Synthesis and bioactivity of hydrazide-hydrazones with the 1-adamantyl-carbonyl moiety

Article abstract of DOI:10.3390/molecules24214000

Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl moiety. The new synthesized compounds were tested for activities against some Gram-negative and Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds 4e and 5e possessed cytotoxicity against tested human cancer cell lines.

Full text of DOI:10.3390/molecules24214000

molecules
Article
Synthesis and Bioactivity of Hydrazide-Hydrazones
with the 1-Adamantyl-Carbonyl Moiety
Van Hien Pham 1 , Thi Phuong Dung Phan 2, Dinh Chau Phan 3,* and Binh Duong Vu 1,
*
1
Drug R&D Center, Vietnam Military Medical University. No.160, Phung Hung str., Phuc La ward, Ha Dong
district, Hanoi 100000, Vietnam; phamvanhien181288@gmail.com
Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy. No. 15, Le Thanh Tong Str.,
Hoan Kiem district, Hanoi 100000, Vietnam; pdungdhd@gmail.com
Hanoi University of Science and Technology. No.1, Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district,
Hanoi 100000, Vietnam
2
3
*
Correspondence: chau.phandinh@hust.edu.vn (D.C.P.); vbduong2978@gmail.com (B.D.V.);
Tel.: +84-983-425-460 (B.D.V.); Fax: +84-243-688-4077 (B.D.V.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Simona Collina
Received: 3 October 2019; Accepted: 4 November 2019; Published: 5 November 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Reaction of 1-adamantyl carbohydrazide (1) with various substituted benzaldehydes and
acetophenones yielded the corresponding hydrazide-hydrazones with a 1-adamantane carbonyl
moiety. The new synthesized compounds were tested for activities against some Gram-negative and
Gram-positive bacteria, and the fungus Candida albicans. Compounds 4a, 4b, 5a, and 5c displayed
potential antibacterial activity against tested Gram-positive bacteria and C. albicans, while compounds
4e and 5e possessed cytotoxicity against tested human cancer cell lines.
Keywords: adamantane derivatives; hydrazide-hydrazone; antimicrobial; cytotoxicity activity
1. Introduction
The hydrazide-hydrazones derivatives, which play an important role in organic and medicine
chemistry, have attracted a large number of researchers over the years because of their promising
biological activities, including antimicrobial [1–4], anticancer [5–7], antituberculosis [2,8–10],
antiviral [11], and anticonvulsant [ ] activities. Some hydrazide-hydrazone components have been
2
considered as drugs and have been used in clinics, such as nitrofurazone, furazolidone, nitrofurantoin.
Adamantane derivatives are important constituents in medicinal chemistry due to their multiple
bioactivities. In the 1960s, the first adamantane derivative, amantadine, was found to have
antiviral [12
hope to find new compounds and biological activities. As a result, many adamantane derivatives
were discovered with numerous biological activities, such as antiviral [15 20], antimicrobial [18 20 30],
anticancer [23 27 31 35], angiogenesis inhibition [36], anti-inflammation [37], 11 hydroxysteroid
dehydrogenase type 1 (11 -HSD1) inhibition [38 40], and tyrosinase inhibition [41] activities.
–14] activity. A number of studies were conducted, focusing on such derivatives with the
–
,
–
,
,
–
β
β
–
Among them, nine compounds were approved for use in clinics, including amantadine, memantine,
rimantadine, tromantadine, adapalene, vildagliptine, saxagliptine, bromanatane, and adapromine.
Therefore, the combination of two moieties, hydrazone and adamantane, had potential to confer new
molecules with promising biological activities. In this study, we report the synthesis and biological
activities of hydrazide-hydrazones with the 1-adamantyl carbonyl moiety.
Molecules 2019, 24, 4000; doi:10.3390/molecules24214000
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4000
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2. Results and Discussion
2.1. Chemistry
In this study, adamantane-1-carbohydrazide was used as the key intermediate. It was initially
prepared by esterification of 1-adamantane carboxylic acid ( ) and methanol under catalysis of
98% H2SO4 to yield methyl ester . Then, ester was reacted with hydrazine hydrate to yield
adamantyl-1-carbohydrazide ( ). Subsequently, compound was condensed with aromatic aldehydes
and ketones to yield the corresponding hydrazide-hydrazones 4a and 5a , as seen in Scheme 1 and
was confirmed by 1H-NMR, 13C-NMR,
1
2
2
3
3
–i
–k
Table 1. The structure of hydrazide hydrazones 4a–i and 5a–k
and electron impact (ESI-MS) mass spectral data.
