Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study

Article abstract of DOI:10.1016/j.bioorg.2021.104885

New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel series of 1,2,4-oxadiazole-

Full text of DOI:10.1016/j.bioorg.2021.104885

Bioorganic Chemistry 111 (2021) 104885
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial
DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular
docking study
a
,
b
,
*
a
c
d
Tarek S. Ibrahim
, Ahmad J. Almalki , Amr H. Moustafa , Rasha M. Allam ,
e,
f
g
h,*
Gamal El-Din A. Abuo-Rahma , Hussein I. El Subbagh , Mamdouh F.A. Mohamed
a
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
b
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
c
Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt
d
Pharmacology Department, National Research Centre, Cairo 12622 (ID: 60014618), Egypt
e
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
f
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt
g
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt
h
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase
is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel
Chalcone
1
,2,4-Oxadiazole
1
series of 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f) were synthesized and characterized by IR, NMR ( H
Antibacterial
DNA gyrase
ADMET
13
and C) and elemental analyses. The title compounds were evaluated for their in-vitro antimicrobial activity by
the modified agar diffusion method as well as their E. coli DNA gyrase inhibitory activity. The minimum
inhibitory concentration (MIC) and the structure activity relationships (SARs) were evaluated. Among all,
compounds 6a, 6c-e, 7b and 7e were the most potent and proved to possess broad spectrum activity against the
tested Gram-positive and Gram-negative organisms. Additionally, compounds 6a (against S. aureus), 6c (against
B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c (against E. coli) and 7d (against B. subtilis), with MIC
Docking studies
value of 3.12
compounds 6c, 7c, 7e and 7b had good inhibitory activity against E. coli gyrase with IC50 values of 17.05, 13.4,
6.9, and 19.6 µM, respectively, in comparison with novobiocin (IC50 = 12.3 µM) and ciprofloxacin (IC50 = 10.5
μM were two-fold more potent than the standard ciprofloxacin (MIC = 6.25
μ
M). Mechanistically,
1
µM). The molecular docking results at DNA gyrase active site revealed that the most potent compounds 6c and 7c
have binding mode and docking scores comparable to that of ciprofloxacin and novobiocin suggesting their
antibacterial activity via inhibition of DNA gyrase. Finally, the predicted parameters of Lipinski’s rule of five and
ADMET analysis showed that 6c and 7c had good drug-likeness and acceptable physicochemical properties.
Therefore, the hybridization of the chalcone and oxadiazole moieties could be promising lead as antibacterial
candidate which merit further future structural optimizations.
1
. Introduction
The treatment of infectious diseases remains as a vital and chal-
antibiotics, the appearance of antibiotic resistant bacterial strains
represent a substantial need for the synthesis and the discovery of new
safer and potent antimicrobial agents [2]. Interrupting the replication of
DNA represents an effective and a promising antibacterial mechanism
[3]. DNA gyrase is classified as type II topoisomerase that is involved in
maintenance of the correct spatial of DNA topology in bacteria and it is
lenging problem due to the rapid rise in multi-drug resistant microor-
ganisms and the limited number of efficacious antimicrobial drugs [1].
Despite the availability of a large number of chemotherapeutics and
*
Corresponding authors at: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia (T.S.
Ibrahim).
E-mail addresses: tmabrahem@kau.edu.sa (T.S. Ibrahim), mamdouh.fawzi@pharm.sohag.edu.eg (M.F.A. Mohamed).
https://doi.org/10.1016/j.bioorg.2021.104885
Received 31 January 2021; Received in revised form 26 March 2021; Accepted 28 March 2021
Available online 1 April 2021
0
045-2068/© 2021 Elsevier Inc. All rights reserved.

