Synthesis, Molecular Docking and Biological Evaluation of 2-Aryloxy-N-Phenylacetamide and N′-(2-Aryloxyoxyacetyl) Benzohydrazide Derivatives as Potential Antibacterial Agents

Article abstract of DOI:10.1002/cbdv.202000907

A new class of 2-aryloxy-N-phenylacetamide and N′-(2-aryloxyoxyacetyl) benzohydrazide derivatives with different active moieties were synthesized and screened for their antibacterial activity. Structural characterization of synthesized compounds was perfo

Full text of DOI:10.1002/cbdv.202000907

DOI: 10.1002/cbdv.202000907
FULL PAPER
Synthesis, Molecular Docking and Biological Evaluation of 2-Aryloxy-
N-Phenylacetamide and N’-(2-Aryloxyoxyacetyl) Benzohydrazide
Derivatives as Potential Antibacterial Agents
Vidyasrilekha Yele,a Mohammad Afzal Azam,*a and Ashish D. Wadhwanib
a
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ooty-643001, Tamil Nadu, India,
e-mail: afzal9azam@hotmail.com; afzal@jssuni.edu.inb
Department of Biotechnology, JSS College of Pharmacy (A Constituent College of JSS Academy of Higher
b
Education and Research) Ooty-643001, Tamil Nadu, India
A new class of 2-aryloxy-N-phenylacetamide and N’-(2-aryloxyoxyacetyl) benzohydrazide derivatives with
different active moieties were synthesized and screened for their antibacterial activity. Structural characterization
1
of synthesized compounds was performed using HR-MS, H-NMR, and 13C-NMR spectral data. Amongst the
synthesized compounds, 4-{2-[2-(2-chloroacetamido)phenoxy]acetamido}-3-nitrobenzoic acid (3h) and 2-chloro-
N-(2-{2-[2-(2-chlorobenzoyl)hydrazinyl]-2-oxoethoxy}phenyl)acetamide (3o) have shown good antibacterial
activity against a selected panel of bacteria. Besides, compounds also exhibited bactericidal activity against P.
aeruginosa (3h, 0.69 μg/mL) and S. aureus (3o, 0.62 μg/mL) as evident by MBC and time-kill kinetics studies. In
silico molecular docking and ADMET properties of newly synthesized compounds revealed that compounds
could be considered as promising antibacterial agents.
Keywords: 2-aryloxy-N-phenylacetamide derivatives, N’-(2-aryloxyoxyacetyl) benzohydrazide derivatives, anti-
bacterial activity, molecular docking, binding free energy.
lance system (GLASS), world antimicrobial awareness
week (WAAW), and interagency coordination group on
Introduction
Antimicrobial resistance (AMR) has become a global antimicrobial resistance (IACG).[7–10] Evaluation of
concern due to the emergence and dissemination of several nominees for combating AMR is under the
new resistance mechanisms.[1,2] Thus, threatening our developmental process that states that the focus of
ability to treat common infections eventually leads to research would be on identifying and discovering new
extended illness and death.[3] Global AMR shows no small molecule entities. Though the present status of
signs of decline, although it may perhaps shift biologics or small molecules for infection control is
direction. AMR’s etiology is multifaceted, and its infancy, its potential to overcome AMR cannot be
consequences pose
worldwide.[4,5] AMR often occurs naturally or through conceivably be pursued logistically. One of the main
genetic manipulations over time. strategies to develop a small molecule is by conjoining
a more remarkable impact overlooked. The search for a significant lead may
Moreover, the overuse of antibiotics is hastening bio-active entities known to possess antibacterial
this phenomenon.[6] To address AMR, the world health activities into a lead. This can be potentially achieved
organization provided multiple initiatives such as by modern drug design and discovery approaches
global antibiotic research and development partner- such as molecular hybridization techniques.[11,12]
ship (GARDP), global antimicrobial resistance surveil-
Benzohydrazide has gained a particular interest in
medicinal chemistry due to its broad range of
pharmacological activities against bacterial, mycobac-
terial, and leishmanial infections. Extensive research
has been performed to discover novel molecules
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.202000907
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Chem. Biodiversity 2021, 18, e2000907
containing benzohydrazide scaffold to treat bacterial describes the synthesis and antimicrobial evaluation of
infections. Martin et al.[13] reported the synthesis of 2-phenoxy derivatives combined with triazolo-quina-
novel 4-(trifluoromethyl) benzohydrazide derivatives zoline complexes. Also, Siddiqui et al.[18] exemplified
against nosocomial pathogens such as mycobacterium the biological activity of phenoxy acetic acid deriva-
sp. and resistant strains. Bala et al.[14] reported the tives against mycobacterium sp. Some studies also
synthesis of substituted-N’-((1E)-substituted phenyl- stated that the phenoxy moiety with heterocyclic
methylidene) benzohydrazide derivatives that dis- scaffolds might increase antimicrobial activity. One
played significant activity against microorganisms. such study by Gaonkar et al.[19] demonstrated the
Further, a study by Raparti et al.[15] has disclosed the increased activity of phenoxy derivatives when con-
novel series of 4-(morpholin-4-yl)-N’-(arylidene) benzo- joined with substituted isooxazoline derivatives using
hydrazide and its derivatives as potential antibacterial 1,3-diploar cycloaddition. Further, More et al.[20] re-
agents. Jorge et al.[16] recently described the synthesis ported the target-based discovery of phenoxy deriva-
of N’-(benzofuroxan-5-yl)methylene benzohydrazide tives as antimycobacterial agents (Scheme 1 (1e–1h)).
