Synthesis and structure insights of two novel broad-spectrum antibacterial candidates based on (E)-N0-[(Heteroaryl)methylene]adamantane-1carbohydrazides

Article abstract of DOI:10.3390/molecules25081934

Two new N⁰-heteroarylidene-1-carbohydrazide derivatives, namely; E-N⁰-[(pyridine-3yl)methylidene]adamantane-1-carbohydrazide (1) and E-N⁰-[(5-nitrothiophen-2-yl)methylidene] adamantane-1-carbohydrazide (2), were produced v

Full text of DOI:10.3390/molecules25081934

molecules
Article
Synthesis and Structure Insights of Two Novel
Broad-Spectrum Antibacterial Candidates Based
0
on (E)-N -[(Heteroaryl)methylene]adamantane-1-
carbohydrazides
1
2
3,
2
Lamya H. Al-Wahaibi , Natalia Alvarez , Olivier Blacque * , Nicolás Veiga
,
Aamal A. Al-Mutairi 4 and Ali A. El-Emam *
5,
1
Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11671,
Saudi Arabia; lhalwahaibi@pnu.edu.sa
2
Química Inorgánica, Facultad de Química, Universidad de la República, Av. General Flores 2124,
Montevideo 11800, Uruguay; nalvarez@fq.edu.uy (N.A.); nveiga@fq.edu.uy (N.V.)
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Department of Chemistry, College of Sciences, Al Imam Mohammad Ibn Saud Islamic University (IMSIU),
Riyadh 11623, Saudi Arabia; aamutairi@imamu.edu.sa
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Correspondence: olivier.blacque@chem.uzh.ch (O.B.); elemam@mans.edu.eg. (A.A.E.-E.);
Tel.: +20-50-2258087 (A.A.E.-E.)
3
4
5
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 5 April 2020; Accepted: 15 April 2020; Published: 22 April 2020
0
0
Abstract: Two new N -heteroarylidene-1-carbohydrazide derivatives, namely; E-N -[(pyridine-3-
0
yl)methylidene]adamantane-1-carbohydrazide (
adamantane-1-carbohydrazide (
with the appropriate heterocyclic aldehyde. Both compounds were chemically and structurally
characterized by H-NMR, C-NMR, infrared and UV-vis spectroscopies, and single crystal X-ray
diffraction. The study was complemented with density functional theory calculations (DFT).
The results show an asymmetrical charge distribution in both compounds, with the electron density
accumulated around the nitrogen and oxygen atoms, leaving the positive charge surrounding the N-H
and C-H bonds in the hydrazine group. Consequently, the molecules stack in an antiparallel fashion
in the crystalline state, although the contribution of the polar contacts to the stability of the lattice is
1
) and E-N -[(5-nitrothiophen-2-yl)methylidene]
), were produced via condensation of adamantane- 1-carbohydrazide
2
1
13
different for
structures. Both molecules show intense UV-Vis light absorption in the range 200–350 nm (
00–500 nm (
1
(18%) and
2
(42%). This difference affects the density and symmetry of their crystal
1) and
2
2
), brought about by π → π* electronic transitions. The electron density difference maps
(
EDDM) revealed that during light absorption, the electron density flows within the
π-delocalized
0
system, among the pyridyl/thiophene ring, the nitro group, and the N -methyleneacetohydrazide
moiety. Interestingly, compounds
displaying potent antibacterial activity with minimal inhibitory concentration (MIC) values around
.5–2.0 g/mL. They also show weak or moderate antifungal activity against the yeast-like pathogenic
1 and 2 constitute broad-spectrum antibacterial candidates,
0
µ
fungus Candida albicans.
Keywords: adamantane-1-carbohydrazides; antibacterial activity; crystal structure; DFT; Hirshfeld
surface analysis; IR; UV-Vis spectra
1
. Introduction
0
Heterocyclic carboxylic acid hydrazides and their N -arylidene derivatives were early identified
as potent chemotherapeutic agents for the control of mycobacterial infections [1,2]. As a result of
Molecules 2020, 25, 1934; doi:10.3390/molecules25081934
www.mdpi.com/journal/molecules