Scheme 1. Synthesis of hydrazide-hydrazones 4a–i and 5a–k.
Table 1. Melting point (m.p), yield (%), molecular formulae, molecular weight (Mol. Wt.) and Rf of
hydrazide-hydrazones 4a–i and 5a–k.
Molecular Formular
Comp. No.
R1
R2
m.p (◦C)
Yield (%)
TLC * (Rf)
(Mol. Wt.)
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5c
5e
5i
H
H
H
3-NO2
3-NO2
H
H
H
H
H
H
3-NO2
H
2-OH
2-CH3
4-OH
4-NO2
4-OC2H5
4-OCH3
4-Cl
252.5–254.1
226.0–227.6
159.5–160.6
182.0–184.1
188.2–189.3
190.7–191.0
171.6–173.0
179.5–180.4
174.4–175.2
289.6–290.5
235.2–236.4
247.8–248.5
186.9–187.2
247.6–248.8
283.5–284.0
30.6
60.5
32.2
33.0
26.2
29.0
30.0
37.3
54.5
44.0
15.1
50.6
60.5
60.4
35.5
C19H24N2O2 (312.41)
C19H23N3O3 (341.41)
C21H28N2O2 (340.47)
C20H25N3O4 (371.44)
C19H22ClN3O3 (375.85)
C19H23BrN2O (375.31)
C20H26N2O2 (326.44)
C20H26N2O (310.44)
C19H24N2O (296.41)
C18H22N2O2 (298.39)
C20H26N2O2 (326.44)
C18H20ClN3O3 (361.83)
C18H22N2O (282.39)
C19H24N2O2 (312.41)
C20H26N2O (310.44)
0.36
0.58
0.57
0.44
0.56
0.62
0.52
0.66
0.59
0.33
0.59
0.55
0.54
0.57
0.45
4-Br
4-OCH3
4-CH3
H
4-OH
4-OC2H5
4-Cl
H
5-CH3
5-CH3
5j
5k
* Solvent: n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v), visualization at UV 254 nm.

Molecules 2019, 24, 4000
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2.2. In Vitro Antimicrobial Activity
The newly synthesized hydrazide-hydrazones 4a
–
i
and 5a
–k
were tested for their in vitro growth
inhibition against standard strains of the National Institute for Food Control (NIFC, Vietnam),
including three Gram-negative bacteria, including Escherichia coli (ATCC25922), Pseudomonas aeruginosa
(ATCC27853), and Salmonella enterica (ATCC12228); three Gram-positive bacteria, including Enterococcus
faecalis (ATCC13124), Staphylococcus aureus (ATCC25923), and Bacillus cereus (ATCC 13245); and one
yeast-like pathogenic fungus, Candida albicans (ATCC10231). The primary screening was conducted
using the microplate dilution method, which utilized Luria-Bertani (LB) broth medium. The antibiotic
Streptomycin and antifungal drug Cyloheximide were used as the positive samples. The results of
preliminary antimicrobial testing of the newly synthesized hydrazide-hydrazones 4a–i and 5a–k are
presented in Tables 2 and 3.
Table 2. Minimum inhibitory concentration (MIC) of synthesized hydrazide-hydrazones 4a–i and 5a–k.
MIC of Synthesized Compounds (µM)
Comp. No.
Gram (+)
Gram (−)
Fungus
CA
EF
SA
BC
EC
PA
SE
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5c
5e
5i
5j
5k
STM
CHM
12.5
25
25
12.5
25
50
25
25
25
12.5
12.5
25
50
50
25
350
NT
12.5
25
25
50
50
50
25
25
50
25
50
25
50
50
25
350
NT
12.5
25
25
100
50
50
100
50
50
25
100
25
50
50
25
175
NT
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12.5
25
25
6.25
25
12.5
25
12.5
25
12.5
12.5
25
50
25
25
NT
114
-
-
-
-
-
-
44
NT
350
NT
175
NT
EF: Enterococcus faecalis (ATCC13124); SA: Staphylococcus aureus (ATCC25923); BC: Bacillus cereus (ATCC 13245); EC:
Escherichia coli (ATCC25922); PA: Pseudomonas aeruginosa (ATCC27853); SE: Salmonella enterica (ATCC12228); CA:
Candida albicans (ATCC10231); STM: streptomycine; CHM: Cycloheximide; NT: not tested; -: inactive.