and its derivatives as anti-trypanosomal agents
(Scheme 1 (1a–1d)).
Phenylacetamide is chosen as another versatile
organic compound incorporated into drug design and
The other organic compounds that have gained discovery to synthesize novel small molecule inhibitors
interest among the necessary scaffolds in the drug with biological significance. Ertan et al.[21] reported the
discovery and development processes are phenoxy synthesis of N-(2-hydroxy-4 (or 5) nitro/aminophenyl)
derivatives because of the broad-range of pharmaco- benzamides and phenylacetamide derivatives as po-
logical activities. A recent report by Abuelizz et al.[17] tential antibacterial and antifungal agents. Further,
Scheme 1. Designing of pharmacophoric groups into 2-aryloxy-N-phenylacetamide and N’-(2-aryloxyoxyacetyl) benzohydrazide
derivatives.
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Esin et al.[22] reported the synthesis of substituted
Here, we report the synthesis of 2-aryloxy-N-
phenylacetamides and benzamide derivatives as po- phenylacetamide and N’-(2-aryloxyoxyacetyl) benzohy-
tential antimicrobials. Additionally, Lu et al.[23] de- drazide derivatives 3a–3r (Scheme 2). The scaffolds are
scribed the efficacy of N-phenylacetamides containing conjoined to evaluate the effect of the substituent’s
4-arylthiazole scaffold as effective antibacterial agents. presence or absence on antibacterial activity. Synthe-
A study by Fan et al.[24] unveiled the biological activity sized compounds 3a–3r were screened against a
of 2-({2-[4-(1H-1,2,4-triazol-1-yl)phenyl]quinazolin-4-yl} selected panel of Gram-negative (GN) and Gram-
oxy)-N-phenylacetamide and its derivatives against positive (GP) nosocomial pathogenic bacteria. ParE has
various phytopathogens (Scheme 1 (1i–1l)).
become an attractive antibacterial target as there is no
The excellent strategy for drug design and develop- human homologue and inhibition of ParE is bacter-
ment is to merge the different pharmacophores icidal for both GP and GN bacteria, thereby making it a
known for their antibacterial or antimicrobial activity druggable target for discovering novel antibacterial
into novel pharmacologically-active compounds. Priya agents. Hence computational studies such as docking,
et al.[25] and Muluk et al.[26] described the effect of binding free energy calculation were employed to
substituted phenoxy moieties with phenylacetamide investigate the binding affinity of these compounds
and benzamide derivatives. Accordingly, from the against S. aureus ParE enzyme. In addition, toxicity
shreds of evidence, we successfully conjoined the properties and drug-like properties of these com-
phenoxy moiety (Scheme 1 (red)) with benzohydrazide pounds were also computed.
(Scheme 1 (blue)) and phenylacetamide (Scheme 1
(purple)).
Scheme 2. Synthesis of 2-aryloxy-N-phenylacetamide and N’-(2-aryloxyoxyacetyl) benzohydrazide derivatives (3a–3r).
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Results and Discussion
multiplet (m). Furthermore, the splitting of all aromatic
protons in 3h revealed the substitution pattern in the
Chemistry
phenyl ring of the phenylacetamide fragment. The H3’
The synthesis of 2-aryloxy-N-phenylacetamide and N’- proton of compound 3h appeared as doublet at
(2-aryloxyoxyacetyl) benzohydrazide derivatives (3a– 8.00 ppm by coupling with H5’ and J value is 2.78.
3r) was carried out using Scheme 2. The intermediates Whereas H5’ appeared as double doublet at 7.76 ppm
1, 2c, 2e and 2h were synthesized by reaction of with J values of 8.29 (ortho coupling with H6’) and 1.65
ortho-hydroxyaniline/substituted anilines with chloroa- (meta coupling with H3’). Further H6’ appeared as
°
cetyl chloride in acetic acid at 0 C using anhydrous doublet at 7.58 ppm with a J value of 7.5 (coupled
sodium acetate. Whereas intermediates 2a, 2b, 2d, 2f, with H5’). The proton H3 and H6 appeared as doublet
2g and 2i–2r were obtained by stirring together a at 6.94 (J=6.59) and 6.93 (J=6.42) ppm by coupling
mixture of appropriate substituted aniline and chlor- with H4 and H5, respectively. Whereas H4 and H5
°
oacetyl chloride in dichloromethane at 0 C using appeared as triplet at 6.92 (J=6.67) and 6.90 (J=6.87)
anhydrous potassium carbonate.
after coupling with adjacent protons.