Molecules 2020, 25, 1934
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0
extensive research based on homocyclic and heterocyclic hydrazides and their N -arylidene derivatives,
numerous derivatives were developed and proved to be superior to their prototype drugs [ ].
In addition, various hydrazide and hydrazine analogues were proved to possess potent antibacterial
and antifungal [ 12], antiviral [13], anticancer [14 16], and antileishmanial [17 18] activities. Moreover,
3–8
9–
–
,
adamantane derivatives have long been known for their diverse biological activities and several
adamantane-based drugs are currently used as efficient therapeutic agents for the treatment of various
pathological disorders [19–21]. Moreover, adamantane-1-carbohydrazide and hydrazone derivatives
were previously studied and displayed potent antibacterial and antifungal activities [22–25].
In view of the above-mentioned observations and continuing with recent studies on the chemical
and pharmacological properties of adamantane-based derivatives [26
synthesis of two novel N -[(heteroaryl)methylene]adamantane-1-carbohydrazides that display potent
–
29], we report herein the
0
antibacterial activity. Both compounds were chemically and structurally characterized using a wide
1
13
range of experimental and computational techniques, including H-NMR, C-NMR, infrared and
UV-vis spectroscopies, single crystal X-ray diffraction, and density functional theory calculations
(DFT) calculations. The results allowed us to gain insights into the chemical identity, molecular
structure, solid-state intermolecular interactions, and light absorption of these two new broad-spectrum
antibacterial compounds.
2
. Results and Discussion
2
.1. Chemical Synthesis
0
The (E)-N -[(heteroaryl)methylene]adamantane-1-carbohydrazides
1
and
2
were prepared starting
with adamantane-1-carboxylic acid
was subsequently reacted with hydrazine to yield adamantane-1-carbohydrazide
B
A
via esterification with methanol to yield the methyl ester, which
30]. The hydrazide
was then reacted with pyridine-3-carboxaldehyde or 5-nitrothiophene- 2-carboxaldehyde in ethanol
B
[
1
to yield the target compounds
1
and
were in full agreement with their structures. The NH protons were
11.01 and 11.24 and the CH=N protons at 8.81 and 8.68 ppm, respectively.
The adamantyl CH and CH protons (15H) were shown as three distinguished peaks at 2.03, 2.02 (3H),
.88, 1.87 (6H), and 1.72, 1.68–1.73 ppm (6H). In addition, the integrations and multiplicities of the
2 in 82% and 95% yields, respectively (Scheme 1). The H-NMR
spectra of compounds
shown as singlets at
1 and 2
δ
δ
δ
2
1
13
pyridine and thiophene protons were properly shown. The C-NMR spectra exhibited the C=O
carbons at 173.86 and 174.18 ppm and the CH=N carbons at 144.35 and 140.63 ppm, respectively.
δ
δ
The adamantyl carbons were shown as four distinguished peaks. The pyridine and thiophene carbons
were shown in the expected regions.
CHO
H
H
1
2
. MeOH, H SO4
OH
N
N
N
NH2
N
2
. NH NH2
EtOH
O
2
O
O
A
B
1
N
CHO
S
EtOH
NO
2
H
N
N
O
S
2
NO2
Scheme 1. Synthesis of compounds 1 and 2.

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2
.2. Crystal Structures
Single crystal X-ray diffraction was used to determine the crystal structures of compounds
1 and
2
. A summary of the crystallographic data and structure refinement parameters are listed in Table 1.
The Oak Ridge Thermal Ellipsoid Plot (ORTEP) representation at 50% probability corresponding to the
asymmetric units of 1 and 2 are depicted in Figure 1.
Figure 1. ORTEP diagrams at 50% probability for the asymmetric units of
1 (a) and 2 (b) with atom
numbering scheme.
Table 1. Crystal data and structure refinement parameters of compounds 1 and 2.
Structural Parameters
Compound 1
Compound 2
Empirical formula
Formula weight
Temperature
C17H23N O
C16H19N O S
333.40
160 (1) K
3
2
3
3
301.38
160(1) K
1.54184 Å
Wavelength
1.54184 Å
Crystal system
Space group
Monoclinic
I 1 2/a 1
Orthorhombic
Pbca
a = 11.34690(10) Å
b = 6.66810(10) Å
c = 40.4828(5) Å
a = 6.78143(15) Å
b = 11.4079(3) Å
c = 39.1760(8) Å
Unit cell dimensions
◦
◦
β = 90
β = 94.9240(10)
Volume (Å3)
3051.72(7)
8
1.312
0.700
1296
3030.74(12)
Z
8
1.461
2.073
3
Calculated density (mg/m )
Absorption coefficient (mm 1)
−
F(000)
Crystal size (mm )
1408
3
0.13 × 0.04 × 0.02
4.385 to 74.475
14, 7,
0.12 × 0.065 × 0.015
◦
◦
4.515 to 74.488
Theta range for data collection
Index ranges
−14
≤
h
≤
−
8
≤
k
≤
−50
≤
l
≤
49
−8
≤
h
≤
7,
−
14
≤
k
≤
14,
−47
≤
l
≤
48
Reflections collected
Independent reflections
Completeness
25245
13432
3122 [R(int) = 0.0342]
100.0%
3102 [R(int) = 0.0384]
100.0%
Max. and min. transmission
Data/restraints/parameters
0.985 and 0.929
3122/0/211
0.973 and 0.846
3102/0/212
2
Goodness-of-fit on F
1.045
1.071
Final R indices [I > 2σ(I)]
R indices (all data)
R = 0.0365, wR = 0.0957
R = 0.0395, wR = 0.1001
1
2
1 2
R = 0.0424, wR = 0.0993
R = 0.0493, wR = 0.1046
1
2
1
2
Largest diff. peak and hole (e.Å 3)
−
0.252 and −0.216
0.505 and −0.273
CCDC number
1992005
1992009

