO-d6, 300 MHZ); δ (ppm) 10.41 (s, 2H, 2×CO-NH),
9.52 (s, 1H, NH-DHP), 8.23 (s, 1H,=C-OH), 7.61-6.82 (m,
14H,Ar-H), 5.21 (s, 1H, H4-DHP), 3.91 (s, 3H, -OCH3),
2.10 (s, 6H, 2×-CH3), 13C-NMR (75 MHz DMSO-d6) δ
(ppm) 167.51 (C=O), 161.66, 148.49, 142.89, 137.98,
130.04, 128.93, 128.07, 121.88, 119.88, 113.79, 110.91,
105.32, 56.98, 41.35, 17.93, Anal. Calcd. For C28H27N3O3:
C, 74.15; H, 6.00; N, 9.27; found: C, 74.08; H, 5.96; N,
9.21.
Elastase inhibitory activity
Compound
Elastase
IC50 ± SEM
(µM)
%Free radical scaveng-
ing
(100 µg/mL)
6a
6b
6c
6d
6e
6f
6g
6h
Oleanolic
acid
0.9 ± 0.0
0.2 ± 0.0
6.3 ± 0.1
0.2 ± 0.0
5.1 ± 0.2
1.2 ± 0.0
2.05 ± 0.1
0.4 ± 0.0
13.5 ± 0.5
95.7
11.5
12.3
39.8
9.1
6.5
Elastase inhibition activity assay
15.5
15.5
-
The elastase inhibitory potency of synthetic compounds
was determined by Thongyoo et al., 2009 method with
some changes. The quantity of free p-nitroaniline, that
was hydrolyzed by the action of elastase from the
substrate (N-succinyl-Ala-Ala-Ala-p-nitroanilide) was
Vitamin C
-
96.5
Values are expressed as mean ± SEM

Bangladesh J Pharmacol 2017; 12: 210-215
213
Scheme 1: Synthesis of 4-Aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines
0.0 µM and it was found to possess several-fold better
activity than the standard oleanolic acid 13.5 ± 0.5 µM.
The compound 6d showed slightly better inhibition
compared to 6b against the elastase enzyme. The
compound 6d possesses methyl group at para position
of aryl ring while compound 6b bears isopropyl group
at para position of aryl ring. The least potential
derivatives in the series were found to be compound 6c
and 6e. The compound 6c contains N,N-dimethyl group
at para position that might play the role in its least
potential while compound 6e possess chlorine atom at
para position and resulted in its minimum inhibition of
the molecule in the series. All the derivatives showed
moderate to excellent elastase inhibition activity.
Free radical scavenging
Newly synthesized compounds 6a-6h were screened for
their possible radical scavenging potency. Compound
6a showed excellent radical scavenging potency in
comparison to reference drug vitamin
compounds did not show significant radical scavenging
potency even at high concentration (100 µg/mL).
C other
Discussion
For the synthesis of molecules (6a-6h) through a multi-
component reaction, first the N-arylacetoacetamide 3
was synthesized. Ethyl acetoacetate was treated with

214
Bangladesh J Pharmacol 2017; 12: 210-215
aniline using ethanol as a medium giving intermediate
3 (which was light green in color and was confirmed by
mp which was around 98-102ºC) under reflux condi-
tion. The reaction was carried out using catalytic
amount potassium tert-butoxide and mechanism was
no doubt a nucleophilic substitution reaction. Synthesis
of substituted dihydropyridines had been accomplished
by adding of compound 3 with different derivatives of
aldehydes 4, and ammonium acetate 5 with the ratio
(2:1:1) respectively, using dry distilled ethanol at a
temperature around 120-150ºC. Usually, 20-35 hours
were required for the completion of the reaction. Some
by-products were also obtained than the desired pro-
ducts. Hence were purified by column chromatography
and preparative TLC (Scheme 1).
Conclusion
The synthesized compounds 4-aryl-2,6-dimethyl-3,5-bis
-N-(aryl)-carbamoyl-1,4-dihydropyridines showed
significant elastase enzyme inhibition. Compound 6d,
2,6-dimethyl-N3,N5-diphenyl-4-(p-tolyl)-1,4-dihydro-
pyridine-3,5-dicarboxamide was found to possess
remarkable inhibition of elastase, 100-fold better than
the standard drug. The compound 6a displayed most
prominent anti-oxidant activity of the series 6a-6h.
Conflict of Interest
All authors have completed the ICMJE uniform disclosure
form and declare no support from any organization for the
submitted work.
The structures of synthesized DHPs were elucidated by
NMR studies. The 1H-NMR spectrum for 6a showed a
singlet for 1H of amide linked with unsubstituted
benzene moiety at 10.45 ppm whereas secondary amine
residing in a heterocycle moiety resonated at 9.52 ppm.
Moreover, the characteristics peaks for methyl and
tertiary hydrogen in a heterocyclic ring were at 2.10
ppm and 5.22 ppm respectively. All the aromatic
regions protons resonated at the aromatic region from
7.85 ppm to 6.97 ppm. The 13C-NMR of 6a showed
carbonyl of amide at 167.51 ppm while rest of ten
aromatic carbons and three carbons of a hetero cycling
ring showed signals ranging from 148.51 ppm to 41.83
ppm. One carbon for methyl resonated at 17.95 ppm.
The other compounds had been confirmed from their
respective 1H-NMR and 13C-NMR spectra.
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Author Info
Aamer Saeed (Principal contact)
e-mail: aamersaeed@yahoo.com

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