The title compounds (3a–3r) were purified using
In the 13C-NMR spectra, the carbonyl groups of all
column chromatography by employing ethyl acetate/ the title compounds appeared as singlet signals in the
hexane mixture as an eluent at a ratio of 6:4. In the region from δ 169.42 to 162.41 ppm. In contrast, the
Fourier-Transform Infrared (FT-IR) spectrum, the title aromatic carbons appeared in the expected region. In
compounds 3a–3r characteristic absorption bands of compound 3h, the three >C=O peaks appeared at δ
amide >C=O appeared in the region 1629– 168.08, 165.34, and 163.45 ppm, whereas two signals
1665 cmÀ 1. While À NHÀ and À NHNHÀ bands were observed at δ 67.22 and 47.80 ppm are ascribed to
observed in the region 3124 to 3357 cmÀ 1. Addition- carbons of À OCH2À and À COCH2À fragments. Twelve
ally, the disappearance of characteristic band of À OH aromatic SP2 hybridized carbon signals appeared in
of 2-chloro-N-(2-hydroxyphenyl)acetamide (compound the expected region. Besides, the HR-MS data of the
1) and appearance of band due to linkage À OCH2À title compounds are in conformity with their respec-
supported the formation of title compounds 3a–3r.
Structural characterization of synthesized com-
pounds 3a–3r was performed using proton-nuclear
tive molecular formula.
magnetic resonance (1H-NMR) (Supplementary data In Vitro Screening
Figure S1(a–r)), 13C-NMR (Supplementary data Fig-
Minimum Inhibitory Concentration (MIC) Determination
ure S2(a–r)) and high resolution-mass spectral (HR-MS)
1
(Supplementary data Figure S3(a–r)) data. In H-NMR All the title compounds 3a–3r were screened for their
spectra of compounds 3a–3r, the specific À NHÀ microbial susceptibility studies using the micro broth
proton signals for phenylacetamide and benzohydra- dilution method by following the Clinical and Labo-
zide derivatives have been observed in the region ratory Standards Institute (CLSI) 2017 guidelines.[27]
from δ 10.78 to 9.42 ppm. Moreover, in compounds The antibacterial screening was performed against a
3c, 3e, and 3h, the carboxylic group OH signal has not selected panel of bacteria such as Staphylococcus
appeared, which may be because of the replacement aureus (NCIM 5022), Staphylococcus epidermis (NCIM
of exchangeable protons with deuterium. The peaks 2493), Escherichia coli (NCIM 2567), Bacillus subtilis
that appeared in the region from δ 4.78 to 4.22 ppm (NCIM 2545), Pseudomonas aeruginosa (NCIM 2036),
were attributed to the characteristic À CH2À singlet Klebsiella pneumonia (NCIM 2706), Salmonella typhi
signals of the title compounds. In compound 3h, the (NCIM 2501), and Mycobacterium sp. (NCIM 2984) in
two characteristic À NH protons were observed as a the concentration range of 0.62 to 15 μg/mL. All tested
singlet signal at δ 10.67 ppm. The two characteristic compounds (3a–3r) have shown substantial inhibitory
À CH2 protons appeared as a singlet signal at δ activity against the selected bacterial strains, as
4.56 ppm. The coupling constants (J values) of the evident by their significant inhibitory values.
synthesized compounds 3a–3r and chemical shift
Compounds 3a, 3c, 3f, 3g and 3h displayed
values were ascribed according to the position and significant activity against GN organisms such as K.
substitution of aromatic protons. Furthermore, aro- pneumonia, E. coli, P. aeruginosa, and S. typhi. However,
matic protons at the ortho, meta, and para positions these compounds exhibited variable activity towards
exhibited characteristic splitting patterns like singlet GP bacteria. Among these, compounds 3a (MIC,
(s), doublet (d), double doublet (dd) triplet (t), and 0.69 μg/mL), 3c (MIC, 0.67 μg/mL), 3f (MIC, 0.64 μg/
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Chem. Biodiversity 2021, 18, e2000907
mL) and 3g (MIC, 0.67 μg/mL) presented substantial compounds showing less activity. On the other hand,
activity against P. aeruginosa. From these results, it is compound 3i exhibited noticeable activity against S.
evident that aryloxy derivatives possessing electron epidermis (MIC, 0.98 μg/mL) and variable activity
withdrawing groups (À NO2, À COOH, À SO3H) at fourth against other tested organisms. The replacement of
position of phenyl ring in phenylacetamide fragment one of the aromatic rings with pyridine (compound
is found to be ideal for potent activity against GN 3p) and hydrazide with sulphonyl acetamide function
bacteria. Further, compound 3h exhibited potent (compound 3r) did not improve the activity against
activity against GN bacteria such as E. coli (MIC, the tested strains of bacteria. It is evident from results
0.70 μg/mL), P. aeruginosa (MIC, 0.69 μg/mL), K. pneu- (Table 1) that tested compounds 3a, 3c, 3f, and 3h
monia (MIC, 0.72 μg/mL), and S. typhi (MIC, 0.72 μg/ exhibited comparable activity with ciprofloxacin
mL). The high activity against these tested strains may against the tested strains of bacteria.
be due to the presence of electron-withdrawing À NO2
and À COOH groups, respectively, at the ortho and para
Minimum Bactericidal Concentration (MBC)
position of the phenyl ring.