Molecules 2020, 25, 1934
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The water molecule in the crystal structure of
1
participates in three classical hydrogen bonds,
two as a donor, O-H···O(carbonyl) and O-H···N(pyridine), and one acting as an acceptor, N2-H···
Table 2, Figure 2). Additionally, O1 participates in a non-classical hydrogen bond C2-H2···O1 with an
presents only one
O
(
◦
H2···O1 distance of 2.46 Å and an angle of 129.20 . On the other hand, compound
2
classical hydrogen bond involving the N atom of the hydrazide group and an O atom of the nitro group
of a contiguous molecule (Table 2). Also, the O3 (carbonyl) participates in a non-classical hydrogen
◦
bond C2-H2···O3 with an H2···O3 distance of 2.80 Å and an angle of 126.62 . The participation of
the carbonyl O atoms in low-energy H-bonds was evidenced by the shift of the carbonyl stretching
vibrational modes to lower frequencies in the experimental FT-IR discussed in Section 2.3.
◦
Table 2. Hydrogen bonding geometrical parameters for compounds 1 and 2 (Å, ).
D-H···A
d(D-H)
d(H···A)
d(D···A)
<(DH···A)
Compound 1
0.881(17)
0.90(2)
N(3)-H(3A) ···O(2)#1a
1.959(17)
1.95(2)
1.93(3)
2.8345(14)
2.8368(14)
2.8118(16)
172.8(15)
165(2)
172(2)
a
O(2)-H(2A) ···N(1)#2
O(2)-H(2B) ···O(1)
0.89(3)
Compound 2
2.19(3)
N(3)-H(3) ···O(2)#1b
0.82(3)
2.881(2)
142(3)
a
a
Symmetry transformations used to generate equivalent atoms:
1
: #1 x
−
1/2,
−
y + 1, z, #2 –x + 1, y + 1/2, z + 1/2;
−
b
2
: #1 –x + 1, y − 1/2, −z + 3/2.
Figure 2. Hydrogen bond (blue dashed line) scheme for compound 1. Atom color code: C (grey),
H (white), O (red), N (blue), S (yellow).
Hirshfeld surface analysis was performed in order to semi-quantitatively interpret intermolecular
interactions present in the crystal structure. The parameter dnorm was mapped throughout the surface,
allowing for the recognition of low energy bond hot-spots. The used color code for dnorm vs. van
der Waal contacts is blue for longer distances, white for equal distances, and red for dnorm distances
shorter than the sum of the van der Waals radii of the participating atoms. To aid in the recognition of
the type of interactions observed in the crystal structure, the electrostatic potential of the gas phase
DFT-optimized molecular models was mapped on an isodensity surface (isodensity value = 0.0004 e)
with a scale ranging from −0.03 V (red) to +0.03 V (blue). The results are shown in Figure 3.

Molecules 2020, 25, 1934
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Figure 3. Isodensity (0.0004 e) and Hirshfeld surfaces for compounds
1
(
a
and
b) and 2 (c and d).
The electrostatic potential is mapped on the isodensity surfaces from red (
Atom color code: C (grey), N (blue), O (red), H (white), S (yellow).
−0.03 V) to blue (+0.03 V).
The charge is asymmetrically distributed in the compounds. Negative charge is located
predominantly around the carbonyl oxygen and pyridine nitrogen atoms for compound and
the carbonyl oxygen and nitro-oxygen atoms for , whereas the positive charge surrounds the N-H
1
2
and C-H bonds in the hydrazine group in both cases. As a consequence, the compounds stack in an
antiparallel fashion in the solid state, generating a layered structure along the crystallographic b axis
for 1 and the a axis for 2 (Figure 4).
Figure 4. View of crystal packing of compound
along the crystallographic b axis (b).
1 along the crystallographic a axis (a) and compound 2
Fingerprint 2D plots were constructed in order to assess the frequency of the different contacts
within the Hirshfeld surface (Figure 5a,b). One of the biggest differences is the splitting of the H
bond zone (marked with green and purple arrows) in the
between hydrogen bonds with an O and a N atom acting as H-bond acceptor. This feature is the
consequence of the pyridine N atom in the structure of . On the other hand, presents various
1 plot, where it is possible to discriminate
1
2
sulfur-mediated contacts, including S···S, S···N and S···H, as it can be seen on Figure 5c in the contact
percentage distribution graph. It is also worth mentioning that there is a significant difference between
the contributions of polar contacts in both compounds. For compound 1, polar contacts account for

Molecules 2020, 25, 1934
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18%, while they constitute 42% of the contacts determined for
2
. This is probably the cause of the
higher calculated density and symmetry for
orthorhombic one.
2; 1 crystallizes in a monoclinic space group and 2 in an
Figure 5. Fingerprint 2D plots for
compounds in the surface (c).
1 (a) and 2 (b). Contact percentage contribution of the studied
2
.3. Infrared Spectra
Infrared spectroscopy was employed to further structurally characterize both molecules.
Such information will also be useful in the future to assess the identity and structure of similar
compounds. The infrared spectral profiles of compounds and are depicted in Figure 6. In order to
1
2
assign the vibrational bands, the spectra were computationally simulated at the B3LYP/6-31+G(d,p)
level of theory (blue spectral profiles in Figure 6), and the results were analyzed in depth on the basis
of the potential energy distribution (PED; see Tables S1 and S2). Even though the calculations were
performed in the gas phase, the computed geometries showed an excellent performance at simulating
the solid-state molecular structures of both compounds (see structural discussion below), giving
evidence of the validity and robustness of the computational model (Figure 7).