The results of antimicrobial testing showed that all newly synthesized hydrazide-hydrazones
possessed various inhibition effects on the tested Gram-positive bacteria and yeast-like fungus from
moderate to serious activities. Strong antibacterial activity was found for compounds 4a
5c. Meanwhile, compound 4a strongly inhibited EF, SA, BC, and CA, with an MIC of 12.5
four strains) and IC50 values of 6.35 M, 6.77 M, 6.12 M, and 6.37 M, respectively. Additionally,
compounds 4d 5a, and 5c have good inhibitory effects on EF and CA, with MICs of 12.5 M and
6.26 M, 12.5 M and 12.5 M, 12.5 M and 12.5 M; and IC50 values of 6.88 M and 3.56 M, 6.73
and 6.25 M, and 6.77 M and 6.66 M, respectively. Moreover, compounds 4f and 4h showed
good results in inhibition of the yeast-like fungus CA with MICs of 12.5 M (for both synthesized
compounds) and IC50 values of 6.77 M and 6.45 M, respectively. Other synthesized compounds
showed moderate inhibition of the tested Gram-positive bacteria and C. albicans.
,
4d, 5a, and
µM (for the
µ
µ
µ
µ
,
µ
µ
µ
µ
µ
µ
µ
µ
µM
µ
µ
µ
µ
µ
µ

Molecules 2019, 24, 4000
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Table 3. IC50 of synthesized hydrazide-hydrazones 4a–i and 5a–k.
IC50 of Synthesized Compounds (µM)
Comp. No.
Gram (+)
Gram (−)
Fungus
CA
EF
SA
BC
EC
PA
SE
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5c
5e
5i
6.35
11.56
13.24
6.88
13.55
24.79
12.56
13.22
12.56
6.73
6.77
6.12
12.56
12.77
52.11
25.99
25.33
56.7
23.88
25.65
12.37
26.78
12.33
26.56
24.33
12.33
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
6.37
12.78
13.11
3.56
13.57
6.77
11.55
6.45
12.33
6.25
11.45
12.67
25.45
25.11
13.44
12.55
13.45
25.66
12.33
26.55
12.67
26.55
24.56
12.45
6.77
6.66
13.25
25.66
24.58
12.35
13.22
25.33
11.45
13.46
5j
5k
EF: Enterococcus faecalis (ATCC13124); SA: Staphylococcus aureus (ATCC25923); BC: Bacillus cereus (ATCC 13245); EC:
Escherichia coli (ATCC25922); PA: Pseudomonas aeruginosa (ATCC27853); SE: Salmonella enterica (ATCC12228); CA:
Candida albicans (ATCC10231); -: inactive.
Regarding the structure–antimicrobial activity relationship of the synthesized compounds,
inhibition increased significantly for compounds possessing an –OH (para) group on the benzyl
ring (compounds 4a and 5a). Within the hydrazide-hydrazones 4a–i, it was suggested that the
inhibition against EF did not change substantially when having –NO2, –OC2H5, or an –OCH3 group
at position 4 of the benzyl ring, but decreased if they were replaced by a –Br group. Otherwise, the
presence of only one substituent on the benzyl ring inhibited SA better than that of two substituents. In
the inhibition against BC, it seemed that the presence of 4-OH, 4-NO2, 4-OC2H5 enhanced the activity;
however, it was reduced when the substituent was a 4-OCH3 group. In addition, the inhibition of
CA showed a good result while having only one substituent of 4-NO2, 4-OC2H5, or 4-OCH3 on the
benzyl ring.
In hydrazide-hydrazones 5a–k, it seemed that the presence of the benzyl ring enhanced the
antimicrobial activity. Compound 5k, containing two methyl groups (2-CH3 and 5-CH3), showed good
inhibition against Gram-positive bacteria and the yeast-like fungus C. albicans. The replacement of
2-CH3 by 2-OH enhanced the activity, particularly against C. albicans, but made no improvement to the
inhibition of Gram-positive bacteria.
2.3. In Vitro Cytotoxicity
All the synthesized hydrazide-hydrazones 4a–i and 5a–k were evaluated for their cytotoxicity in
four human cancer cell lines, including hepatic cancer cell line Hep3B, human cervical cancer cell line
HeLa, human lung cancer cell line A549, and human breast carcinoma MCF-7, in line with a previous
publication [42]. As shown in Table 4, some of the synthesized hydrazide-hydrazones exhibited
antiproliferative activity against the tested cancer cell lines. Among them, compound 5e demonstrated
the most potent cytotoxicity on cell viability of 37.78
2.22% in HeP3B, Hela, A549, and MCF-7 cell lines, respectively, at a concentration of 100
addition, compound 4e inhibited Hela, A549, and MCF-7 cells, with cell viabilities of 44.37
38.51 1.59%, and 38.69 1.20% at a concentration of 100 M, respectively. Other compounds showed
±
2.44%, 40.42
±
0.38%, 19.62
±
1.74%, and 34.13
M. In
1.39%,
±
µ
±
±
±
µ
slight cytotoxicity on the tested cancer cell lines. Structure–cytotoxicity relationship analysis revealed
that compounds 4e and 5e, containing both 3-NO2 and 4-Cl groups on the benzyl ring, have significant
cytotoxicity against the four tested cancer cell lines.

