Synthesis and crystallographic insight into the structural aspects of some novel adamantane-based ester derivatives

Article abstract of DOI:10.3390/molecules201018827

Adamantyl-based compounds are commercially important in the treatments for neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their values in drug design are chronicled as multi-dimensional. In the present study, a series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a-q), and 2-(adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone with various carboxylic acids using potassium carbonate in dimethylformamide medium at room temperature. Three-dimensional structures studied using X-ray diffraction suggest that the adamantyl moiety can serve as an efficient building block to synthesize 2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore, three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation of albumin denaturation.

Full text of DOI:10.3390/molecules201018827

Molecules 2015, 20, 18827-18846; doi:10.3390/molecules201018827
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Crystallographic Insight into the Structural
Aspects of Some Novel Adamantane-Based Ester Derivatives
C. S. Chidan Kumar 1,2,*, Huey Chong Kwong 3, Siau Hui Mah 4, Tze Shyang Chia 1,
Wan-Sin Loh 1, Ching Kheng Quah 1,*, Gin Keat Lim 3, Siddegowda Chandraju 5
and Hoong-Kun Fun 1,6
1
X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800,
Malaysia; E-Mails: chiatzeshyang@hotmail.com (T.S.C.); wansin_loh@live.com (W.-S.L.);
hkfun@usm.my (H.-K.F.)
2
Department of Chemistry, Alva’s Institute of Engineering & Technology,
Visvesvaraya Technological University, Mijar, Moodbidri 574225, India
3
School of Chemical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia;
E-Mails: stonekg01@gmail.com (H.C.K.); limgk@usm.my (G.K.L.)
4
School of Biosciences, Taylor’s University, Lakeside Campus, Subang Jaya 47500, Selangor,
Malaysia; E-Mail: siauhui.mah@taylors.edu.my
5
Department of Sugar Technology & Chemistry, University of Mysore, Sir M.V. PG Center,
Mandya 571402, Karnataka, India; E-Mail: chandraju1@yahoo.com
6
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
* Authors to whom correspondence should be addressed; E-Mails: chidankumar@gmail.com (C.S.C.K.);
ckquah@usm.my (C.K.Q.); Tel.: +60-4-653-3888 (ext. 3690) (C.K.Q.);
Fax: +60-4-657-9150 (C.K.Q.).
Academic Editor: Derek J. McPhee
Received: 24 August 2015 / Accepted: 5 October 2015 / Published: 16 October 2015
Abstract: Adamantyl-based compounds are commercially important in the treatments for
neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their
values in drug design are chronicled as multi-dimensional. In the present study, a series of
2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a–q), and 2-(adamantan-1-yl)-2-oxoethyl
2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone
with various carboxylic acids using potassium carbonate in dimethylformamide medium at
room temperature. Three-dimensional structures studied using X-ray diffraction suggest

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that the adamantyl moiety can serve as an efficient building block to synthesize
2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal
packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong
antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore,
three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation
of albumin denaturation.
Keywords: adamantyl; synclinal; crystal packing; antioxidant; anti-inflammatory
1. Introduction
Adamantane is the simplest diamondoid with a chemical formula of C10H16. It consists of four
cyclohexane rings in an armchair configuration. To date, seven adamantane derivatives have been
applied in clinical usage to treat acne vulgaris [1], Alzheimer’s disease [2], as an anti-viral [3–7] and
for type-2 diabetes [8–10], while the others are in development as potential therapeutics for iron
overload disease, neurological conditions, malaria, tuberculosis and cancers [11]. Previous studies on
adamantyl-based compounds revealed their antioxidant and anti-inflammatory properties [12–14]. As a
reactive oxygen species, hydrogen peroxide is generated as a by-product of biological reaction. These
reactive species will cause oxidative damaging effects in living cells. Hydrogen peroxide acts as a
weak oxidizing agent and reacts with Fe2+ or Cu2+ ions to form the hydroxyl radical [15]. Similarly,
free radicals, such as DPPH (2,2-diphenyl-1-picrylhydrazyl), are readily attacked and promote oxidative
damage of biomolecules, such as lipids, proteins and DNA, leading to many human pathological
conditions [16,17]. On the other hand, failure in the downregulation of pro-inflammatory mediators will
result in an imbalance between inflammation and its regulation, which leads to chronic inflammation
due to excessive macrophage responses. The resulting disease conditions from chronic inflammation
include asthma, rheumatic arthritis, atherosclerosis and cancer [18]. Protection against protein denaturation,
a well-documented phenomenon caused by the inflammation process, is the main consideration in
developing non-steroidal anti-inflammatory drugs (NSAIDs) [19].
Encouraged by the biological activities of adamantane derivatives, we herein present FTIR, 1H-NMR
and 13C-NMR spectra and single-crystal X-ray diffraction analysis of some new adamantyl-based ester
derivatives. Using a group comparison of single-crystal X-ray diffraction data, the structural conformation,
structural occupancy and crystal packing similarity were studied. Their antioxidant activities were
evaluated by hydrogen peroxide and the DPPH radical scavenging assay. In addition, the anti-inflammatory
activity of these adamantyl-based ester derivatives was determined by the protein denaturation assay.
2. Results and Discussion
The full reaction involved the synthesis of 1-adamantyl bromomethyl ketone, 1, which is essential for
subsequent synthesis of 2(a–r) in accordance with the reported procedure [20], as shown in Scheme 1.
The structures of the intermediate and final compounds were elucidated by various spectral techniques,
1
like FTIR, H-NMR, 13C-NMR and single-crystal X-ray diffraction analysis. The asymmetric and

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symmetric stretchings of the methyl group (asym 2960 cm−1: sym 2870 cm−1) in 1 had changed to
methylene stretchings (asym 2920 cm−1: sym 2850 cm−1); however, the synthesis of 1 is confirmed by
1H-NMR when the peak corresponding to the methyl group of 1-adamantyl methyl ketone is replaced by
the peak corresponding to the methylene group near δ 4.1 ppm. Esterification of 2(a–r) was confirmed
by FTIR, where the peak corresponding to the hydroxyl of carboxylic acid disappeared. Furthermore,
some peaks were observed at ~1300 cm−1–1020 cm−1, which corresponded to C—O stretching of ester.
1
Similarly, the H-NMR of 2(a–r) displays a singlet corresponding to the methylene group at higher
chemical shifts (δ 5.1 ppm) associated with the other required aromatic peaks. In the FTIR spectra of
2(a–r), the exceptional and predictable observations are the occurrences of N=O stretching in 2(l–m)
and the N—H stretching in 2(o–q) at ~1530 cm−1 and ~3490 cm−1, respectively; whereas for 13C-NMR,
the constant appearances of carbonyl carbons peaks at 207 and 165 ppm further support the formation
of the ester bond in Compounds 2(a–r). The crystal structure for all compounds, except 2m and 2q,
were determined by single-crystal X-ray diffraction analysis. All spectra, crystallography data and crystal
packing are described in detail in the Supplementary Data.
Scheme 1. Reaction scheme for 2(a–r).
2.1. General Description of the Crystal Structure Conformations
The asymmetric unit (Z′) of the studied compounds consists of either one (2c, 2d, 2g, 2h, 2j, 2k,
2n–p and 2r) or two (2a, 2b, 2e, 2f, 2i and 2l) crystallographic independent molecules. For a crystal
with Z′ = 2, the independent molecules are hereafter denoted as Molecules A and B, respectively. The
orientational disorder of the adamantane group is observed in 2a, 2b, 2f, 2j, 2l and 2o with a refined