Molecules 2020, 25, 1934
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Figure 6. Experimental and calculated IR spectra of compounds 1 (a) and 2 (b). Theoretical spectra were
determined from the gas-phase optimized geometries at the B3LYP/6-31+G(d,p) level. The assignment
of the most important IR bands are depicted.
Figure 7. Density functional theory (DFT)-optimized geometries of compounds 1 (a) and 2 (b) at the
B3LYP/6-31+G(d,p) level of theory. The corresponding crystal structures are shown superimposed in
green. Atom color code: C (grey), H (white), O (red), N (blue), S (yellow).

Molecules 2020, 25, 1934
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2
.3.1. Vibration Modes of the Adamantyl Component
Both IR spectra show bands that indicate the presence of the adamantyl group, related to vibrations
involving single C-H and C-C bonds. In detail, the C-H bond stretchings are registered as strong
−
1
−1
1, and 2909 and 2849 cm for compound 2.
peaks centered at 3015, 2903, and 2849 cm for compound
The same vibrational modes have been reported for other adamantyl-containing compounds in the
range 2982 to 2902 cm
have been experimentally observed to be scattered over a wide frequency range. In particular,
modes are found between 1508 and 1416 cm for compound
−1
[31
,
32]. Besides, the in-plane C-H bending modes of the adamantyl fragment
HCH
, and at around 1431 cm for compound
δ
−
1
−1
1
−
1
2
, in line with previous evidence for similar molecules (reported between 1514 and 1405 cm ) [31,33].
The CH and C-CH wagging, twisting, and rocking normal vibrations (summarized as torsional and
2
out-of-plane bending modes in Tables S1 and S2) are predicted as several peaks in the ranges 1352 to 862
−
1
−1
(2
cm
with
(
ρ
1
) and 1333 to 910 cm
). This is a characteristic spectral feature of the adamantyl fragment,
−
1
(C-H) vibrations experimentally located between 1343 and 840 cm
[31]. Other molecular
vibrations that evidence the presence of the adamantyl moiety are the single C-C bond stretching
−
1
modes. They have been found in the range 1039 to 748 cm
[31], and are in fact present in the IR
−
1
−1
spectra of compound 1 (1043–704 cm ) and 2 (1032–669 cm ).
0
2
.3.2. Vibration Modes of the of the N -Methyleneacetohydrazide Moiety
The peaks observed at 3447 cm 1 (compound
−
1
−1
) and 3445 cm (compound 2) can be accounted
0
for by the N-H stretching present in the N -methyleneacetohydrazide moiety. This mode has been
computationally predicted at around 3463 cm , in agreement with the experimental evidence reported
−
1
−
1
for aromatic compounds [34
in compound spectrum, and those in the range 1452 to
the expected frequency interval [36].
,35]. In-plane HNN bending modes are assigned to the peaks at 1508 cm
−1
1
−
1431 cm in compound 2 spectrum, within
Other vibrational modes related to the stretching of N-N and C-N bonds are indicative of
0
the presence of the N -methyleneacetohydrazide group.
ν
(N-N) normal modes have been recently
−
1
reported [37] at 1157 and 1012 cm and, in fact, they are observed in the spectral profiles of compound
(1182 and 1107 cm 1) and compound
the spectrum of compound at 1595 and 1263 cm can be safely ascribed to
The same vibrations are experimentally observed for compound at 1537, 1179, 1032, and 972 cm .
Indeed, the characteristic region for these vibrations has been theoretically predicted between 1646 and
−
2 (1179 and 1107 cm ). The sharp and intense peaks found in
−1
1
−1
1
ν(C-N) normal modes.
−1
2
−
1
8
41 cm [38].
The presence of the N -methyleneacetohydrazide group in both molecules can also be verified
by looking at the intense and sharp peaks at 1663 and 1686 cm for compound
0
−
1
1 and compound 2,
respectively. These bands are ascribed to the C=O stretching vibration, in agreement with previous
−1
reports on similar systems (ν˜exp = 1661 cm ) [39]. In general terms, carbonyl compounds show
very intense and narrow peaks related to this normal mode, mainly located in the range 1800 to
−1
1600 cm
[36,39]. The low values of the carbonyl stretching wavenumbers for both molecules can be
explained by the conjugation of the C=O bond with the hydrazide moiety, which decreases its double
bond character. Another factor that contributes to this effect is the participation of the carbonyl group
in the net of H-bonds within the crystal structure (vide infra).
2
.3.3. Vibration Modes of the of the Pyridine or 2-Nitrothiophene Groups
The infrared spectrum of compound displays characteristic bands of the pyridyl fragment.
The stretching of the single C-H bonds are observed as a broad and intense peak at 3175 cm , slightly
1
−1
−
1
above of the frequency range of the equivalent vibration modes for pyridine (3083–3030 cm ) [37].
−
1
The
vibrations have been reported for pyridine at 1581, 1573, 1030, and 991 cm
ν(C-N) and ν(C-C) normal modes are also registered at 1555, 1263, 1182, 983, and 941 cm . Similar
−
1
[40]. In-plane bending