Molecules 2019, 24, 4000
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Table 4. The effect of newly synthesized hydrazide-hydrazone 4a–i and 5a–k on the viability of HeP3B,
Hela, A549, and MCF-7 cells after 48 h of incubation.
Comp. No.
Conc.
Hep3B
Hela
A549
MCF-7
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
30 µM
100 µM
0.3 µM
14.4 µM
63.89 ± 0.69
56.53 ± 1.32
66.83 ± 1.15
56.49 ± 2.17
80.62 ± 1.25
72.74 ± 2.00
96.80 ± 0.26
84.59 ± 2.39
94.59 ± 2.20
55.91 ± 1.70
>100
97.95 ± 2.43
91.63 ± 2.63
77.00 ± 1.84
98.29 ± 2.46
75.83 ± 2.76
81.96 ± 1.67
80.7 ± 2.17
87.03 ± 1.28
68.89 ± 2.18
88.96 ± 0.91
78.97 ± 1.82
57.77 ± 1.59
37.78 ± 2.44
83.16 ± 1.19
74.90 ± 1.34
92.80 ± 2.24
85.71 ± 2.28
98.51 ± 0.38
83.34 ± 1.65
69.56 ± 1.27
37.65 ± 1.21
73.09 ± 2.31
66.87 ± 1.10
82.84 ± 1.37
77.20 ± 0.90
93.64 ± 0.88
90.51 ± 1.28
>100
86.34 ± 1.35
80.07 ± 1.87
44.37 ± 1.39
88.26 ± 1.74
83.18 ± 0.20
96.61 ± 1.98
79.46 ± 1.28
>100
99.77 ± 1.89
88.70 ± 1.79
87.75 ± 0.29
87.53 ± 0.21
68.26 ± 2.02
89.07 ± 1.21
85.41 ± 1.34
76.75 ± 1.07
40.42 ± 0.38
89.12 ± 2.43
84.28 ± 2.12
68.96 ± 2.38
57.90 ± 1.35
82.96 ± 0.59
74.27 ± 1.67
57.06 ± 1.35
18.61 ± 0.56
67.78 ± 0.26
51.63 ± 0.81
66.89 ± 0.94
62.26 ± 0.15
77.76 ± 1.51
70.20 ± 0.13
65.33 ± 1.28
62.01 ± 2.37
64.43 ± 0.49
38.51 ± 1.59
76.22 ± 0.98
73.68 ± 1.03
87.40 ± 0.95
70.61 ± 1.66
78.42 ± 0.83
68.99 ± 2.36
68.43 ± 1.72
67.73 ± 1.89
69.08 ± 2.56
50.78 ± 1.86
90.47 ± 2.23
81.32 ± 1.20
36.42 ± 0.94
19.62 ± 1.74
79.49 ± 0.94
55.22 ± 1.63
78.71 ± 1.75
59.18 ± 2.01
62.55 ± 0.59
52.39 ± 1.54
67.68 ± 1.88
26.74 ± 2.16
63.28 ± 1.41
58.60 ± 0.32
64.32 ± 2.92
52.64 ± 2.02
79.36 ± 1.40
67.78 ± 0.95
90.20 ± 0.25
78.82 ± 2.22
60.94 ± 1.39
38.69 ± 1.20
94.68 ± 1.33
91.27 ± 2.26
83.11 ± 2.86
71.75 ± 1.71
91.59 ± 2.29
70.66 ± 2.57
59.77 ± 2.41
57.24 ± 0.75
86.14 ± 0.49
64.33 ± 1.76
70.30 ± 1.23
65.62 ± 0.64
52.56 ± 0.75
34.13 ± 2.22
71.53 ± 1.64
65.31 ± 1.66
86.48 ± 2.08
79.86 ± 2.13
91.80 ± 0.35
77.66 ± 1.54
56.68 ± 0.68
28.89 ± 1.07
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5c
5e
5i
5j
5k
CPT *
* Camptothecine. Data is presented as percentage of the cell viability ± SD.