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
independently crucial for bacterial DNA replication [4,5]. DNA gyrase
includes two copies of GyrA (which contains the catalytic tyrosine) and
two copies of GyrB (which comprises the ATPase activity) [6]. DNA
gyrase has a vital role in all bacteria except higher eukaryotes as it is
absent in humans and this makes it an attractive and validated thera-
peutic target for development of new antibacterial agents for decades,
being the target of fluoroquinolones antibiotics [7]. As the currently
used drugs have undesirable side effects and have the abilities in
developing rapid resistance, the discovery of more potent and effective
antimicrobial agents is strongly recommended.
attention due to their diverse and interesting biological activities [8]
such as analgesic [9] anti-inflammatory [10], antimalarial [11,12],
antioxidant [13,14], antifungal [15,16], anti-tuberculosis [17], anti-
bacterial (Fig. 1, compounds I and II) [18], parasitic protease inhibitors
[19], antiviral [20], anti-human immunodeficiency virus (HIV) [21],
HDAC inhibitors [22], antitumor activities [23,24] and as insulin
mimetic in 3 T3-L1 adipocyte [25]. Moreover, many chalcone de-
rivatives exhibited good antimicrobial activity via inhibition of DNA
gyrase such as compounds III-VI [26] (Fig. 1).
On the other hand, the five membered heterocyclic 1,2,4-oxadizole
scaffold has been widely utilized as a core unit in a diversity of bioac-
tive molecules displaying diverse biological activities such as anti-
inflammatory, anticonvulsant, anticancer, anxiolytic, antidepressant,
Although chalcones have no structural or pharmacodynamic simi-
larities with the broad-spectrum antibiotics, they have been identified to
be such alternative. Chalcones and their derivatives gained a great
Fig. 1. Representative examples antibacterial chalcones (A), oxadiazole derivatives (B) and the target 1,2,4-oxadiazole-chalcone/oxime hybrids (6a-f and 7a-f) (C).
2

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
analgesic, antiparasitic, antifungal [27] and antimicrobial such as
chalcone/oxime (6a-f) and (7a-f) is described in Scheme 1. The key
chalcone acid 3 [22], cyano derivatives 4a-f and amidoximes 5a-f were
produced according to the reported procedures as described in the
literature [32,33,35].
compounds VII and VIII [28], antibacterial via inhibition of DNA gyrase
(
Fig. 1, compounds IX-XIV) [29–31]. Moreover, it was proved that
,2,4-oxadizole-containing compounds show inhibitory potency against
1
Penicillin-Binding Protein (PBP2a), cyclooxygenase (COX-1 and COX-2),
Human Deacetylase Sirtuin 2 (HDSirt2), Histone Deacetylase (HDAC),
Carbonic Anhydrase (CA), dual COX-2/15-LOX inhibitors and dual
iNOS/PGE2 inhibitors [27,32,33]. In addition, 1,2,4-oxadiazole scaffold
has emerged an acceptable pharmacokinetic profile; this recommend it
to be used in the “hit-to-lead” optimization in drug discovery [33].
Importantly, 1,2,4-oxadiazole exhibited rigid equivalence to amide and
ester functional groups due to creation of specific interaction such as
hydrogen bonding and/or when the instability of those groups is noticed
due to factors like hydrolysis [32].
1,2,4-Oxadiazole-chalcone derivatives 6a-f were formed via reaction
′
of the acetic acid derivative 3 with amidoximes 5a-f, using N,N -car-