Molecules 2020, 25, 1934
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−1
of C-N-C, C-C-C, and C-C-N bonds of the pyridyl ring were observed at 704 and 584 cm , near the
reported values of 653 and 604 cm for pyridine [40].
−1
The infrared bands associated with the 2-nitrothiophene fragment are present in the spectral
−
1
profile of compound
with the expected wavenumber range for aromatic compounds [41]. The
2
. The C-H stretchings at the thiophene ring appear at 3221 and 3102 cm , in line
(C=C) normal modes are
also observable in the spectrum, mainly near 1504 and 1431 cm , close to the values already reported
ν
−1
−1
for the thiophene ring (1500 and 1430 cm ) [41]. Regarding the C-S stretching mode, the analysis is
not straightforward, since it is highly coupled with the C-C and C-N stretching vibrations. However,
(C-S), and it has been observed between 522
and 680 cm for similar systems [33]. Finally, the presence of the nitro group is revealed by the
intense bands registered at 1504 and 1452 cm (N-O antisymmetric stretching) and at 1333 cm (N-O
symmetric stretching). Moreover, a sharp and intense peak centered at 733 cm is also ascribed to the
in-plane O-N-O bending. These wavenumbers are comparable with the ones reported in the literature:
−
1
the peak at 584 cm has an important contribution of
ν
−1
−
1
−1
−
1
−
1
−1
−1
νasym(N-O) = 1530 cm , νsym(N-O) = 1350 cm , and δ(O-N-O) = 734 cm [42].
2
.4. Electronic Spectra
As a first step to assess the electronic spectra of
1 and 2, the compounds’ geometries were
DFT-optimized in methanolic medium. The results indicate that, in solution, the pyridyl and
◦
2
-nitrothiophene rings rotate 180 as a consequence of the absence of the intermolecular interactions
observed in the solid state (Figure 8).
Figure 8. DFT-optimized geometries of
1 (a) and 2 (b). The corresponding crystal structures are shown
superimposed in green. Atom color code: C (grey), H (white), O (red), N (blue), S (yellow).
UV-vis absorption spectra of compounds
1 and 2 in methanol were recorded in the 200–600
nm range. The results are shown in Figure 9a,b. To aid in the discussion, a holistic view of the
light absorption process was furnished by single-point TD-DFT calculations carried out in solution.
That allowed us to compute the electron density difference maps (EDDM) associated with the most
probable electronic transitions, which show, in a picturesque way, how the electron density changes
during the light absorption (it moves from purple to cyan zones; see Figure 8a,b). As expected, the
saturated adamantyl group does not contribute to the registered UV-vis absorption bands [33].

Molecules 2020, 25, 1934
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Figure 9. UV-vis spectra of a 10
spectra (CAM-B3LYP-SMD/6-311+G(d,p)) are depicted as solid and dashed lines, respectively. For the
theoretical spectra, the half-width at half-height is 0.333 eV. In ( ) and ( ), the molecular orbitals involved
µg/mL methanolic solution of 1 (a) and 2 (b). Experimental and calculated
c
d
in the different electronic transitions and their energies are shown for both systems. The electron density
difference maps (EDDM) associated with the electronic transitions are also depicted. The electron
density changes from purple to cyan upon light absorption. Atom color code: C (grey), H (white),
O (red), N (blue), S (yellow).
The spectral profile of compound
1 shows two main bands centered at λmax = 215 and λmax = 292
nm, which are satisfactorily simulated by the computational model (Figure 9a). The first one (
λ
calculated
=
206 nm) is predicted to involve π → π* electronic transitions, with two main associated electronic
promotions: HOMO-5 LUMO (66% contribution) and HOMO LUMO+1 (17% contribution).
On the other hand, the experimental absorption band at 292 nm is computationally predicted at
79 nm, and it comprises one electronic transition brought about by a π → π* HOMO-LUMO
electronic promotion (96% contribution). According to the EDDM surfaces of both UV-visible bands,
→
→
2
during the light absorption, the electron density flows within the
π
-delocalized system, from the
0
N -methyleneacetohydrazide moiety to the pyridyl ring at 292 nm and backwards at 215 nm.
The electronic spectra of compound 2 exhibits three absorption bands, showing a satisfactory fit
with the calculated spectral profile (Figure. 8b). The most energetic one was registered at 217 nm and
computationally predicted at 213 nm. It is ascribed to a π → π* electronic transition that has a 92%
contribution of the electron promotion from HOMO-14 to LUMO. Interestingly, the EDDM surface
reveals that, during the light absorption associated with this band, the electron density is transferred
from the nitro group towards the thiophene ring and the methyleneacetohydrazide moiety. The band
located around 262 nm (
λ
= 261 nm) is brought about by the contribution of two electronic π →
calculated