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site occupancy ratio, as summarized in the table below (Table 1). All disordered components of
adamantane are rotationally-related, and in particular, two-fold rotation disorder (ca. 180°) is observed
in 2a (Molecule B) and 2f (Molecule B).
Table 1. Refined site occupancy ratio for disordered compounds.
Compound
Refined Site Occupancy Ratio
0.390 (10):0.610 (10) (A)
0.695 (4):0.305(4) (B)
0.431 (10):0.569 (10) (A)
0.716 (6):0.284 (6) (A)
0.793 (4):0.207 (4) (B)
0.753 (3):0.247 (3)
2a
2b
2f
2j
2l
0.873 (4):0.127 (4) (B)
0.897 (4):0.103 (4)
2o
Molecular conformation of these compounds can be characterized by three degrees of freedom, which
are the torsion angles of C1—C8—C11—O2 (τ1), C11—C12—O1—C13 (τ2) and O1—C13—C14—C15
(τ3) (Figure 1). Although the torsion angle between the adamantane moiety and the adjacent carbonyl
group (C1—C8—C11—O2, τ1) is one of the degrees of freedom, it was irrelevant for the comparison
due to its randomness and the effect of disordered orientations. By referring to the previous report [20],
torsion angle τ2, which interconnects two carbonyl groups, tends to adopt two types of conformations,
either synclinal or periplanar. However, all structures reported in this study adopt only one conformation
in which τ2 torsion angles are all in synclinal conformation ranging from 70°–86°, which may be due to
the introduction of the bulky adamantane moiety. The range of the O1—C13—C14—C15 τ3 torsion
angle, which defines the twisted angle between the carboxylate group and the six-membered ring,
is relatively larger compared to τ2, ranging from 1.25°–39.08° and 126.4°–179.57°. In compounds 2e
(2,4-dichlorobenzene), 2i (2-methoxybenzene) and 2l (2-nitrobenzene), the τ3 is probably induced by the
steric repulsion between the o-substituent and the adjacent carbonyl oxygen atom. Nevertheless,
exceptional cases are observed in 2b (2-chlorobenzene), 2f (2-methylbenzene) and 2o (2-aminobenzene)
with small deviations of 3.78°, 11.55°, 6.64°, 9.58° and 8.08° from perfect planarity. The amino
substituent at the -ortho position (2o) forms a strong intramolecular N—H···O hydrogen bond with the
adjacent carbonyl group to improve the planarity of the benzoate group (τ3 = 171.92°). Torsion angles
between two carbonyl group (C11—C12—O1—C13, τ2) and torsion angles between the carbonyl group
with its adjacent benzene ring (O1—C13—C14—C15, τ3) of the reported compounds are summarized in
Table 2.
Figure 1. General chemical scheme for all compounds, showing τ1, τ2 and τ3 as torsion angles.

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Table 2. Summary of the C11—C12—O1—C13 and O1—C13—C14—C15 torsion angles.
Torsion Angles
C11—C12—O1—C13, τ2
−81.31, 75.84
78.96, 75.23
73.10
Torsion Angles
Compound
Substituent
O1—C13—C14—C15, τ3
−9.95, 2.84
11.55, −3.78
3.22
2a
2b
2c
2d
2e
2f
Benzene
2-Chlorobenzene
3-Chlorobenzene
4-Chlorobenzene
2,4-Dichlorobenzene
2-Methylbenzene
3-Methylbenzene
4-Methylbenzene
2-Methoxybenzene
3-Methoxybenzene
4-Methoxybenzene
2-Nitrobenzene
73.75
−179.57
−69.7, −85.50
−76.09, 77.77
−72.91
138.13, 135.26
−9.58, 6.64
1.25
2g
2h
2i
75.42
−170.83
−86.12, −79.34
−75.05
39.08, 156.87
−173.58
2j
2k
2l
−76.60
168.36
−70.96, −70.23
73.57
126.4, 130.00
−1.86
2n
2o
2p
2r
4-Nitrobenzene
2-Aminobenzene
3-Aminobenzene
2-Pyridine
−76.5
171.92
77.13
−17.86
−75.07
−17.79, 22.32
2.2. Structural Occupancy and Crystal Packing Similarity
Sixteen present adamantyl-based ester derivatives and thirty-six reported phenacyl benzoate derivatives,
which are found from the Cambridge Structure Database (CSD 5.35) search, are compared to each
other in order to identify the effect of the replacement of the electron-rich phenyl ring (search result)
with the bulky adamantane moiety (present compounds) or vice versa on the molecular conformation
and structural occupancy. In the aspect of molecular conformation, it is noteworthy to observe that
neither periplanar conformation nor mixed (periplanar and synclinal) conformation is adopted by the
currently studied compounds, unlike the variations displayed in phenacyl benzoates. All present
compounds adopt synclinal conformation with C13—O1—C12—C11 torsion angles falling in the
range from 69.7°–86.12°, which is comparable to those previously reported for phenacyl benzoate
derivatives that adopt the same conformation (71°–91°) [20]. The structural occupancies of all present
and reported compounds are listed in Table 3. The structural occupancy of phenacyl benzoate derivatives
has a larger range compared to adamantyl-based ester derivatives and is mostly in between 63% and
69% (30 out of 36). All of the present adamantyl-based compounds are below this range, except 2n
(Figure 2). The existence of the adamantane moiety in the present compounds not only reduces the weak
intermolecular π…π or C—H…π interactions as compared to phenacyl benzoates, it also limits the packing
patterns of adamantyl-based ester derivatives as indicated by the high occurrence of isostructures.

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Table 3. List of the structural occupancy of the present and reported compounds i.
Packing
Packing
Coefficient (%)
63.94
Packing
Compound
Compound
Compound
Coefficient (%)
61.11
Coefficient (%)
64.40
2a
CIXVUC [20]
CIXWAJ [20]
CIXWEN [20]
CIXWIR [20]
CIYCAQ [20]
CIYCEU [20]
CIYCIY [20]
CIYCOE [20]
CIYFUN [20]
CIYGAU [20]
EVAFOX [31]
EVAJAN [33]
EVAJIV [35]
EVAZEH [37]
EVEGIW [39]
EVEGOC [41]
EVEVEH [44]
GARCEJ [46]
GITHUN [21]
MANGIR [22]
OBOYIP [23]
OCAKUA [24]
OCAQUG [25]
OCEFEJ [26]
PECZAA [27]
PODQIK [28]
PODRAD [29]
USIWID [30]
USIWOJ [32]
VOBYUI [34]
YAFWEJ [36]
YAFZAI [38]
YAHGUL [40]
YAHYOX [42]
2b
61.32
64.33
61.06
2c
62.33
62.08
67.22
2d
62.53
63.98
63.92
2e
60.79
67.27
66.98
2f
60.97
65.07
68.55
2g
61.68
68.83
64.37
2h
61.02
62.96
60.66
2i
61.58
62.38
63.77
2j
61.08
64.89
62.53
2k
61.07
68.00
66.04
2l
61.85
65.64
63.97
2n
63.05
64.03
66.25
2o
61.24
63.03
68.65
2p
2r
61.81
63.25
63.55
60.61
63.22
63.37
AZULUD [43]
63.85
64.07
63.04
CIQNEW [45]
65.80
i
Each reported compound is represented by the Cambridge Crystallographic Data Centre (CCDC) reference
code, and its systematic name is provided in the Supplementary Materials.
Figure 2. Structural occupancy comparison of the present and reported compounds.
In the investigation of the crystal structural similarity among the current compounds, there are four pairs
of compounds (2a/2f, 2c/2g, 2h/2k and 2d/2n) found, and each pair is crystallized in the same space group
with similar lattice constants, which are two main characteristics of 3D structural similarity. Indeed,
these four pairs of compounds show isostructural relationships with a similar packing pattern, as shown
in their overlaid crystal structure diagrams (Figures 3–6, respectively). Besides that, 2D similarities are

Molecules 2015, 20
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observed in 2b/2a and 2b/2f, while Compounds 2c, 2d, 2g and 2n show 2D similarity among each
other (Figure 7).
Figure 3. Crystal packing comparison of Compounds 2a and 2f.
Figure 4. Crystal packing comparison of Compounds 2c and 2g.