Compounds belonging to the benzohydrazide MBC of the test compounds 3a–3r was assessed using
series containing electron releasing groups in 3 l (MIC, CLSI guidelines 2017.[27,28] MBC indicates the lower-
0.67 μg/mL) and 3m (MIC, 0.89 μg/mL) exhibited most concentration of antibiotics essential to kill the
significant activity against K. pneumonia. Besides, bacteria or 99% inhibition of bacteria. MBC/MIC ratio
compounds 3n (MIC, 0.71 μg/mL) and 3q (MIC, designates the profile of antibiotics (bactericidal or
0.68 μg/mL) exhibited their noteworthy activity against bacteriostatic). The ratio MBC/MIC�2 specifies bacter-
S. typhi. It is conceivable that the activity against S. icidal activity, while the ratio�4 of MBC/MIC ratio
typhi may be due to the electron-withdrawing group indicates bacteriostatic activity. MBC determination
À NO2 on the phenyl ring.
results are presented in Table 2. Compounds 3a, 3c, 3f,
Moreover, compounds 3b, 3j, 3k, and 3o exhibited and 3g exhibited bactericidal activity against P.
maximum activity against GP organisms such as B. aeruginosa (MBC/MIC: 2), while compounds 3h, 3o,
subtilis, S. epidermis, and S. aureus. Nevertheless, these and 3r are observed to be bactericidal against E. coli
compounds 3b (MIC, 0.69 μg/mL), 3i (MIC, 0.92 μg/ (MBC/MIC: 2). However, these compounds are found
mL), 3k (MIC, 0.68 μg/mL) and 3o (MIC, 0.62 μg/mL) to possess bacteriostatic properties against GP bac-
exhibited promising activity against S. aureus when teria. The compound 3h having electron-withdrawing
compared to other GP bacteria in the study. The groups À NO2 at ortho and À COOH groups at para
activity against GP pathogenic bacteria may conceiv- positions on the phenyl ring showed bactericidal
ably be attributed to the presence of chlorine atom in activity against GN pathogens whereas, it displayed
the phenyl ring attached either to hydrazide or bacteriostatic activity against GP bacteria. Further,
acetamide moieties.
compound 3h exhibited bactericidal property at one-
The compound 3o displayed substantial activity fold MIC (MBC/MIC: 1) against P. aeruginosa. Thus, it is
against GP pathogenic bacteria such as S. aureus (MIC, evident that electron-withdrawing groups capable of
0.62 μg/mL), followed by S. epidermis (MIC, 0.64 μg/ making hydrogen bonding interactions with the
mL), and B. subtilis (MIC, 0.67 μg/mL) may be attrib- receptor residues may be required to increase activity
uted
to
the
formylformohydrazide against GN bacteria. Further, compounds 3b, 3j, 3k
(O=CÀ NHÀ NHÀ C=O) fragment present between the displayed bactericidal property against GP organisms
two aromatic rings and À Cl at position two of the such as S. aureus (MBC/MIC: 2), S. epidermis (MBC/MIC:
phenyl ring attached to this fragment.
3), and B. subtilis (MBC/MIC: 3). On the other hand,
In the case of Mycobacterium. sp. compound 3d, these compounds exhibited bacteriostatic properties
3e, and 3q exhibited significant inhibition with MIC against GN bacteria. It is evident that À Cl functionality
values in the range 0.75 to 0.98 μg/mL. It is evident on the aromatic ring is responsible for activity against
that presence of strong electron-withdrawing groups S. epidermis, S. aureus, and B. subtilis. In addition,
on the benzene ring at positions two and four is compound 3o exhibited potent bactericidal activity
favorable. Compound 3d was observed to be the most against S. aureus at one-fold MIC (MBC/MIC: 1) and
active with MIC value of 0.75 μg/mL. However, no promising bactericidal activity against all the selected
correlation was observed with the substitution pattern organisms except against K. pneumonia. Furthermore,
on the benzene ring and MIC values. This may be due compounds 3d (MBC/MIC: 2) and 3e (MBC/MIC: 2)
to the impermeability of the bacterial cell by other displayed substantial bactericidal activity against My-
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cobacterium. sp., may be because of the disubstituted insight into their binding affinity. Extra-precision (XP)
phenylacetamide group in the molecular structure of docking poses of the test ligands exhibited significant
these compounds. However, these two compounds interactions such as п-п stacking, п-cation, hydrogen
exhibited bacterial tolerance against other tested bonding and halogen bonding interactions with
bacterial strains.
conserved N-terminal domain residues Asn49, Glu53,
Asp76, Arg79, Gly80, Hie86, Lys87, Gly103, Gly104,
Phe106, Lys112, Ala122, Arg138 and Thr168 (Table 3
and Supplementary Figure S4(a–r)).