Molecules 2020, 25, 1934
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π
* promotions: HOMO-5
similarly to the band registered at 215 nm for compound
= 384 nm) and exhibits a tail that extends toward the visible range. The associated light
→
LUMO (23% contribution) and HOMO
→
LUMO+1 (72% contribution),
1. Finally, the third band is centered at 380 nm
(λ
calculated
absorption mechanism is similar to the one described for the 292 nm absorption band of compound
, and entails a HOMO-to-LUMO electronic transition (93% contribution). It is worth noting that,
according to the calculated EDDM surfaces, there is a retrodonation of electron density from the
1
methyleneacetohydrazide and thiophene moieties to the nitro group upon light absorption at
and 380 nm.
λ = 262
2
.5. In Vitro Antimicrobial and Antifungal Activity
The in vitro antimicrobial activity of compounds
1 and 2 was assessed against the standard
Gram-positive bacterial strains of the American type culture collection (ATCC), Staphylococcus aureus
ATCC 6571, Bacillus subtilis ATCC 5256, and Micrococcus luteus ATCC 27141, the Gram-negative
bacterial strains, Escherichia coli ATCC 8726 and Pseudomonas aeruginosa ATCC 27853, and the yeast-like
pathogenic fungus Candida albicans MTCC 227. The primary screening was performed using the
semi-quantitative agar-disc diffusion method with Müller–Hinton agar medium [43]. The results of
the preliminary antimicrobial screening of compounds 1, 2 (200 µg/disc), the antibacterial antibiotics
gentamicin sulfate and ampicillin trihydrate, and the antifungal drug clotrimazole (100
outlined in Table 3.
µg/disc) are
Table 3. In vitro diameter of growth inhibition zones of compounds
the broad-spectrum antibacterial drugs Gentamicin sulfate and Ampicillin trihydrate, and the antifungal
drug Clotrimazole (100 g/8 mm disc) against Staphylococcus aureus ATCC 6571 (SA), Bacillus subtilis
1, 2 (200 µg/8 mm disc),
µ
ATCC 5256 (BS), Micrococcus luteus ATCC 27141 (ML), Escherichia coli ATCC 8726 (EC), Pseudomonas
aeruginosa ATCC 27853 (PA), and the yeast-like pathogenic fungus Candida albicans MTCC 227 (CA).
Diameter of Growth Inhibition Zone (mm)
SA
BS
ML
EC
PA
CA
Compound 1
Compound 2
Gentamicin sulfate
Ampicillin
28
31
27
26
32
26
23
22
20
12
22
22
14
19
21
15
11
NT
2
2
23
20
16
16
NT
21
trihydrate
Clotrimazole
NT
NT
NT
NT
NT
NT: not tested.
The main features of the results of the antimicrobial activity testing show that compounds
exhibit potent activity against the tested Gram-positive bacteria, with growth inhibition zones
and minimal inhibitory concentration (MIC) values comparable to the positive control antibiotics.
Compound specifically displays broad-spectrum antibacterial activity. The inhibitory activity of the
compounds against yeast-like pathogenic fungus C. albicans was lower than their antibacterial activity,
with moderate and weak activities for and 2, respectively. Taking into consideration the lipophilicity
of both compounds (calculated log P values: 2.513 ( ) and 3.3405 ( )), it could be concluded that the
1
and
2
2
1
1
2
inhibitory activity against the Gram-negative bacteria is correlated to their lipophilicty, the opposite
relationship is observed for the antifungal activity. The values of the minimal inhibitory concentration
(
MIC) in Müller–Hinton broth [44] for the tested compounds (Table 4) were correlated to the results
obtained in the preliminary screening.