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Figure 5. Crystal packing comparison of Compounds 2h and 2k.
Figure 6. Crystal packing comparison of Compounds 2d and 2n.
Figure 7. Crystal packing relationship in some studied compounds. Red boxes and yellow
arrows indicate 3D and 2D similarities, respectively.

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2.3. Antioxidant and Anti-Inflammatory Properties
The antioxidant properties of adamantane-based compounds were determined by two methods, which
are hydrogen peroxide and DPPH radicals scavenging abilities. The scavenging effects of hydrogen
peroxide by the adamantyl-based compounds were evaluated at a concentration of 250 μg/mL and are
summarized in Figure 8. Eleven adamantane derivatives show positive scavenging effects on H2O2.
Compound 2b possesses the strongest scavenging activity, which is 48.55%, followed by Compounds 2q
and 2g with 42.96% and 42.56%, respectively. The scavenging activities of these compounds are
comparable to the standard compound, ascorbic acid, with an inhibition percentage of 43.38%. On the
other hand, adamantyl-based compounds did not show positive DPPH radical scavenging properties at
a concentration of 1000 μg/mL. The results show that adamantane derivatives are selective to the
inhibition of hydrogen peroxide radicals.
Figure 8. Hydrogen peroxide radical scavenging. The data represent the percentage of
hydrogen peroxide radical inhibition (mean ± SD), and experiments were performed
in triplicate.
The anti-inflammatory effects of adamantyl-based compounds at a concentration of 250 μg/mL were
evaluated by the protein denaturation assay. The results of the percentage of inhibition against protein
denaturation are presented in Figure 9. Compounds 2p, 2q and 2r are strong protein denaturation
inhibitors with inhibition percentages of 41.92%, 43.94% and 40.91%, respectively, which are better
than the standard drug, diclofenac sodium, with an inhibition percentage of 37.88%. These three
compounds consist of either an amino-substituted phenyl ring or a pyridine ring. Hence, the high
inhibition effects are deduced to be the direct contribution from the nitrogen-containing group in
adamantyl-based compounds.

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Figure 9. Inhibition of protein denaturation. The data represent the percentage of hydrogen
peroxide radical inhibition (mean ± SD), and experiments were performed in triplicate.
3. Experimental Section
The reagents and solvents for the synthesis work were obtained commercially from Sigma Aldrich
Corporation (St. Louis, MO, USA) and used without any additional purification. Melting points were
1
13
determined on a Stuart (Staffordshire, UK) SMP10 apparatus. H and C nuclear magnetic resonance
(NMR) spectra were determined in CDCl3 at 500 MHz and 125 MHz, respectively, using a Bruker
Advance III 500 spectrometer (Bruker Corporation, Billerica, MA, USA). Fourier transform infrared
spectroscopy (FTIR) spectra were recorded on a Perkin Elmer Frontier FTIR spectrometer (PerkinElmer,
Inc., Waltham, MA, USA) equipped with attenuated total reflection (ATR).
The X-ray analysis for all samples was performed using a Bruker APEX II DUO CCD diffractometer
(Bruker Corporation) employing MoKα radiation (λ = 0.71073 Å) with φ and ω scans. X-ray data for
all compounds were collected at room temperature. Data reduction and absorption correction were
performed using the SAINT and SADABS program [47]. All structures were solved by the direct
method and refined by full-matrix least-squares techniques on F2 using the SHELXTL software
package [48]. All non-hydrogen atoms were refined anisotropically, except for the minor disordered
components of 2l and 2o with a site occupancy of less than 0.2. The C-bound H atoms were calculated
geometrically with isotropic displacement parameters set to 1.2-times the equivalent isotropic U value of
the parent carbon atoms. N-bound H atoms are located by the difference Fourier map and refined freely
(N—H = 0.77 (5)—0.87 (6) Å). A similar geometry restraint (SAME) was applied to the disordered
adamantane moiety in 2f and 2o and also the full molecule in 2r. Packing coefficient (%)/structure
occupancy was calculated using the Olex2 program with the command (-calcvoid) [49]. Crystallographic
data for the structures reported in this paper (2a–r, excluding 2m and 2q) have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as supplementary publication. CCDC 1030854–1030869
contain the supplementary crystallographic data for this paper. These data can be obtained free of charge

Molecules 2015, 20
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via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
3.1. Synthesis
1-Adamantyl methyl ketone was refluxed with N-bromo succinimide and petroleum ether in methanol
at 333 K for two hours. The resultant 1-adamantyl bromomethyl ketone (1) precipitate was filtered and
recrystallized with ethanol. After that, 1-adamantyl bromomethyl ketone (1) (0.51 g, 0.002 mol) was
reacted with the corresponding carboxylic acid (0.003 mol) with the presence of potassium carbonate
in DMF (8 mL) and stirred at room temperature for about 3 h. The reaction progress was monitored by
thin layer chromatography (TLC). After the reaction completed, the reaction mixture was poured into
ice-cooled water and kept stirring for 10 min. The solid obtained was filtered out, washed successively
with distilled water and recrystallized from acetone after it dried [20]. All targeted compounds were
synthesized in good yield and high purity. Suitable single-crystal specimens were obtained from various
types of solvents, as described below. The chemical structures were characterized by using FTIR and
NMR spectroscopies. The crystal structures for all compounds except 2m and 2q were determined by
single-crystal X-ray diffraction analysis.
3.2. Spectroscopic Details
1-Adamantyl bromomethyl ketone (1): Solvent for growing crystal: ethanol; yield: 85%; M.P. 326–328 K;
FTIR (ATR (solid) cm−1): 2905, 2851 (C–H, ν), 1709 (C=O, ν), 1254, 1094, 1063 (C–O, ν), 733 (C–Cl,
ν); 1H-NMR (500 MHz, CDCl3): δ ppm 4.18 (s, 2H, -CH2), 2.09 (br-s, 3H, adamantane-CH), 1.91–1.90
13
(br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2); C-NMR (125 MHz, CDCl3):
δ ppm 205.57 (C=O), 46.62 (-CH2), 38.53, 36.34, 31.83, 27.83 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl benzoate (2a): Solvent for growing crystal: acetone; yield: 80%; M.P.
374–376 K; FTIR (ATR (solid) cm−1): 2917, 2850 (C–H, ν), 1709 (C=O, ν), 1602, 1413 (Ar, C=C, ν),
1277, 1120 (C–O, ν), 706 (C–H, ω); 1H-NMR (500 MHz, CDCl3): δ ppm 8.10–8.08 (d, 2H, J = 7.5 Hz,
Ar), 7.58–7.55 (t, 1H, J = 7.5 Hz, Ar), 7.46–7.42 (t, 2H, J = 7.5 Hz, Ar), 5.10 (s, 2H, -CH2), 2.08(br-s,
3H, adamantane-CH), 1.94–1.93 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2);
13C-NMR (125 MHz, CDCl3): δ ppm 207.16 (C=O), 166.04 (O-C=O), 133.19, 129.87, 129.58, 128.37
(Ar), 64.94 (-CH2), 45.39, 38.02, 36.47, 27.79 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 2-chlorobenzoate (2b): Solvent for growing crystal: acetone and ethanol
(1: 1 v/v); yield: 83%; M.P. 348–350 K; FTIR (ATR (solid) cm−1): 2904, 2850 (C–H, ν), 1709 (C=O, ν),
1
1590, 1416 (Ar, C=C, ν), 1247, 1024 (C–O, ν), 742 (C–Cl, ν); H-NMR (500 MHz, CDCl3): δ ppm
8.01–8.00 (d, 1H, J = 8.0 Hz, Ar), 7.47–7.43 (q, 2H, J = 8.0 Hz, Ar), 7.35–7.32 (t, 1H, J = 8.0 Hz, Ar),
5.12 (s, 2H, -CH2), 2.09 (br-s, 3H, adamantane-CH), 1.93–1.93 (br-d, 6H, adamantane-CH2), 1.80–1.72
(br-q, 6H, adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm 206.98 (C=O), 164.89 (O-C=O), 133.98,
132.84, 131.95, 131.03, 129.35, 126.62 (Ar), 65.18(-CH2), 45.38 37.99, 36.44, 27.75 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 3-chlorobenzoate (2c): Solvent for growing crystal: acetone, ethanol and
acetonitrile (1:1:1 v/v/v); yield: 73%; M.P. 403–405 K; FTIR (ATR (solid) cm−1): 2911, 2850 (C–H, ν),