Time-Kill Study
Compounds 3h and 3o exhibited promising MIC and
The high active compounds 3h (Gscore; À 6.132 kcal/
MBC values, respectively, against GN and GP organ- mol) and 3o (Gscore; À 5.011 kcal/mol) fit well within
isms and are considered for further antibacterial the enzyme’s binding pocket. In addition, compound
evaluation. The time-kill study determined the bacter- 3h displayed two hydrogen-bonding interactions with
icidal property of compounds 3h against P. aeruginosa binding pocket residues. A hydrogen-bonding inter-
(Figure 1a) and 3o against S. aureus (Figure 1b). The action appeared between the À NH moiety of 2-
bacteria P. aeruginosa and S. aureus were serially chlorophenylacetamide and backbone >C=O of Glu53
diluted to achieve a concentration of À 105 CFU/mL (À NH⋯O=C<). The second hydrogen-bonding inter-
and treated with respective test compounds 3h, 3o, action was formed between the À NH of Gly104 (>
and ciprofloxacin (positive control) at concentrations C=O⋯HN) and the carbonyl oxygen of À NHCOCH2OÀ
°
of 0.5 and 1 MIC. After incubating the culture at 37 C, linker. A salt bridge interaction was observed between
50 μL was collected and sub-cultured on nutrient agar carboxylate oxygen present on the nitrobenzoic acid
medium at the regular time intervals of 0, 2, 4, 6, 8, 12, fragment and Lys87 (Figure 2a).
and 24 h, respectively. After the incubation period,
In the binding pose of compound 3o, chlorine
CFU was calculated, and a graph was plotted for time- atom occupies the hydrophobic region of the catalytic
kill kinetics by taking CFU/mL on ordinate and time on pocket. Probably this may be the reason for high
the abscissa. Tested compounds displayed significant activity against S. aureus (Supplementary Figure S4o).
bactericidal activity against chosen bacteria compared Further, compound 3o exhibited two hydrogen-bond-
to the untreated bacteria and bacteria treated with ing interactions with Asn49 and His86. A >C=O of 2-
ciprofloxacin.
chlorophenylacetamide demonstrated a hydrogen
bonding interaction with À NH of side-chain imidazole
nucleus of His86. The other hydrogen bonding inter-
action was formed between one of the À NH of
COÀ NHNHÀ COÀ fragment and the backbone >C=O of
Asn49. Besides, compound 3o also displayed a halo-
Computational Studies
Molecular Docking and Binding Free Energy Calculation
It was of particular interest to elucidate the mecha- gen bonding interaction with Gly103 (Figure 2b).
nism by which the title compounds persuaded their The binding free energy of compounds 3a–3r with
antibacterial activities. The interaction energies of all S. aureus ParE enzyme was determined using Prime-
the synthesized molecules 3a–3r (Table 3) against S. MM-GBSA (Table 3). The observed values of ΔGbind
aureus ParE enzyme (pdb.4URL) were assessed to get were observed in the range of À 37.29 to À 77.73 kcal/
Figure 1. Time-kill plot of (a) compound 3h against P. aeruginosa (b) compound 3o against S. aureus.