Molecules 2020, 25, 1934
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Table 4. The minimal inhibitory concentration (MIC) of compounds 1, 2, the broad-spectrum
antibacterial drugs Gentamicin and Ampicillin, and the antifungal drug Clotrimazole against
Staphylococcus aureus ATCC 6571 (SA), Bacillus subtilis ATCC 5256 (BS), Micrococcus luteus ATCC
2
7141 (ML), Escherichia coli ATCC 8726 (EC), Pseudomonas aeruginosa ATCC 27853 (PA), and the yeast-like
pathogenic fungus Candida albicans MTCC 227 (CA).
MIC, µg/mL (µM)
SA
BS
ML
EC
PA
CA
Compound
Compound
Gentamicin
Ampicillin
Clotrimazole
1
2
1 (3.53)
1 (3.53)
2 (7.06)
1 (3.0)
64 (225.85)
2 (6.0)
>64
2 (6.0)
0.5 (1.05)
8 (22.90)
NT
64 (225.85)
>64
NT
NT
4 (11.60)
0.5 (1.50)
0.5 (1.50)
1
1
1
1
1
1 (2.09)
2 (4.19)
1 (2.86)
2 (4.19)
2 (5.72)
NT
0.5 (1.05)
8 (22.90)
2 (5.72) 2
NT
2
2
2
2
NT
NT
1
M values were calculated based on Gentamicin base, 2
µM values were calculated based on anhydrous Ampicillin,
µ
NT: not tested.
3
. Materials and Methods
3
.1. Instrumentation
◦
Melting points ( C, uncorrected) were measured in open glass capillaries using a Branstead 9100
Electrothermal melting point apparatus. Nuclear magnetic resonance (NMR) spectra were obtained on
1
13
a Bruker Ascend 700 NMR spectrometer at 700.17 MHz for H and 176.08 MHz for C, using DMSO-d6
as solvent. Monitoring the reactions and checking the purity of the final products were carried out
by thin layer chromatography (TLC) using silica gel precoated aluminum sheets (60 F254, Merck) and
visualization with ultraviolet light (UV) at 365 and 254 nm. Single-crystal X-ray diffra ction data
were collected on a Rigaku OD XtaLAB Synergy, Dualflex, Pilatus 200K diffractometer, using a single
wavelength X-ray source (Cu Kα radiation: λ = 1.54184 Å) from a micro-focus sealed X-ray tube and an
Oxford liquid-nitrogen Cryostream cooler. Fourier transform infrared (FT-IR) spectra were measured
−1
using KBr pellets in the 400–4000 cm region on a Shimadzu IR Prestige 21 spectrometer. UV-Vis
spectra were determined using a Shimadzu UV-1601 PC UV-Visible double-beam spectrophotometer
with matched 1 cm path-length quartz cell. The experimental details of the determination of in vitro
antimicrobial activity are given in Supplementary Materials.
3
.2. Synthesis, Crystallization, and Single Crystal X Ray Determination
0
3
.2.1. E-N -[(Pyridine-3-yl)methylidene]adamantane-1-carbohydrazide 1
Pyridine-3-carboxaldehyde (1.07 g, 0.01 mol) was added to a solution of adamantane-1-
carbohydrazide (1.94 g, 0.01 mol), in ethanol (15 mL), and the mixture was heated under reflux
for two hours. The mixture was then concentrated to half the original volume and water (5 mL) was
added and allowed to stand overnight. The precipitated crude product was filtered, washed with
water, dried, and crystallized from EtOH/H O to yield (2.32 g, 82%) of the monohydrate of compound
2
1
as transparent colorless needle crystals. The anhydrous compound was obtained after drying in a
◦
1
desiccator for 24 h. Mp: 185–187 C. H-NMR:
δ 11.01 (s, 1H, NH), 8.81 (s, 1H, CH=N), 8.61 (s, 1H,
Pyridine-H), 8.47 (d, 1H, Pyridine-H, J = 4.5 Hz), 8.01 (s, 1H, Pyridine-H), 7.48 (t, 1H, Pyridine-H,
J = 4.5 Hz), 2.03 (s, 3H, Adamantane-H), 1.88 (s, 6H, adamantane-H), 1.72 (s, 6H, adamantane-H).
13
C-NMR:
δ 173.86 (C=O), 150.95, 149.05, 133.73, 130.79, 124.48 (Pyridine-C), 144.35 (CH=N), 39.77,
3
3
8.73, 36.53, 28.05 (adamantane-C).
0
.2.2. E-N -[(5-Nitrothiophen-2-yl)methylidene]adamantane-1-carbohydrazide 2
5
-Nitrothiophene-2-carboxaldehyde (1.57 g, 0.01 mol) was added to a solution of adamantane-1-
carbohydrazide (1.94 g, 0.01 mol), in ethanol (15 mL), and the mixture was heated under reflux for

Molecules 2020, 25, 1934
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one hour. On cooling, the precipitated crude product was filtered, washed with cold ethanol, dried,
and crystallized from EtOH to yield (3.17 g, 95%) of compound as transparent pale yellow crystals.
Single crystals suitable for X-ray diffraction were obtained by slow evaporation of a solution of the title
2
◦
1
compound in EtOH/CHCl (1:2, v/v) at room temperature. Mp: 233–235 C. H-NMR: δ 11.24 (s, 1H,
3
NH), 8.68 (s, 1H, CH=N), 8.12 (d, 1H, Thiophene-H, J = 4.2 Hz), 7.51 (d, 1H, Thiophene-H, J = 4.2 Hz),
.02 (s, 3H, Adamantane-H), 1.87 (s, 6H, adamantane-H), 1.68–1.73 (m, 6H, adamantane-H). 1 C-NMR:
3
2
δ
174.18 (C=O), 151.03, 147.73, 130.99, 129.58 (Thiophene-C), 140.63 (CH=N), 39.74, 38.55, 36.42, 27.96
(adamantane-C).
The selected suitable single crystals of compounds
1
and 2 were mounted using polybutene oil
on a flexible loop fixed on a goniometer head and immediately transferred to the diffractometer.
Pre-experiment, data collection, data reduction, and analytical absorption correction [45] were
performed with the program suite CrysAlisPro [46] using the Olex2 program [47]. The structures were
solved with the SHELXT [48] small molecule structure solution program and refined with the SHELXL
2
2
018/3 program package [49] by full-matrix least-squares minimization on F . PLATON [50] was used
to check the result of the X-ray analysis. For more details about the data collection and refinement
parameters, see the CIF files.
3
.3. Computational Details
3
.3.1. Hirshfeld Surface Analysis
Hirshfeld surfaces were calculated in order to provide a semi-quantitative analysis of
intermolecular interactions using CRYSTAL EXPLORER17 [51]. The normalized contact distance
(dnorm), mapped throughout the surface, is defined as:
vdW
vdW
e
vdW
d − r
i
de − r
i
dnorm =
+
vdW
r
r
e
i
where d
e
and d represent the distances from a point on the surface to the nearest nucleus outside and
i
vdW
inside the surface, respectively, and r
involved. Based on that information, a 2D fingerprint plot of d
corresponds to the van der Waals (vdW) radii of the atoms
vs. d distances within the surface and
e
i
their frequency was determined to provide quantitative information on the interactions throughout
the crystal structure [52,53].
3
.3.2. DFT Calculations
Starting geometries for compounds 1 and 2 were extracted from the X-ray crystallographic data
and fully optimized without symmetry constraints by means of the density functional theory method
DFT) [54], employing the B3LYP functional [55] and the 6-31+G** basis set [56]. The calculations
(
were performed in the gas phase, with an ultrafine integration grid, employing the Gaussian 09
code [57]. To make a detailed assignation of the infrared spectra, the calculated vibrational modes
were characterized by means of the potential energy distribution (PED) with the program VEDA 4 [58].
The computed vibrational frequencies were scaled using a factor of 0.964 [59].
To model the electronic spectra in methanol, the X-ray crystallographic structures of both
molecules were pre-optimized in solution by molecular mechanics, employing the MMFF94X forcefield
3
(
energy gradient = 0.01 kcal/mol/Å ), as implemented in MOE [60]. The solvent was modeled by
means of the Generalized Born model (ε = 33.1). To explore the conformational space, a search on
the potential energy surface was carried out with the LowModeMD method [61] using the same
3
forcefield and solvation method, without cut-offs, and with a RMS gradient = 0.005 kcal/mol/Å
(
rejection limit = 100; RMSD limit = 0.25 Å; energy window = 7 kcal/mol; iteration limit = 10,000).
The number of conformations found were 4 for and 16 for . Then, the most stable conformers
were re-optimized in solution by DFT (B3LYP/6-31+G**). The influence of the solvent was simulated
1
2