3. Experimental
3.1. General
Melting point (◦C) was measured in a glass microtube using a MP50 Mettler Teledo electrothermal
melting point apparatus. NMR spectra were obtained with a Bruker Biospin AVANCE III spectrometer
system monitoring at 500 MHz in DMSO-d6; the chemical shifts (δ, ppm) were expressed and coupling
constants (J) were given in Hz using tetramethylsilane as the internal standard. Mass spectra (MS)
were recorded on an Agilent 910-TQ-FT-MS system. Monitoring the reactions and preliminary purity
checking of synthesized compounds were conducted by thin layer chromatography (TLC) using
precoated aluminum sheet 60 F254 plates (Merck KGaA Co., Darmstadt, Germany; EMD Milipore
Corp., MA, USA) and visualization with UV at 254 nm. The bacterial and fungus strains were
supplied by National Institute for Food Control (NIFC, Hanoi, Vietnam) including Escherichia coli
(ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella enterica (ATCC12228), Enterococcus
faecalis (ATCC13124), Stapphylococus aureus (ATCC25923), Bacillus cereus (ATCC 13245), and Candida
albicans (ATCC10231). This study was conducted on cancer cell lines supplied by Advanced Center
for Bioorganic Chemistry (ACBC) of the Institute of Marine Biochemistry (IMBC), Vietnam Academy
Science and Technology (VAST), i.e., hepatic cancer cell line Hep3B, human cervical cancer cell line
HeLa, human lung cancer cell line A549, and human breast carcinoma MCF-7.

Molecules 2019, 24, 4000
6 of 11
3.2. Synthesis of Methyl Adamantane-1-Carboxylate (2)
A mixture of 5 g (2.7 mmoL) adamantane-1-carboxylic acid, 50 mL methanol (1235 mmoL), and
9.2 g H2SO4 98% was stirred under reflux conditions. The reaction was monitored by TLC performed
in n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) and visualized under UV at 254 nm. After the
reaction, the mixture was adjusted to pH 7–8 with 10% NaHCO3 aqueous solution. Then, the mixture
was stabilized to room temperature before 200 mL ice water was poured into it to cause precipitation.
The separate precipitate was filtered, washed with water, dried, and crystallized to obtain 4.92 g of
white, needle-shaped crystals with a yield of 98.4% [18].
3.3. Synthesis of Adamantane-1-Carbohydrazide (3)
A mixture of 4 g (20 mmoL) compound
2
and 25 mL (412 mmoL) 80% hydrazine
hydrate aqueous solution were refluxed.
The reaction was monitored by TLC using
n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) as the mobile phase and visualized under UV
at 254 nm. At completion, 200 mL of ice water was added to the mixture. The separate precipitate
was filtered and washed with water, dried to obtain 3.82 g of opalescent scaly solid with a yield of
95.5% [18].
3.4. Synthesis of Hydrazide-Hydrazones 4a–i and 5a–k
A mixture of adamantane-1-carbohydrazide (3) and 1 mmoL of the appropriate aldehydes or
ketones and 15 mL EtOH was stirred in reflux conditions. The reaction was monitored by TLC using
the mobile phase as n-hexane/ethylacetate/dichloromethane (2/1/1, v/v/v) and visualized under UV
at 254 nm. At completion, the solvent was removed under vacuum to yield a viscous liquid. It was
allowed to stand at 0–5 ◦C to crystallize. Then, the crystal was filtered, washed with cold ethanol, and
dried to obtain hydrazide-hydrazones 4a–i and 5a–k.
N0-(1-(4-hydroxyphenyl)ethylidene)adamantane-1-carbohydrazide (4a): M.p.: 252.5–254.1 ◦C, Yield
1
30.6%. H-NMR (500 MHz, DMSO-d6,
δ ppm): 9.74 (1H, s, NH-N); 9.44 (1H, s, OH); 7.64 (2H, dd, J1 =
2.0 Hz, J2 = 7.0 Hz; Ar-H); 6.78 (2H, m, Ar-H); 2.16 (3H, s, CH3); 2.00 (3H, s, Adamantane-H); 1.90 (6H,
s, C ppm): 172.6 (1C, O); 158.8
2 Ad); 1.70 (6H, s, Adamantane-H). 13C-NMR (500 MHz, DMSO-d6,
(1C, Ar-C); 156.5 (1C, =N); 128.9 (1C, C1); 127.9 (2C, Ar-C); 115.0 (2C, Ar-C); 38.2 (3C, Adamantane-C);
H
δ
C
C
36.0 (3C, Adamantane-C); 27.6 (3C, Adamantane-C); 14.0 (1C, C
H
3). ESI-MS (m/z): [M
−
1]−1 = 311.0;
[M + 1]+1 = 313.1.