Molecules 2015, 20
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1718 (C=O, ν), 1571, 1442 (Ar, C=C, ν), 1295, 1253, 1130 (C–O, ν), 745 (C–Cl, ν); 1H-NMR (500 MHz,
CDCl3): δ ppm 8.07 (s, 1H, Ar), 7.98–7.96 (d, 1H, J = 8.0 Hz, Ar), 7.55–7.54 (d, 1H, J = 8.0 Hz, Ar),
7.41–7.38 (t, 1H, J = 8.0 Hz, Ar), 5.11 (s, 2H, -CH2), 2.09 (br-s, 3H, adamantane-CH), 1.93–1.93 (br-d,
6H, adamantane-CH2), 1.800–1.719 (br-q, 6H, adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm
206.94 (C=O), 164.88 (O-C=O), 134.56, 133.27, 131.27, 129.95, 129.73, 128.01 (Ar), 65.23(-CH2), 45.37,
37.98, 36.43, 27.74 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 4-chlorobenzoate (2d): Solvent for growing crystal: acetone, ethanol and
acetonitrile (1:1:1 v/v/v); yield: 75%; M.P. 411–413 K; FTIR (ATR (solid) cm−1): 2910, 2851 (C–H, ν),
1
1723 (C=O, ν), 1593, 1421 (Ar, C=C, ν), 1269, 1119 (C–O, ν), 752 (C–Cl, ν); H-NMR (500 MHz,
CDCl3): δ ppm 8.03–8.01 (d, 2H, J = 8.8 Hz, Ar), 7.43–7.41 (d, 2H, J = 8.8 Hz, Ar), 5.09 (s, 2H,
-CH2), 2.08 (br-s, 3H, adamantane-CH), 1.93–1.92 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H,
adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm 207.07 (C=O), 165.19 (O-C=O), 139.71, 131.27,
128.76, 128.01 (Ar), 65.11(-CH2), 45.37, 37.99, 36.43, 27.75 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 2,4-dichlorobenzoate (2e): Solvent for growing crystal: acetone; yield:
85%; M.P. 395–397 K; FTIR (ATR (solid) cm−1): 2912, 2850 (C–H, ν), 1711 (C=O, ν), 1583, 1417
1
(Ar, C=C, ν), 1244, 1129, 1098, 1023 (C–O, ν), 829 (C–Cl, ν); H-NMR (500 MHz, CDCl3): δ ppm
7.98–7.96 (d, 1H, J = 8.5 Hz, Ar), 7.48 (s, 1H, Ar), 7.33–7.31 (d, 1H, J = 8.5 Hz, Ar), 5.11 (s, 2H,
-CH2), 2.09 (br-s, 3H, adamantane-CH), 1.93–1.92 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H,
adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm 206.86 (C=O), 164.01 (O-C=O), 138.66,
135.20, 133.00, 131.00, 127.62, 127.06 (Ar), 65.30(-CH2), 45.38, 37.98, 36.42, 27.73 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 2-methylbenzoate (2f): Solvent for growing crystal: acetone; yield:
83%; M.P. 367–369 K; FTIR (ATR (solid) cm−1): 2905, 2851 (C–H, ν), 1708 (C=O, ν), 1602, 1415
1
(Ar, C=C, ν), 1253, 1026 (C–O, ν), 733 (C–H, ω); H-NMR (500 MHz, CDCl3): δ ppm 8.02–8.00 (d,
1H, J = 8.0 Hz, Ar), 7.42–7.39 (t, 1H, J = 8.0 Hz, Ar), 7.25–7.24 (m, 2H, Ar), 5.09 (s, 2H, -CH2),
2.09 (br-s, 3H, adamantane-CH), 1.94–1.94 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H,
adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm 207.41 (C=O), 166.98 (O-C=O), 140.43,
132.19, 131.58, 130.89, 129.06, 125.72 (Ar), 64.74 (-CH2), 45.37, 38.03, 36.47, 27.78 (adamantane-Cs),
21.60 (-CH3).
2-(Adamantan-1-yl)-2-oxoethyl 3-methylbenzoate (2g): Solvent for growing crystal: acetone, ethanol and
acetonitrile (1:1:1 v/v/v); yield: 75%; M.P. 372–374 K; FTIR (ATR (solid) cm−1): 2902, 2848 (C–H, ν),
1
1724 (C=O, ν), 1588, 1421, (Ar, C=C, ν), 1302, 1279, 1195, 1109 (C–O, ν), 740 (C–H, ω); H-NMR
(500 MHz, CDCl3): δ ppm 7.91 (s, 1H, Ar), 7.89–7.88 (d, 2H, J = 7.5 Hz, Ar), 7.39–7.37 (d, 1H,
J = 7.5 Hz, Ar), 7.35–7.32 (t, 1H, J = 7.5 Hz Ar), 5.09 (s, 2H, -CH2), 2.08 (br-s, 3H, adamantane-CH),
1.94–1.93 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2); 13C-NMR (125 MHz,
CDCl3): δ ppm 207.32 (C=O), 166.25 (O-C=O), 138.17, 134.00, 130.39, 129.44, 128.29, 127.04 (Ar),
64.91 (-CH2), 45.39, 38.01, 36.47, 27.78 (adamantane-Cs), 21.26 (-CH3).
2-(Adamantan-1-yl)-2-oxoethyl 4-methylbenzoate (2h): Solvent for growing crystal: acetone; yield: 81%;
M.P. 413–415 K; FTIR (ATR (solid) cm−1): 2902, 2853 (C–H, ν), 1714 (C=O, ν), 1610, 1418, (Ar,