bonyldiimidazole (CDI) and heating under reflux. The structural formula
of 3-aryl-1,2,4-oxadiazole-chalcone hybrids 6a-f were elucidated by IR,
1
H NMR, C NMR spectra and elemental analyses. The 1H NMR spec-
13
trum of 6b exhibited the appearance of two singlet signals at δ 3.83 and
5.76 ppm which were assigned to methoxy and methylene protons,
respectively. The aromatic protons and 13C NMR signals appeared at
their expected chemical shift. (see Supporting Information). Conden-
sation of 3-aryl-1,2,4-oxadiazoles 6a-f with hydroxylamine hydrochlo-
ride afforded the keto-oxime derivatives 7a-f. The structure of oximes
7a-f was elucidated based on IR, 1H NMR, C NMR spectra and
elemental analyses. IR spectrum of 7b exhibited the appearance of the
Molecular hybridization in which two pharmacophoric moieties are
combined in a one single molecule with additive biological properties is
a promising approach in drug design and development. This strategy
aims to innovate new hybrids with the potential not only to improve
affinity and efficacy but also to overcome cross resistance compared
with the parent drugs and can result in modified selectivity profile and/
or dual modes of action with reduced undesirable side effects [34].
Therefore, encouraged and motivated by the known antibacterial
importance of both chalcones and 1,2,4-oxadiazole moieties, this
research study aims at the first-in-class synthesis of novel 1,2,4-oxadia-
zole-chalcone/oxime hybrids (Fig. 1). Meanwhile, the antimicrobial
evaluation of the target compounds was done using a panel of Gram-
positive, Gram-negative and fungal strains. Moreover, the DNA-gyrase
inhibition assay is reported and molecular docking into DNA gyrase
protein pocket (PDB ID: 4DUH) is carried out to investigate the binding
affinity and binding mode of the most active compounds.
13
ꢀ 1
new characteristic broad band at 3263 cm due to O H, and disap-
–
1
ꢀ
pearance of characteristic absorption band at 1652 cm for carbonyl
1
group. The H NMR spectrum of 7b revealed the appearance of the new
singlet signal at δ 11.36 ppm which is attributed to the oximic OH group;
1
3
in addition to other signals in aliphatic and aromatic regions. Also,
C
NMR and elemental analyses confirms the structure (see Supporting
Information). The configuration of the double bond of chalcone moiety
1
could be confirmed by the H NMR spectrum. For example, chalcone 7d
showed an olefinic proton H-β as singlet at 5.63 ppm and the other as
doublet at 6.68 ppm with high J coupling constant of 16.4 Hz attributed
to H- of chalcone double bond. Thus, both protons are magnetically
α
inequivalent besides high J coupling constant support the characteristic
E-configuration of the synthesized chalcones [8,36,37]. Furthermore,
the 13C NMR spectrum of compound 7f, as a representative example,
characterized by the presence of downfield signals corresponding to the
2
. Results and discussion
carbons of
α,β-unsaturated system represented at 116.0 and 136.9 ppm
2
.1. Chemistry
evidencing the (E)-configuration of the synthesized chalcones [38,39].
The synthetic approach to obtain the target 1,2,4-oxadiazole-
Scheme 1. Synthesis of target compounds 6a-f and 7a-f. Reagents and conditions: (a) 10% NaOH, EtOH, then HCl; (b) NH
2
OH.HCl, K
2
CO
3
, MeOH, reflux; 5–8 h;
(
c) CDI, CH
3
CN, reflux, 24 h; (d) NH
2
OH.HCl, pyridine, CDI, 60
ͦ
C, 4 h, then HCl.
3