N0-(1-(4-nitrophenyl)ethylidene)adamantane-1-carbohydrazide (4b): M.p.: 226.0–227.6 ◦C; Yield 60.5%;
1H-NMR (500 MHz, DMSO-d6,
ppm): 9.72 (1H, s, N -N); 8.26 (2H, dd, J1 = 2.0 Hz, J2 = 7.0 Hz, Ar-H);
3); 2.01 (3H, s, Adamantane-H); 1.95 (6H, s,
δ
H
8.05 (2H, dd, J1 = 2.0 Hz, J2 = 7.5 Hz, Ar-H); 2.32 (3H, s, C
H
Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M − 1]−1 = 340,0; [M + 1]+1 = 342,0.
N0-(1-(4-ethoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4c): M.p.: 159.5–160.6 C; Yield
◦
32.2%; 1H-NMR (500 MHz, DMSO-d6,
(2H, d, J = 9,0 Hz, Ar-H); 4.06 (2H, dd, J1 = 7.0 Hz; J2 = 14.0 Hz, OC
δ
ppm): 9.47 (1H, s, N
H
-N); 7.74 (2H, d, J = 9.0 Hz, Ar-H); 6.95
2); 2.19 (3H, s, C 3); 2.00 (3H, s,
H
H
Adamantane-H); 1.91 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); 1.33 (3H, t, J1 = 7.0 Hz, J2 =
14.0 Hz, CH3). ESI-MS (m/z): [M + 1]+1 = 341.0.
N0-(1-(3-nitro-4-methoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4d): M.p.: 182–184.1 ◦C;
Yield 33.0%; 1H-NMR (500 MHz, DMSO-d6,
δ ppm): 9.61 (1H, s, NH-N); 8.25 (1H, d, J = 2,5 Hz, Ar-H);
8.08 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.42 (1H, d, J = 7.0 Hz, Ar-H); 2.25 (3H, s, CH3); 2.00 (3H,
s, Adamantane-H); 1.92 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1
= 372.0; [M − 1]−1 = 370.0.
N0-(1-(3-nitro-4-chlorophenyl)ethylidene)adamantane-1-carbohydrazide (4e): M.p.: 188.2–189.3 ◦C;
1
Yield 26.2%. H-NMR (500 MHz, DMSO-d6,
δ ppm): 9.72 (1H, s, NH-N); 8.39 (1H, d, J = 2.0 Hz, Ar-H);

Molecules 2019, 24, 4000
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8.09 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.83 (1H, d, J = 8.5 Hz, Ar-H); 2.29 (3H, s, CH3); 2.00 (3H,
s, Adamantane-H); 1.94 (6H, s, Adamantane-H); 1.71 (6H, s, Adamantane-H). ESI-MS (m/z): [M + 1]+1
= 375.9; [M − 1]−1 = 373.9.
N0-(1-(3-nitro-4-chlorophenyl)ethylidene)adamantane-1-carbohydrazide (4f): M.p.: 190.7–191 ◦C. Yield:
29.0%; 1H-NMR (500 MHz, DMSO-d6,
δ ppm): 9.59 (1H, s, NH-N); 7.76 (2H, d, J = 8.5 Hz, Ar-H); 7.63
(2H, d, J = 8.5 Hz, Ar-H); 2.25 (3H, s, CH3); 2.02 (3H, s, Adamantane-H); 1.94 (6H, s, Adamantane-H);
1.72 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 374.9.
N0-(1-(4-methoxyphenyl)ethylidene)adamantane-1-carbohydrazide (4g): M.p.: 171.6–173 ◦C; Yield
30.0%; 1H-NMR (500 MHz, DMSO-d6,
δ
ppm): 9.48 (1H, s, N
H
-N); 7.75 (2H, d, J = 8.5 Hz, Ar-H); 6.97
(2H, d, J = 9.0 Hz, Ar-H); 3.79 (3H, s, OC
H
3); 2.20 (3H, s, C
H3); 2.00 (3H, s, Adamantane-H); 1.91 (6H, s,
Adamantane-H); 1,70 (6H, s, Adamantane-H). ESI-MS (m/z): [M + 1]+1 = 327.0.
N0-(1-(4-methylphenyl)ethylidene)adamantane-1-carbohydrazide (4h): M.p.: 179.5–180.4 ◦C; Yield
37.3%; 1H-NMR (500 MHz, DMSO-d6,
δ
ppm): 9.48 (1H, s, N
H
-N); 7.75 (2H, d, J = 8.5 Hz, Ar-H); 6.97
(2H, d, J = 9.0 Hz, Ar-H); 3.79 (3H, s, OC
H
3); 2.20 (3H, s, C
H3); 2.00 (3H, s, Adamantane-H); 1.91 (6H, s,
Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 311.0.