Molecules 2015, 20
18839
C=C, ν), 1258, 1115, (C–O, ν), 747 (C–H, ω); 1H-NMR (500 MHz, CDCl3): δ ppm 7.98–7.97 (d, 2H,
J = 8.0 Hz, Ar), 7.25–7.23 (d, 2H, J = 8.0 Hz, Ar), 5.08 (s, 2H, -CH2), 2.41 (s, 3H, -CH3), 2.08 (br-s, 3H,
adamantane-CH), 1.93–1.93 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2);
13C-NMR (125 MHz, CDCl3): δ ppm 207.37 (C=O), 166.12 (O-C=O), 143.93, 129.92, 129.10, 126.80
(Ar), 64.82 (-CH2), 45.39, 38.01, 36.47, 27.79 (adamantane-Cs), 21.70 (-CH3).
2-(Adamantan-1-yl)-2-oxoethyl 2-methoxybenzoate (2i): Solvent for growing crystal: acetone and ethanol
(1: 1 v/v); yield: 80%; M.P. 362–364 K; FTIR (ATR (solid) cm−1): 2902, 2851 (C–H, ν), 1702 (C=O, ν),
1599, 1442 (Ar, C=C, ν), 1248, 1096, 1020 (C–O, ν), 758 (C–H, ω); 1H-NMR (500 MHz, CDCl3): δ ppm
7.97–7.95 (d, 1H, J = 8.5 Hz, Ar), 7.50–7.47 (t, 1H, J = 8.5 Hz, Ar), 7.01–6.97 (t, 2H, J = 8.5 Hz, Ar), 5.07
(s, 2H, -CH2), 3.91 (s, 3H, -CH3), 2.07 (br-s, 3H, adamantane-CH), 1.93–1.93 (br-d, 6H, adamantane-CH2),
13
1.79–1.71 (br-q, 6H, adamantane-CH2); C-NMR (125 MHz, CDCl3): δ ppm 207.41 (C=O), 165.23
(O-C=O), 159.52, 133.90, 132.21, 120.17, 119.19, 111.99 (Ar), 64.72 (-CH2), 56.03 (-CH3), 45.38,
38.01, 36.48, 27.79 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 3-methoxybenzoate (2j): Solvent for growing crystal: acetone and ethanol
(1: 1 v/v); Yield: 74%; M.P. 430–432 K; FTIR (ATR (solid) cm−1): 2926, 2853 (C–H, ν), 1711 (C=O, ν),
1
1584, 1489 (Ar, C=C, ν), 1288, 1221, 1029 (C–O, ν), 759 (C–H, ω). H-NMR (500 MHz, CDCl3):
δ ppm 7.70–7.68 (d, 1H, J = 8.0 Hz, Ar), 7.60 (s, 1H, Ar), 7.37–7.33 (t, 1H, J = 8.0 Hz, Ar), 7.13–7.11
(m, 1H, Ar), 5.09 (s, 2H, -CH2), 3.85 (s, 3H, -CH3), 2.08 (br-s, 3H, adamantane-CH), 1.94–1.93 (br-d,
13
6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2); C-NMR (125 MHz, CDCl3): δ ppm
207.18 (C=O), 165.96 (O-C=O), 159.56, 130.79, 129.42, 122.35, 120.04, 114.05 (Ar), 65.04 (-CH2),
55.44 (-CH3), 45.39, 38.01, 36.46, 27.77 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 4-methoxybenzoate (2k): Solvent for growing crystal: acetone and
ethanol (1: 1 v/v); yield: 80%; M.P. 390–392 K; FTIR (ATR (solid) cm−1): 2903, 2851 (C–H, ν), 1710
1
(C=O, ν), 1605, 1417 (Ar, C=C, ν), 1253, 1167, 1028 (C–O, ν), 767 (C–H, ω); H-NMR (500 MHz,
CDCl3): δ ppm 8.05–8.04 (d, 2H, J = 9.0 Hz, Ar), 6.93–6.91 (d, 2H, J = 9.0 Hz Ar), 5.07 (s, 2H,
-CH2), 3.86 (s, 3H, -CH3), 2.08 (br-s, 3H, adamantane-CH), 1.93–1.93 (br-d, 6H, adamantane-CH2),
13
1.80–1.72 (br-q, 6H, adamantane-CH2); C-NMR (125 MHz, CDCl3): δ ppm 207.54 (C=O), 165.77
(O-C=O), 163.61, 131.96, 121.94, 113.66 (Ar), 64.73 (-CH2), 55.44 (-CH3), 45.39, 38.02, 36.47,
27.79 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 2-nitrobenzoate (2l): Solvent for growing crystal: acetone, ethanol and
acetonitrile (1:1:1 v/v/v); yield: 70%; M.P. 391–393 K; FTIR (ATR (solid) cm−1): 2919, 2850 (C–H, ν),
1731 (C=O, ν), 1579, 1450 (Ar, C=C, ν), 1535, 1353 (N–O, ν), 1290, 1132, 1079 (C–O, ν), 732 (C–H, ω);
1H-NMR (500 MHz, CDCl3): δ ppm 7.97–7.95 (d, 1H, J = 7.5 Hz, Ar), 7.94–7.92 (d, 1H, J = 7.5 Hz Ar),
7.73–7.70 (t, 1H, J = 7.5 Hz, Ar), 7.66–7.63 (t, 1H, J = 7.5 Hz, Ar), 5.12 (s, 2H, -CH2), 2.09 (br-s, 3H,
adamantane-CH), 1.92(br-s, 6H, adamantane-CH2), 1.78–1.74 (br-d, 6H, adamantane-CH2); 13C-NMR
(125 MHz, CDCl3): δ ppm 206.75 (C=O), 164.97 (O-C=O), 147.74, 133.17, 131.78, 130.35, 127.46,
123.94 (Ar), 65.92 (-CH2), 45.39, 37.95, 36.41, 27.72 (adamantane-Cs).