Molecules 2020, 25, 1934
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by an IEFPCM method (implicit solvation), with radii and non-electrostatic terms from Truhlar and
coworkers’ SMD solvation model [62]. Finally, single-point TD-DFT calculations were carried out on
the optimum geometries to simulate the UV-visible light absorption process [55]. Fifty singlet-to-singlet
electronic transitions were considered and their vertical energies were computed in methanol at the
CAM-B3LYP-SMD/6-311+G(d,p) level of theory [63]. An in-depth analysis of the light absorption
mechanism was carried out with the aid of the GaussSum 3.0 program [64]. The electron density
difference maps (EDDM) and the molecular orbitals related to the most probable electronic transitions
were computed, considering the contribution of three molecular fragments, namely: i) pyridyl (
1
) or
0
2
-nitrothiophen-2-yl (
2) group, ii) N -methyleneacetohydrazide moiety, and iii) adamantyl group. In all
cases, the nature of the stationary states was verified by analytically computing the Hessian matrix.
The optimized geometries were found to have only real vibrational frequencies. The computational
results were rendered with Discovery Studio Visualizer and Gaussview 5.0 [65].
4
. Conclusions
In the present study, two novel N -[(heteroaryl)methylene]adamantane-1-carbohydrazides
compounds and ) were prepared and tested for growth inhibitory activity. Both molecules displayed
potent antibacterial activity against a panel of pathogenic Gram-positive and Gram-negative bacteria
and the yeast-like pathogenic fungus Candida albicans. Compound showed potent broad-spectrum
antibacterial activity and marginal antifungal activity, while compound displayed potent activity
0
(
1
2
2
1
against the tested Gram-positive bacterial strains and moderate activity against the tested Gram-negative
bacteria and Candida albicans. According to the preliminary antimicrobial results, the tested compounds
are considered to be good candidates as new antibacterial agents.
Compounds
1 and 2 were fully characterized by applying a wide range of experimental and
computational methods. They revealed that the electron density is asymmetrically distributed in both
molecules, giving rise to positively and negatively charged zones that interact through polar contacts
in the crystalline state. This interaction scheme extends along the lattice, compelling the molecules to
stack themselves in an antiparallel fashion. Nevertheless, there is a differential contribution of the
polar contacts to the stability of the lattice:
1 (18%) and 2 (42%), modulating the density and symmetry
observed in the crystals. Additionally, both molecules act as chromophores, showing intense UV-vis
light absorption bands brought about by electronic transitions within the π-delocalized system.
Further investigations, including the preparation of novel related derivatives, are required for
optimization of the antibacterial activity and for exploration of the mechanism of the compounds’
biological activity. We are currently working on those lines, and the results will be published in
due course.
Supplementary Materials: The experimental details of the determination of in vitro antimicrobial activity,
1
13
H NMR, C-NMR spectra and the infrared spectroscopy data of compounds
available online. The supplementary crystallographic data for compounds
992009) can be obtained free of charge from The Cambridge Crystallographic Data Centre at: www.ccdc.cam.ac.uk.
1
(Table S1) and
2
(Table S2) are
1
(CCDC 1992005) and
2
(CCDC
1
Author Contributions: L.H.A.-W., A.A.E.-E., and A.A.A.-M. designed the study, synthesized and characterized
the title compounds, and prepared the single crystals. N.A. and N.V. conducted the infrared, UV-vis spectroscopy,
Hirshfeld analysis, and DFT studies. O.B. performed the X-ray data collection and the solution of the crystal
structure. All authors contributed in the preparation of the manuscript, discussed the contents, and approved the
submission. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman
University through the Fast-track Research Funding Program.
Acknowledgments: N. Alvarez and N. Veiga thank PEDECIBA Química.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2020, 25, 1934
15 of 17
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