N0-(1-phenyl)ethylidene)adamantane-1-carbohydrazide (4i): M.p.: 174.4–175.2 ◦C; Yield 54.5%;
1H-NMR (500 MHz, DMSO-d6,
δ ppm): 9.54 (1H, s, NH-N); 7.79 (2H, m, Ar-H); 7.43–7.41 (3H,
m, Ar-H); 2.24 (3H, s, CH3); 2.01 (3H, s, Adamantane-H); 1.93 (6H, s, Adamantane-H); 1.71 (6H, s,
Adamantane-H). ESI-MS (m/z): [M + 1]+1 = 297.0.
◦
N0-(4-hydroxybenzylidene)adamantane-1-carbohydrazide (5a): M.p.: 289.6–290.5 C; Yield 44.0%;
1H-NMR (500 MHz, DMSO-d6,
δ
ppm): 10.56 (1H, s, N -C); 9.86 (1H, s, O ); 8.28 (1H, s, N=C );
H
H
H
7.49 (2H, d, J = 8.5 Hz, Ar-H); 6.82 (2H, d, J = 8.5 Hz, Ar-H); 2.01 (3H, s, Adamantane-H); 1.87 (6H, s,
Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 298.9; [M − 1]−1 = 296.9.
◦
N0-(4-ethoxybenzylidene)adamantane-1-carbohydrazide (5c): M.p.: 235.2–236.4 C; Yield 15.1%;
1H-NMR (500 MHz, DMSO-d6,
H2, H6); 6.97 (2H, d, J = 9.0 Hz, H3, H5); 4.07 (2H, m, OC
1.70 (6H, s, CH2 Ad); 1.34 (3H, t, J1 = 7.0 Hz, J2 = 14.0 Hz, CH3); ESI-MS (m/z): [M + 1]+1 = 327.0.
δ
ppm): 10.61 (1H, s, N
H
-C); 8.32 (1H, s, N=C
H
); 7.57 (2H, d, J = 8.5 Hz,
H
2); 2.00 (3H, s, C
H
Ad); 1.86 (6H, s, C 2 Ad);
H
◦
N0-(3-nitro-4-chlorobenzylidene)adamantane-1-carbohydrazide (5e): M.p.: 247.8–248.5 C; Yield:
50.6%; 1H-NMR (500 MHz, DMSO-d6,
δ
ppm): 11.12 (1H, s, N -C); 8.43 (1H, s, N=C ); 8.29 (1H, d, J =
H
H
2.0 Hz, Ar-H); 7.96 (1H, dd, J1 = 2.0 Hz, J2 = 8.5 Hz, Ar-H); 7.82 (1H, d, J = 8.5 Hz, Ar-H); 2.01 (3H, s,
Adamantane-H); 1.87 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1
361.9; [M − 1]−1 = 359.9.
=
N0-(benzylidene)adamantane-1-carbohydrazide (5i): M.p.: 186.9–187.2 ◦C; Yield: 60.5%; 1H-NMR (500
MHz, DMSO-d6, δ ppm): 10.77 (1H, s, NH-C); 8.40 (1H, s, N=CH); 7.66–7.61 (2H, m, Ar-H); 7.45–7.40
(3H, m, Ar-H); 2.01 (3H, s, Adamantane-H); 1.88 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H);
ESI-MS (m/z): [M + 1]+1 = 283.0.
N0-(2-hydroxy-5-methylbenzylidene)adamantane-1-carbohydrazide (5j): M.p.: 247.6–248.8 ◦C; Yield
1
60.4%; H-NMR (500 MHz, DMSO-d6,
δ ppm): 11.15 (1H, s, OH); 11.08 (1H, s, NH-C); 8.48 (1H, s,
N=CH); 7.23 (1H, d, J = 1.5 Hz, Ar-H); 7.07 (1H, dd, J1 = 2.0 Hz, J2 = 8.0 Hz, Ar-H); 6.79 (1H, d, J = 8.5 Hz,
Ar-H); 2.23 (3H, CH3); 2.01 (3H, s, Ar-H); 1.87 (6H, s, Adamantane-H); 1.70 (6H, s, Adamantane-H);
ESI-MS (m/z): [M + 1]+1 = 313.0; [M − 1]−1 = 310.9.