Molecules 2015, 20
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2-(Adamantan-1-yl)-2-oxoethyl 3-nitrobenzoate (2m): yield: 72%; M.P. 385–387 K; FTIR (ATR
(solid) cm−1): 3092 (Ar, C–H, ν), 2917, 2851 (C–H, ν), 1727 (C=O, ν), 1631, 1421 (Ar, C=C, ν), 1533,
1
1347 (N–O, ν), 1297, 1261, 1131 (C–O, ν), 716 (C–H, ω); H-NMR (500 MHz, CDCl3): δ ppm 8.92
(s, 1H, Ar), 8.45–8.43 (d, 1H, J = 8.1 Hz, Ar), 8.42–8.40 (d, 1H, J = 8.1 Hz, Ar), 7.69–7.65 (t, 1H,
J = 8.1 Hz, Ar), 5.17 (s, 2H, -CH2), 2.10 (br-s, 3H, adamantane-CH), 1.94 (br-s, 6H, adamantane-CH2),
13
1.79–1.76 (br-d, 6H, adamantane-CH2); C-NMR (125 MHz, CDCl3): δ ppm 206.60 (C=O), 164.00
(O-C=O), 148.31, 135.52, 131.35, 129.67, 127.66, 124.92 (Ar), 65.61 (-CH2), 45.39, 37.99, 36.42,
27.74 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 4-nitrobenzoate (2n): Solvent for growing crystal: acetone, ethanol and
acetonitrile (1:1:1 v/v/v); yield: 76%; M.P. 437–439 K; FTIR (ATR (solid) cm−1): 3112 (Ar, C–H, ν),
2905, 2854 (C–H, ν), 1723 (C=O, ν), 1606, 1422 (Ar, C=C, ν), 1530, 1344 (N–O, ν), 1283, 1118
1
(C–O, ν), 714 (C–H, ω); H-NMR (500 MHz, CDCl3): δ ppm 8.31–8.29 (d, 2H, J = 8.5 Hz, Ar),
8.27–8.25 (d, 2H, J = 8.5 Hz Ar), 5.16 (s, 2H, -CH2), 2.10 (br-s, 3H, adamantane-CH), 1.94 (br-s, 6H,
adamantane-CH2), 1.81–1.73 (br-q, 6H, adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm
206.61 (C=O), 164.21 (O-C=O), 150.72, 134.97, 131.00, 123.56 (Ar), 65.61 (-CH2), 45.40, 37.99,
36.41, 27.73 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 2-aminobenzoate (2o): Solvent for growing crystal: acetone, ethanol
and acetonitrile (1:1:1 v/v); yield: 76%; M.P. 440–442 K; FTIR (ATR (solid) cm−1): 3497, 3373 (N–H, ν),
2902, 2848 (C–H, ν), 1695 (C=O, ν), 1613, 1418 (Ar, C=C, ν), 1581 (N–H, δ), 1243, 1104 (C–O, ν),
1
746 (C–H, ω); H-NMR (500 MHz, CDCl3): δ ppm 7.95–7.94 (d, 1H, J = 8.3 Hz, Ar), 7.29–7.26
(t, 1H, J = 8.3 Hz Ar), 6.67–6.64 (m, 2H, Ar), 5.07 (s, 2H, -CH2), 2.08 (br-s, 3H, adamantane-CH),
1.93 (br-s, 6H, adamantane-CH2), 1.80–1.72 (br-d, 6H, adamantane-CH2); 13C-NMR (125 MHz,
CDCl3): δ ppm 207.64 (C=O), 167.29 (O-C=O), 150.52, 134.38, 131.63, 116.67, 116.41, 110.34 (Ar),
64.46 (-CH2), 45.38, 38.05, 36.47, 27.79 (adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 3-aminobenzoate (2p): Solvent for growing crystal: acetone, ethanol
and acetonitrile (1:1:1 v/v/v); yield: 70%; M.P. 396–398 K; FTIR (ATR (solid) cm−1): 3465, 3347
(N–H, ν), 2902, 2849 (C–H, ν), 1700 (C=O, ν), 1631, 1461 (Ar, C=C, ν), 1603 (N–H, δ), 1248, 1113
(C–O, ν), 751 (C–H, ω); 1H-NMR (500 MHz, CDCl3): δ ppm 7.50–7.49 (d, 1H, J = 7.9 Hz, Ar), 7.42
(s, 1H, Ar), 7.24–7.21 (t, 1H, J = 7.9 Hz, Ar), 6.91–6.89 (d, 1H, J = 7.9 Hz, Ar), 5.08 (s, 2H, -CH2),
2.08 (br-s, 3H, adamantane-CH), 1.93–1.92 (br-d, 6H, adamantane-CH2), 1.79–1.72 (br-q, 6H,
adamantane-CH2); 13C-NMR (125 MHz, CDCl3): δ ppm 207.36 (C=O), 166.17 (O-C=O), 145.98,
130.49, 129.34, 120.42, 119.99, 116.28 (Ar), 64.91 (-CH2), 45.39, 38.00, 36.46, 27.77(adamantane-Cs).
2-(Adamantan-1-yl)-2-oxoethyl 4-aminobenzoate (2q): yield: 76%; M.P. 428–430 K; FTIR (ATR
(solid) cm−1): 3493, 3362 (N–H, ν), 2906, 2850 (C–H, ν), 1697 (C=O, ν), 1619, 1414 (Ar, C=C, ν),
1
1600 (N–H, δ), 1276, 1118 (C–O, ν), 768 (C–H, ω); H-NMR (500 MHz, CDCl3): δ ppm 7.91–7.89
(d, 2H, J = 8.5 Hz, Ar), 6.65–6.63 (d, 2H, J = 8.5 Hz, Ar), 5.04 (s, 2H, -CH2), 2.07 (br-s, 3H,
adamantane-CH), 1.93–1.92 (br-d, 6H, adamantane-CH2), 1.79–1.71 (br-q, 6H, adamantane-CH2);
13C-NMR (125 MHz, CDCl3): δ ppm 207.90 (C=O), 166.03 (O-C=O), 151.08, 132.00, 119.04, 113.92
(Ar), 64.50 (-CH2), 45.57, 38.02, 36.60, 27.77 (adamantane-Cs).

Molecules 2015, 20
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2-(Adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate (2r): Solvent for growing crystal: acetone,
ethanol and acetonitrile (1:1:1 v/v/v); yield: 76%; M.P. 402–404 K; FTIR (ATR (solid) cm−1): 2903,
2849 (C–H, ν), 1707 (C=O, ν), 1582, 1419 (Ar, C=C, ν), 1304 (C–N, ν) 1242, 1128 (C–O, ν), 745 (C–H,
ω); 1H-NMR (500 MHz, CDCl3): δ ppm 8.79–8.78 (d, 1H, J = 4.7 Hz, Ar), 8.19–8.17 (d, 1H, J = 4.7 Hz,
Ar), 7.88–7.86 (t, 1H, J = 4.7 Hz, Ar), 7.52–7.50 (q, 1H, J = 4.7 Hz, Ar), 5.20 (s, 2H, -CH2), 2.09 (br-s,
3H, adamantane-CH), 1.93–1.93 (br-d, 6H, adamantane-CH2), 1.80–1.72 (br-q, 6H, adamantane-CH2);
13C-NMR (125 MHz, CDCl3): δ ppm 206.36 (C=O), 164.54 (O-C=O), 149.86, 147.41, 137.12, 127.18,
125.53 (Ar), 65.70 (-CH2), 45.31, 37.99, 36.44, 27.75 (adamantane-Cs).
3.3. Bioactivity Methods
3.3.1. Hydrogen Peroxide Radical Scavenging Assay
The abilities of adamantyl-based compounds to scavenge hydroxyl radical were determined by
following the method of [50] with some modifications. The solution of hydrogen peroxide (40 mM)
was prepared in PBS (phosphate-buffered saline). The adamantyl-based derivatives with a concentration
of 250 μg/mL were prepared in PBS and added to 0.6 mL of hydrogen peroxide solution. The mixture
was mixed well and incubated at room temperature for 10 min. The absorbance was determined at
230 nm by using a spectrophotometer. Ascorbic acid was used as a standard drug, while PBS was used
as the blank. The percentage of hydrogen peroxide scavenging activity was calculated by using the
following formula:
Absorbance of control − Absorbance of sample
Percentage of scavenging activity =
×100
(1)
Absorbance of control
3.3.2. DPPH Radical Scavenging Assay
The DPPH radical scavenging assay was used to evaluate the antioxidant properties of the
adamantyl-based compounds. This assay was carried out following the method of [51]. The DPPH
solution (0.16 mM) was prepared in ethanol. The adamantyl-based derivatives were prepared in ethanol
with concentrations of 250, 500 and 1000 μg/mL. Approximately 100 μL of each adamantyl-based
derivative were mixed with 100 μL of DPPH solution in a 96-well plate. Each sample and the control
were prepared in triplicate. The plate was then incubated in a dark room at room temperature for
30 min, and the absorbance was measured at 517 nm with a microplate reader. Ascorbic acid was used
as a standard drug. The percentage of DPPH free radical scavenging activity was calculated by using
the following formula:
Absorbanceof blank − Absorbanceof sample
Percentage of scavenging activity =
×100
(2)
Absorbanceof blank
3.3.3. Protein Denaturation Assay
Adamantyl-based compounds were tested on egg albumin to observe their anti-inflammatory activity
against protein denaturation. The assay was performed following the method described by [52] with
some modifications. The 2.5 mL of reaction mixture consisted of 0.1 mL of egg albumin, 1.4 mL of PBS