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Table 3. The XP-docking results (kcal/mol) of synthesized compounds 3a–3r against S. aureus ParE enzyme (Pdb. 4URL)
[a]
[b]
[c]
[d]
Com-
G
G
G
G
emodel
[e]ΔGbind
[f]ΔGcov
[g]ΔGlipo
[h]Δ.GvdW
score
evdw
energy
pound
3a
3b
3c
3d
3e
3f
3g
3h
3i
À 5.204
À 4.567
À 4.956
À 5.124
À 5.272
À 5.687
À 5.667
À 6.132
À 5.059
À 5.525
À 5.665
À 5.51
À 39.686
À 38.676
À 39.633
À 46.011
À 34.289
À 41.839
À 39.85
À 42.242
À 44.567
À 50.876
À 48.336
À 44.155
À 48.092
À 49.78
À 61.97
À 62.77
À 45.895
À 60.87
À 57.7
37.63
30.56
26.97
9.33
31.33
28.33
23.35
41.44
16.09
31.75
0.5
À 18.13
À 20.56
À 18.07
À 20.96
À 18.82
À 16.79
À 15.2
À 45.4
À 60.342
À 62.957
À 70.207
À 67.433
À 73.625
À 70.711
À 81.23
À 45.89
À 48.69
À 51.54
À 58.56
À 52.33
À 47.47
À 60.14
À 39.96
À 36.99
À 37.37
À 41.51
À 63.78
À 43.38
À 49.79
À 38.77
À 45.96
À 41.8
À 46.09
À 53.89
À 56.05
À 77.73
À 59.55
À 60.29
À 53.13
À 42.36
À 55.5
À 44.469
À 38.18
À 46.925
À 44.632
À 48.092
À 48.683
À 41.688
À 46.958
À 35.476
À 47.66
À 23.52
À 18.29
À 17.16
À 17.64
À 15.39
À 21.38
À 14.39
À 19.88
À 15.09
À 15.33
À 17.64
À 53.901
À 65.104
À 63.15
3j
À 41.352
À 44.752
À 38.797
À 45.414
À 33.22
3k
3 l
3m
3n
3o
3p
3q
3r
À 52.686
À 60.54
À 2.19
À 4.369
À 2.814
À 5.011
À 4.824
À 5.99
5.71
À 44.204
À 62.168
À 60.014
À 67.396
À 63.383
À 41.88
À 63.51
À 60.54
À 65.6
18.12
19.86
À 4.06
À 13.43
80.73
À 41.347
À 41.122
À 43.136
À 43.149
À 42.712
À 47.203
À 42.471
À 5.008
À 37.29
[a] glide score (kcal/mol); [b] glide van der Waals energy (kcal/mol); [c] glide energy (kcal/mol); [d] glide model (kcal/mol); [e] Free energy
of binding (kcal/mol); Covalent energy (kcal/mol); hydrophobic energy (kcal/mol); van der Waals energy (kcal/mol).
[f]
[g]
[h]
energy term (ΔGlipo; À 14.39 to À 23.52 kcal/mol)
appeared to be a moderately favorable for the ligand
binding. However, the covalent energy term (ΔGcov
;
9.33 to 41.44 kcal/mol) was unfavorable for binding of
compounds to the S. aureus ParE enzyme. From these
results, the high negative value of van der Waal energy
term indicated it as the main driving force for the
ligand binding. This is in agreement with glide Emodel
(Gemodel; À 81.23 to À 44.204 kcal/mol), obtained from
XP-docking.
Pharmacological and Toxicological Parameters
To determine the pharmacological, toxicological (AD-
MET) parameters and to speculate the acceptability of
title compounds (3a–3r), the QikProp algorithm
(Schrödinger 2019–2) was used. The results show that
all the compounds possess druggable properties and
obeyed the Lipinski rule of five with 0 to 1 violation
(Table 4). The speculated activity of the central nervous
system (CNS) of the compounds was observed in the
range of (+2 as active and À 2 as inactive), demon-
strating a lack of CNS effect. Oral absorption of these
compounds was computed, and the values were found
to be in the recommended range (QPlogO/W; 1.757 to
Figure 2. 3D-interaction diagram of compound (a) 3h and (b)
3o.
mol. Further, van der Waals energy (ΔGvdW; À 36.99 to 4.415). The polar surface area (PSA) of compounds 3a–
À 63.78 kcal/mol) term was observed to be favorable 3r was observed to in the range found to be within
for the binding affinity, whereas non-polar solvation the range 78.528 to 175.629 Å2, which is within
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recommended range (7–200 Å2), This shows better terial activity against P. aeruginosa (0.69 μg/mL). Addi-
van der Waal surface area around these molecules.
tionally, compound 3o possessing À Cl group at
Furthermore, speculated apparent Caco-2 cell per- position two has shown potential antibacterial activity
meability of the title compounds was observed in the against S. aureus (0.62 μg/mL). Further, these studies
range 31.503 to 2037.029 nm/sec, indicating the high were validated using MBC and time-kill kinetics. More-
permeability of these compounds. In addition, solvent over, XP-docking studies were correlated to the
accessible surface area (SASA) of title compounds observed antibacterial study, and results obtained for
were observed in the range of 562.571 to 699.599 Å2, the compounds 3h (Gscore; À 6.132 kcal/mol), and 3o
showing the well-fitting of these molecules within the (Gscore; À 5.011 kcal/mol) indicates the significant bind-
binding pocket. The speculated 50% inhibitory con- ing affinity of the ligands within the binding pocket of
centration values obtained by the blocking of human- the enzyme. Thus, these two compounds 3h and 3o
ether-a-go-go (QPlogHERG) potassium channels (K+) can be considered effective candidates to invent new
were found to be in the range À 4.008 to À 6.768, broad-spectrum antibacterial agents.
indicative of the safety of the synthesized compounds.