N0-(2,4-diemthylbenzylidene)adamantane-1-carbohydrazide (5k): M.p.: 283.5–284.0 ◦C; Yield 35.5%;
1H-NMR (500 MHz, DMSO-d6,
δ ppm): 10.72 (1H, s, NH-C); 8.63 (1H, s, N=CH); 7.59 (1H, s, H6);
7.11 (2H, s, Ar-H); 2.36 (3H, s, CH3); 2.29 (3H, s, CH3); 2.02 (3H, s, Adamantane-H); 1.88 (6H, s,
Adamantane-H); 1.71 (6H, s, Adamantane-H); ESI-MS (m/z): [M + 1]+1 = 311.0.

Molecules 2019, 24, 4000
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Spectra of synthesized compounds were displayed in Supplemental Material file.
3.5. Dertemination of Antimicrobial Activity by the Dilution Method
The tested compounds 4a 5a were dissolved in dimethylsulphoxide at the concentration
–
i
,
–k
of 100 mM, separately, to prepare the parent solutions. A total of 0.4 mL of the parent solution was
withdrawn and 9.6 mL LB was added and mixed homogenously to obtain a working solution. Then,
we prepared twofold serial dilution solutions in LB media at the concentrations of 100
µ
M, 50
M in 96 well plates, in triplicate. After that,
105 CFU/mL was inoculated to each well and incubated
µM,
25
50
µ
M, 12.5 µM, 6.25 µM, 3.13 µM, 1.56 µM, and 0.78 µ
µ
L◦of microorganism suspension at 2
×
at 37 C for 24 h. Streptomycin and cycloheximide were used as the positive samples. Minimum
inhibitory concentration (MIC) was determined as the lowest concentration that completely inhibited
the growth of the microorganism, which was detected by the naked eye. Half of the maximal inhibitory
concentration (IC50) is defined as the concentration of tested compounds that inhibits 50% visual
growth of the test microorganism, which was determined by turbidity measurement on a Bitotech
microplate reader and using RawData software [43].
3.6. Determination of Cytotoxicity Activity
The MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide) method was conducted
to determine the cytotoxicity of the synthesized compounds 4a–i, 5a–k on human cancer cell lines,
including hepatic cancer cell line Hep3B, human cervical cancer cell line HeLa, human lung cancer cell
line A549, and human breast carcinoma MCF-7, according to a previous publication [43]. The cells,
which were seeded at 5
containing 10% fetal bovine serum (FBS), penicillin (100 IU/mL), and streptomycin (100
37 ◦C in a humid air incubator supplied with 5% CO2. The cells were allowed to grow for 24 h and
then were removed to old media and treated with the sample. A total of 200 L of the test samples was
added to the well and incubated for 72 h in culture conditions. After removing the medium, 50 L MTT
solution (1 mg/mL in phosphate buffer saline) was then added to each well and the cells were further
incubated at 37 ◦C for 4 h. After removing the MTT solution, 100
L of isopropanol was added to each
well. The absorbance was measured on a microplate reader (iMark Microplate Absorbance Reader,
×
106 cell/well, were grown in 96-well plates with RPMI 1640 or DMEM media
µg/mL) at
µ
µ
µ
™
Bio-Rad Laboratories, CA, USA) at 570 nm. Suitable blank and positive controls (Camptothecine) were
included. Cytotoxicity of the synthesized compounds was determined as the percent of cell survival,
as follows: [OD (72 h)–OD (0 h)]/[OD(DMSO)–OD (0 h)]; where OD (72 h), OD (0 h), OD(DMSO) are
the absorbance of test sample at 72 h, test sample at 0 h, and DMSO sample [42].
4. Conclusions
The synthesis and characterization of hydrazide-hydrazones with a 1-adamantane carbonyl
moiety, 4a
adamantane-1-carbohydrazide (
with substituted benzaldehydes to get compounds 5a
synthesized compounds were determined. The screening results revealed that compounds 4a
–
i
and 5a
–
k
, were achieved.
) with substituted acetophenones to get compounds 4a
. The antimicrobial and cytotoxicity of the
4d
The synthesis was conducted by condensing
3
–i
, and
–
k
,
,
5a, and 5c showed good antibacterial activity against Gram-positive bacteria and Candida albicans
compared to known antibacterial and antifungal drugs. These compounds are considered as good
candidates for new antimicrobial agents. Moreover, among the synthesized compounds, 4e and 5e
displayed promising inhibitory activity against the growth of tested human cancer cell lines. Although
the active compounds are considered to be good candidates as antimicrobial and antitumor agents,
further studies, such as mechanism determination, should be undertaken.
Supplementary Materials: Supplementary materials can be found online.
Author Contributions: The manuscript was written by the contribution of all authors: Methodology, D.C.P.;
Supervision, B.D.V.; Writing—original draft, V.H.P.; Writing—review & editing, T.P.D.P.

Molecules 2019, 24, 4000
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Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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