Molecules 2015, 20
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and 1 mL of adamantyl-based derivatives with a concentration of 250 μg/mL. A similar volume of PBS
with egg albumin was used as the control. The mixture solutions were incubated at 37 °C for 15 min and
then heat in a water bath at 70 °C for 5 min. After cooling to room temperature, the absorbance was
measured at 660 nm using a microplate reader. Diclofenac sodium was used as the standard drug. The
percentage of inhibition of protein denaturation was calculated by using the following formula:
Absorbance of control − Absorbance of sample
Percentage of scavenging activity =
4. Conclusions
×100
(3)
Absorbance of control
A series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a–q), and 2-(adamantan-1-yl)-2-oxoethyl
2-pyridinecarboxylate, 2r, were synthesized and structurally characterized by FTIR, NMR and
single-crystal X-ray diffraction analysis. Introduction of the adamantane moiety into the synthesis of
2-oxopropyl benzoate derivatives produced all molecular structures in synclinal conformation. In crystals,
molecules are commonly packed in a head-to-tail (adamantane moiety to phenyl moiety) pattern. These
similarities lead to redundant 2D or 3D structural similarity in adamantane-based ester derivatives. The
adamantyl-based compounds show selective antioxidant abilities and good hydrogen peroxide radical
scavenging activities, especially 2-(adamantan-1-yl)-2-oxoethyl 2-chlorobenzoate, which outperformed
the standard compound. Besides that, three nitrogen-containing adamantane compounds, 2p, 2q and 2r,
show strong anti-inflammatory effects towards protein denaturation, which performed better than
diclofenac sodium. Thus, further modifications of adamantane compounds with nitrogen-containing
groups can potentially produce promising anti-inflammatory agents for clinical use in the future.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/10/18827/s1.
Acknowledgments
The authors thank the Malaysian Government and Universiti Sains Malaysia (USM) for the
Research University Individual Grant (1001/PFIZIK/811278). CSCK thanks USM for a postdoctoral
research fellowship (2013–2015). HCK and WSL thank the Malaysian Government for the MyBrain15
(MyPhD) scholarship.
Author Contribution
C.S.C.K. conceived of and designed the experiments. C.S.C.K. and H.C.K. performed the
experiments. C.S.C.K., H.C.K., T.S.C., W.S.L., C.K.Q., G.K.L., S.C. and H.K.F. analyzed the data.
S.H.M. performed the bioassays (antioxidant and anti-inflammatory). C.K.Q. contributed reagents/
materials/analysis tools. All authors wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.

Molecules 2015, 20
18843
References
1. Piérard, G.E.; Piérard-Franchimont, C.; Paquet, P.; Quatresooz, P. Spotlight on adapalene.
Expert Opin. Drug Metab. Toxicol. 2009, 5, 1565–1575.
2. Reisberg, B.; Doody, R.; Stöffler, A.; Schmitt, F.; Ferris, S.; Möbius, H.J. Memantine in
moderate-to-severe alzheimer’s disease. N. Engl. J. Med. 2003, 348, 1333–1341.
3. Rosenthal, K.S.; Sokol, M.S.; Ingram, R.L.; Subramanian, R.; Fort, R.C. Tromantadine: Inhibitor
of early and late events in herpes simplex virus replication. Antimicrob. Agents Chemother. 1982, 22,
1031–1036.
4. Kelly, J.M.; Miles, M.A.; Skinner, A.C. The anti-influenza virus drug rimantadine has trypanocidal
activity. Antimicrob. Agents Chemother. 1999, 43, 985–987.
5. De Clercq, E. Antiviral agents active against influenza a viruses. Nat. Rev. Drug Discov. 2006, 5,
1015–1025.
6. Cady, S.D.; Luo, W.; Hu, F.; Hong, M. Structure and function of the influenza a M2 proton
channel. Biochemistry 2009, 48, 7356–7364.
7. Zoidis, G.; Kolocouris, N.; Kelly, J.M.; Prathalingam, S.R.; Naesens, L.; de Clercq, E. Design and
synthesis of bioactive adamantanaminoalcohols and adamantanamines. Eur. J. Med. Chem. 2010,
45, 5022–5030.
8. Von Geldern, T.W.; Trevillyan, J.M. The next big thing in diabetes: Clinical progress on DPP-IV
inhibitors. Drug Dev. Res. 2006, 67, 627–642.
9. Havale, S.H.; Pal, M. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4
for the treatment of type 2 diabetes. Bioorg. Med. Chem. 2009, 17, 1783–1802.
10. Zettl, H.; Schubert-Zsilavecz, M.; Steinhilber, D. Medicinal chemistry of incretin mimetics and
DPP-4 inhibitors. ChemMedChem 2010, 5, 179–185.
11. Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. The many faces of the adamantyl group in drug
design. Eur. J. Med. Chem. 2011, 46, 1949–1963.
12. Al-Omar, M.A.; Al-Abdullah, E.S.; Shehata, I.A.; Habib, E.E.; Ibrahim, T.M.; El-Emam, A.A.
Synthesis, antimicrobial, and anti-inflammatory activities of novel 5-(1-adamantyl)-4-arylideneamino-
3-mercapto-1,2,4-triazoles and related derivatives. Molecules 2010, 15, 2526–2550.
13. Lamanna, G.; Russier, J.; Dumortier, H.; Bianco, A. Enhancement of anti-inflammatory drug
activity by multivalent adamantane-based dendrons. Biomaterials 2012, 33, 5610–5617.
14. Antoniadou-Vyza, E.; Avramidis, N.; Kourounakis, A.; Hadjipetrou, L. Anti-inflammatory properties
of new adamantane derivatives. Design, synthesis, and biological evaluation. Arch. Pharm. 1998, 331,
72–78.
15. Priyanka, B.; Anitha, K.; Shirisha, S.; Dipankar, B.; Rajesh, K. Evaluation of anti-oxidant activity
of ethanolic root extract of albizla lebbeck l. Int. Res. J. Pharm. Appl. Sci. 2013, 3, 93–101.
16. Joyce, D.A. Oxygen radicals in disease. Advers. Drug React. Bull. 1987, 127, 476–479.
17. Farber, J.L. Mechanisms of cell injury by activated oxygen species. Environ. Health Perspect.
1994, 102, 17–24.
18. Lee, C.T.; Repasky, E.A. Opposing roles for heat and heat shock proteins in macrophage
functions during inflammation: A function of cell activation state? Front. Immunol. 2012, 3, 1–7.