Also, compounds possess topological surface area
(TSA) within the recommended range (<120 Å2), Experimental Section
which indicates the total sum of overall polar atoms or
molecules (primarily oxygen and nitrogen, including
Chemistry
their attached hydrogen atoms). Except compounds The glassware used for the synthesis was dried in a
3b, 3i, 3j, and 3k, all other compounds exhibited non- hot air oven before use. The distillation and drying of
permeability through the blood-brain barrier. The solvents were performed wherever required. Thin-layer
compounds 3g, 3h, 3n, 3p, and 3q are considered to chromatography (TLC) was employed for monitoring
P-glycoprotein substrate, actively pumped up from the the reactions, and the plates were obtained from
brain or to the gastrointestinal lumen while the Merck, TLC silica gel 60 F254. Isolated yields of material
remaining compounds are not substrates for P-gp. are reported. For purification purposes, silica gel of
Cytochrome P450 is a superfamily of enzymes contain- 200–400 mesh particle size and pH=7 was employed,
ing heme as a cofactor that function as monooxyge- wherever required. Proton (1H) NMR spectra were
nases involved in the metabolism of xenobiotics. All documented on Bruker 500 MHz instruments, whereas
compounds are considered as inhibitors of some of carbon (13C) NMR spectra were recorded on Bruker
the Cytochrome P450s. LogKp is a skin permeation 126 MHz instrument using deuterated dimethyl
indicator showing the compound absorption through sulfoxide ((D6)DMSO). The chemical shifts are de-
the skin. From results it is clear that absorption of scribed as δ ppm and adjusted with (D6)DMSO as an
compounds 3a–3r is by permeation through the skin. internal reference. Further, coupling constant (J) was
All the title compounds exhibited significant bioavail- also reported in Hz, wherever required. Besides,
ability score (BS), indicative of the permeability and molecular weight predictions were carried out using
bioavailability properties of these compounds. All Mass Spectrometric studies on LC instrument (Agilent
compounds exhibited zero Pains alert (PA) (PAN assay 1200 series), which is equipped with an ESI source and
interference compounds), that indicates the specific coupled with Q-tof mass spectrometer Q-TOF-LC\MS-
interaction with desired target and no interaction with 6540 series), and operated in a positive ionization
other biological targets rather than non-specifically mode at À 70 eV.
affecting one desired target.
A General Protocol for the Synthesis of Compounds 1,
2c, 2e, 2f, and 2h
Conclusions
The polar groups substituted anilines follows a differ-
In summary, novel 2-aryloxy-N-phenylacetamide and ent procedure for the acetylation. The appropriate
N’-(2-aryloxyoxyacetyl) benzohydrazide derivatives solution of anilines (1 g, 10 mM) and sodium acetate
(3a–3r) were synthesized and characterized using (0.98 g, 10 mM) in glacial acetic acid (20 mL) was
spectral data. All synthesized compounds were eval- supplemented with chloroacetyl chloride (0.88 mL,
uated for their antibacterial activity. Compound 3h 11 mM) in a dropwise manner after the reaction
°
having electron-withdrawing and polar groups on the mixture attains 0 C. Further, the reaction mixture was
°
phenylacetamide ring have shown promising antibac- subjected to stirring for 18 h at 27 C. TLC was used to
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Chem. Biodiversity 2021, 18, e2000907
monitor the reaction progress and allow it to dry at (NCIM 2567), S. (NCIM 2493), S. aureus (NCIM 5022), B.
°
27 C. Extraction of the reaction mixture was per- subtilis (NCIM 2545), and M. sp (NCIM 2984) using the
formed with an excess of chloroform. The extracted Clinical Laboratories Standard Institute (CLSI) guide-
organic layer was dried under a vacuum, and the lines, 2017.[27] Various bacterial cultures were diluted
resultant crude product was stored at a cool temper- at a ratio of 1:1000 nutrient broth to attain turbidity
ature.
of McFarland 0.5. The micro-broth dilution method in
the Mueller-Hinton medium (Hi-media) was used to
determine the MIC. Ciprofloxacin and sterile dimethyl
sulfoxide (DMSO) was used as positive and negative
control, respectively. Before the study, title com-
The General Synthetic Procedure of Compounds 2a, 2b,
2d, 2g, and 2i–2r
Substituted anilines subjected to acetylation with pounds (3a–3r) and positive control were liquified in
chloroacetyl chloride using anhydrous K2CO3 as a base sterile DMSO. In each 96-well plate, 100 μL of bacterial
and DCM as a solvent. To the mixture of substituted culture was added, followed by 50 μL of title com-
anilines (1 g, 1 equiv.), K2CO3 (1.629 g, 1.5 equiv.) in pounds, and serial dilution of the mixture was carried
DCM (25 mL), chloroacetyl chloride (0.9 mL, 1 equiv.) out. After inoculation of the specific bacteria, the
[28,29]
°
°
was added drop-wise with stirring at 0 C.
The plates were incubated at 37 C for 20–24 h, except for
reaction mixture was subjected to stirring for 4 h at P. aeruginosa, the incubation was performed for 24–
°
°
27 C. TLC was used to monitor the reaction progress. 28 h at 37 C. Bacterial inoculums were corrected to
After completion, the excess solvent was removed 1×106 CFU/mL. The absorbance was recorded at a
from the mixture under vacuum, and the separated wavelength of 600 nm in Tecan-i-control, 1.7.1.12. The
solid was mixed with 25 mL of cold water. The obtained MIC data are expressed in micrograms per
obtained solid was splashed twice with water and milliliter (μg/mL) and are represented in Table 2.[30,31]
dried. The obtained intermediates 2a, 2b, 2d, 2g, 2i–
2r were used for the next step without further
Minimum Bactericidal Concentration (MBC) Determina-
purification (Scheme 2 and Table 1).
tion
The lowest concentration of a chemical compound/
General Synthetic Procedure of 2-aryloxy-N-phenylaceta-
drug/antibiotic to kill the bacterial cells over a fixed
mide and N’-(2-aryloxyoxyacetyl) Benzohydrazide Deriv-
period under precise conditions is known as the
atives (3a–3r)
compound’s minimum bactericidal concentration
To the solution of 2-chloro-N-(2-hydroxyphenyl) (MBC). MBC determination was carried out for the title
acetamide (1) (1 g, 1 equiv.) in acetone (30 mL), compounds (3a–3r) against the selected panel of
anhydrous K2CO3 (2.471 g, 3 equiv.) was mixed and pathogenic bacteria using the reported method.[32]
°
subjected to stirring at 40 C for 2 h. The appropriate The three successive concentrations above the MIC
2-chloro-N-phenylacetamides (2a–2r) was supple- were used, wherein 20 μL of the bacterial aliquots
mented to the above mixture and further stirred at were sub-cultured onto the nutrient agar plates. The
[28,29]
°
40 C for 24 h.
The TLC was used to monitor the agar plates’ incubation was performed for 24 h at
°
progression of the reaction. Upon completion of the 37 C, after which the colonies were counted with the
reaction, the excess acetone was removed under initial inoculum, and colony-forming unit per milliliter
vacuum, and the solid thus separated was washed was calculated. The concentration at which the�99%
twice with water and dried. Column chromatography reduction or kill or inhibition of growth (3 log10
was employed to purify the title molecules 3a–3r reduction CFU/mL) of bacteria is considered MBC. The
using ethyl acetate/hexane (7:3) as an eluent.
obtained MBC and MBC/MIC ratio are represented in
Table 3.
In Vitro Screening
Time-Kill Analysis
Minimum Inhibitory Concentration (MIC) Determination
Time-kill kinetics is the study to assess an antibacterial
The minimum inhibitory concentration of the title agents bactericidal or bacteriostatic property over
molecules 3a–3r was evaluated against GN and GP time and was performed using a standard protocol
pathogens such as P. aeruginosa (NCIM 2036), K. provided by CLSI.[33] The sample concentrations of 1×
pneumonia (NCIM 2706), S. typhi (NCIM 2501), E. coli MIC and 0.5×MIC were prepared with bacterial culture
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Chem. Biodiversity 2021, 18, e2000907
°
and incubated at 37 C. At regular time intervals of 0,
2, 4, 6, 8, 12, and 24 h, 50 μL aliquot of the culture was
inoculated onto the solidified agar plate, followed by Vidyasrilekha Yele was the author, who synthesized
Authors Contribution
°
incubation for 24 h at 37 C. Ciprofloxacin and DMSO the literature, drafted the article, and revised the
as a positive and negative control, respectively, were manuscript. Dr. Ashish D. Wadhwani was involved in
employed in the current study. To abolish the in vitro assessment. Dr. M. Afzal Azam provided
predisposition results, nutrient broth and nutrient agar conceptual inputs. All authors read and approved the
were also cultured on to the solidified agar plate and final article.
incubated separately. A colony-forming unit (CFU) was
determined, which was observed on the solidified agar
plate. A time-kill graph of the log CFU/mL was plotted
against time.
Acknowledgement
The authors acknowledge the AllIndia Council of
Technical Education, National doctoral fellowship
Computational Studies
(NDF) -56149, for providing the funding support.
Molecular Docking and Free Energy Calculation (Prime
MM-GBSA)
The three-dimensional molecular structures of title
ligands were prepared and optimized using Maestro
12 builder panel (Schrödinger suite 2019-2) and
LigPrep.[34,35] For the present work, the 3D-crystal
structure of S. aureus ParE enzyme (pdb.4URL, resolu-
tion 2.29 Å) was retrieved from the RCSB-Protein Data
Bank and optimized by the Protein Preparation Wizard
incorporated in Maestro 12. Minimization of the
prepared system was performed using the OPLS3e
force field, and a 10 Å 3D-grid box was created by
keeping the bound ligand as the centroid of the
catalytic pocket.[36] Without considering constraints,
XP-molecular docking was performed using the mod-
ule Glide.[37] Further, docked complexes binding free
energy was calculated using VSGB 2.0 implicit energy
model in the module Prime with OPLS3e force field.[38]
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Received November 4, 2020
Accepted February 8, 2021
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