Molecules 2015, 20
18844
19. Saso, L.; Valentini, G.; Casini, M.; Grippa, E.; Gatto, M.; Leone, M.; Silvestrini, B. Inhibition
of heat-induced denaturation of albumin by nonsteroidal antiinflammatory drugs (NSAIDs):
Pharmacological implications. Arch. Pharm. Res. 2001, 24, 150–158.
20. Kumar Chandraju Sadolalu, C.; Chia Tze, S.; Ooi Chin, W.; Quah Ching, K.; Chandraju, S.;
Fun, H.K. Conformational studies of 2-(4-bromophenyl)-2-oxoethyl benzoates. Z. Kristallogr.
Cryst. Mater. 2014, 229, doi:10.1515/zkri-2013–1709.
21. Jin, Y.; Guo, J.N.; Lin, K.; Tang, G.; Zhao, Y.F. Benzoylmethyl 4-chlorobenzoate. Acta Crystallogr.
Sect. E Struct. Rep. Online 2008, 64, doi:10.1107/S1600536807066469/ng2408Isup2.hkl.
22. Komarov, I.V.; Gorichko, M.V.; Shishkin, O.V.; Kornilov, M.Y. Short communications—Unusual
by-product in the bromination of 3,3-dibromocamphor. Russ. J. Org. Chem. 1999, 35, 1388–1389.
23. Fun, H.K.; Shahani, T.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 4-methylbenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811045272.
24. Fun, H.K.; Quah, C.K.; Vijesh, A.M.; Isloor, A.M.; Arulmoli, T. 2-(4-chlorophenyl)-2-oxoethyl
3,4-dimethoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811048264.
25. Fun, H.K.; Chia, T.S.; Shenvi, S.; Isloor, A.M.; Garudachari, B. 2-(2,4-dichlorophenyl)-2-oxoethyl
4-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811048720.
26. Fun, H.K.; Loh, W.S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-fluorophenyl)-2-
oxoethyl 4-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811049233.
27. Khan, I.; Ibrar, A.; Korzanski, A.; Kubicki, M. 2-(4-methylphenyl)-2-oxoethyl 3-bromobenzoate.
Acta Crystallogr. Sect. E Struct. Rep. Online 2012, 68, doi:10.1107/S1600536812046995.
28. Chidan Kumar, C.S.; Yohannan Panicker, C.; Fun, H.-K.; Sheena Mary, Y.; Harikumar, B.;
Chandraju, S.; Quah, C.K.; Ooi, C.W. Molecular structure, FT-IR, first order hyperpolarizability,
NBO analysis, HOMO and LUMO analysis of 2-(4-chlorophenyl)-2-oxoethyl 3-methylbenzoate
by HF and density functional methods. Spectrochim. Acta A 2014, 128, 327–336.
29. Chidan Kumar, C.S.; Panicker, C.Y.; Fun, H.-K.; Mary, Y.S.; Harikumar, B.; Chandraju, S.;
Quah, C.K.; Ooi, C.W. FT-IR, molecular structure, first order hyperpolarizability, HOMO and
LUMO analysis, MEP and NBO analysis of 2-(4-chlorophenyl)-2-oxoethyl 3-nitrobenzoate.
Spectrochim. Acta A 2014, 126, 208–219.
30. Fun, H.K.; Arshad, S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-oxo-2-phenylethyl
benzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/S1600536811018976.
31. Fun, H.K.; Arshad, S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 4-bromobenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811020654.
32. Fun, H.K.; Loh, W.S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 4-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811018988.

Molecules 2015, 20
18845
33. Fun, H.K.; Loh, W.S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-chlorophenyl)-2-
oxoethyl 3-(trifluoromethyl)benzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67,
doi:10.1107/S1600536811020629.
34. Chidan Kumar, C.S.; Fun, H.K.; Tursun, M.; Ooi, C.W.; Chandraju, S.; Quah, C.K.; Parlak, C.
Synthesis, molecular structure, FT-IR and XRD investigations of 2-(4-chlorophenyl)-2-oxoethyl
2-chlorobenzoate: A comparative DFT study. Spectrochim. Acta A 2014, 124, 595–602.
35. Fun, H.K.; Arshad, S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-chlorophenyl)-2-
oxoethyl 2,4-difluorobenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811020630.
36. Fun, H.K.; Arshad, S.; Garudachari, B.; Isloor, A.M.; Shivananda, K.N. 2-(4-fluorophenyl)-2-oxoethyl
3-(trifluoromethyl)benzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S160053681103947X.
37. Fun, H.K.; Asik, S.I.J.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-chlorophenyl)-2-
oxoethyl 2-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811021246.
38. Fun, H.K.; Loh, W.S.; Garudachari, B.; Isloor, A.M.; Satyanarayana, M.N. 2-(4-bromophenyl)-2-
oxoethyl 4-hydroxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811040311.
39. Fun, H.K.; Yeap, C.S.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 4-chlorobenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811022963.
40. Fun, H.K.; Loh, W.S.; Garudachari, B.; Isloor, A.M.; Satyanarayana, M.N. 2-(4-chlorophenyl)-2-
oxoethyl 4-methylbenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811042851.
41. Fun, H.K.; Quah, C.K.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 2-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811023002.
42. Fun, H.K.; Ooi, C.W.; Garudachari, B.; Isloor, A.M.; Satyanarayan, M.N. 2-(4-bromophenyl)-2-
oxoethyl 2-methylbenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811044564.
43. Fun, H.K.; Shahani, T.; Garudachari, B.; Isloor, A.M.; Shivananda, K.N. 2-(4-chlorophenyl)-2-
oxoethyl 4-hydroxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, doi:10.1107/
S1600536811037500.
44. Fun, H.K.; Shahani, T.; Garudachari, B.; Isloor, A.M.; Satyganarayan, M.N. 2-(4-chlorophenyl)-
2-oxoethyl benzoate. Acta Crystallogr. Sect. E: Struct. Rep. Online 2011, 67, doi:10.1107/
S160053681102383X.
45. Ji, T.; Wang, X.L.; Gao, Y.X.; Tang, G.; Zhao, Y.F. Benzoylmethyl 4-methoxybenzoate. Acta
Crystallogr. Sect. E Struct. Rep. Online 2007, 63, doi:10.1107/S1600536807055250.
46. Isloor, A.M.; Garudachari, B.; Satyanarayan, M.N.; Gerber, T.; Hosten, E.; Betz, R.
2-(4-fluorophenyl)-2-oxoethyl 2-methoxybenzoate. Acta Crystallogr. Sect. E Struct. Rep. Online
2012, 68, doi:10.1107/S1600536812002577.
47. Bruker. Apex2, Saint and Sadabs; Bruker AXS Inc.: Madison, WI, USA, 2009.

Molecules 2015, 20
18846
48. Sheldrick, G.M. A short history of shelx. Acta Cryst. 2008, 64, 112–122.
49. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.; Puschmann, H. OLEX2: A complete
structure solution, refinement and analysis program. J. Appl. Cryst. 2009, 42, 339–341.
50. Ruch, R.J.; Cheng, S.; Klaunig, J.E. Prevention of cytotoxicity and inhibition of intercellular
communication by antioxidant catechins isolated from chinese green tea. Carcinogenesis 1989, 10,
1003–1008.
51. Farasat, M.; Khavari-Nejad, R.A.; Nabavi, S.M.B.; Namjooyan, F. Antioxidant activity, total
phenolics and flavonoid contents of some edible green seaweeds from northern coasts of the
persian gulf. Iran. J. Pharm. Res. 2014, 13, 163–170.
52. Ashok Kumar, B.S.; Saran, G.; Harshada, R.; Manoj, B.; Archana, P.G. Evaluation of anti-arthritic
activity of vitex negundo by in vitro protein denaturation method. J. Tradit. Med. 2014, 1, 1–3.
Sample Availability: Samples of the compounds are available from the authors.
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