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
2
2
.2. Biology evaluation
It was noticed that only 6e and 6f yielded similar MIC value (6.25 µM) to
ciprofloxacin and sulfamethoxazole. The antifungal effectiveness
against C. albicans ranged from weak to no effect at all for all tested
compounds. Compounds 6f and 7e showed potencies against C. albicans
.2.1. Antimicrobial activity
The synthesized 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f),
were screened for their antimicrobial activity against panel of Gram-
positive bacteria (Bacillus subtilis, Staphylococcus aureus, Enterococcus
hirae), Gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella
pneumonia, Escherichia coli) and yeast (C. albicans). Sulfamethoxazole,
Ciprofloxacin and Clotrimazole were used as antibacterial and anti-
fungal standards, respectively. Results are showed in Table 1, as mini-
mal inhibitory concentrations (MICs).
with MIC value of 25 M.
μ
2.2.2. Inhibition of DNA-Gyrase supercoiling activity
The observed antimicrobial activity (MIC values) of the tested
compounds against E. coli inspired the assessment of their potential anti-
gyrase activity. The reference drugs that targeting DNA gyrase by the
two main mechanisms were used: Ciprofloxacin (the inhibitor of GyrA
active site DNA complex) and Novobiocin (the inhibitor of GyrB subunit
ATPase function) [40,41].
The antibacterial results against E. hirae showed that all 1,2,4-oxa-
diazole/oxime hybrids 7a-f, except for 7d, revealed good antimicro-
bial activity with MIC value 6.25 similar to ciprofloxacin and
sulfamethoxazole (MIC = 6.25 µM). Among 1,2,4-oxadiazole/chalcone
hybrids 6a-f, hybrids 6c and 6e showed the best potential MIC value
Regarding 1,2,4-oxadiazole/oxime hybrids, compounds 7c, 7e and
7b exhibited good inhibitory activity against E. coli gyrase with IC50
values of 13.4 µM, 16.9 µM, and 19.6 µM, respectively in comparison
with Novobiocin (IC50 = 12.3 µM) and ciprofloxacin (IC50 = 10.5 µM).
While hybrids 7a, 7d, and 7f displayed low inhibitory activity against
E. coli gyrase with IC50 values of 35.5 µM, 23.6 µM, 30.5 µM, respec-
tively. Concerning, 1,2,4-oxadiazole/chalcone hybrids, in general, all
compounds 6a-f showed moderate inhibition of E. coli gyrase with IC50
range from 29.6 µM to 44.9 µM except for 6c that showed good E. coli
gyrase inhibition with IC50 of 17.05 µM. The IC50 values are listed in
Table 2 and demonstrated in Fig. 2. From these results, it is obvious that
compounds 7c and 6c were the most active compounds among their
series with IC50 values of 13.49 and 17.05 µM, respectively.
(
3.21 µM) with two-fold higher in activity than ciprofloxacin and sul-
famethoxazole. Compound 6b with MIC = 6.25 µM showed equal po-
tency to ciprofloxacin. Compounds 6d and 6f (MIC = 12.5 µM) showed
moderate antibacterial activity whereas compound 6a was the least
active compound against E. hirae (MIC = 25 µM). Regarding S. aureus,
Compound 6a proved the highest activity with a MIC value of 3.12 µM,
which was two-fold more potent than ciprofloxacin (S. aureus MIC =
6
1
.25 µM) and four-fold higher than sulfamethoxazole (S. aureus MIC =
2.5 µM). Compound 7d showed similar antimicrobial activity as cip-
rofloxacin. Where compounds 6c, 6e, 7c, 7e, 7f exhibited comparable
antibacterial activity compared to sulfamethoxazole but with lower
activity than ciprofloxacin. Compounds 6d, 7a, 7b displayed weaker
antibacterial activity compared to the used standards. Finally, com-
pounds 6b and 6f were devoid of any bacterial activity. Concerning
B. subtilis, compounds 6c and 7d (MIC = 3.12) were the most potent and
displayed two-fold higher in activity than ciprofloxacin (MIC = 6.25).
Compounds 6a, 6d, 6f and 7f showed good activity while the remaining
derivatives demonstrated moderate potencies in comparison with the
reference drugs.
2.2.3. Cell viability assay
Cell viability assay was carried out using human mammary gland
epithelial cell line (MCF-10A) [42]. Compounds 6c and 7c have been
incubated with MCF-10A cells for 96 h and 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) assay was used to determine
Table 2
Inhibition of DNA-Gyrase supercoiling activity of compounds 6a-f and 7a-f.
E. coli was one of the highly sensitive Gram-negative bacteria for the
tested compounds. Compounds (6f, 7a, 7c) and (6c, 7b, 7e, 7f) dis-
played equipotent antibacterial activity against E. coli with MIC of 3.12
and 6.25 µM, respectively, and of almost four and two-fold higher ac-
tivity than Sulfamethoxazole (MIC = 12.5 µM). The remaining com-
pounds except for 6e demonstrated similar potencies in comparison with
sulfamethoxazole and with lower potencies compared to ciprofloxacin
E. coli DNA-gyrase inhibition
Compound No.
IC50 (µM)
Compound No.
IC50 (µM)
6
a
44.95 ± 2.56
40.66 ± 2.32
17.05 ± 0.97
33.57 ± 1.91
38.95 ± 2.22
29.62 ± 1.69
10.5 ± 0.6
7a
35.55 ± 2.02
19.65 ± 1.12
13.49 ± 0.77
23.7 ± 1.35
16.99 ± 0.97
30.53 ± 1.74
12.36 ± 0.7
6b
7b
6
6
6
6
c
d
e
f
7c
7d
7e
(
MIC
= 6.25 µM). Additionally, the promising activity against
7f
P. aeruginosa was observed from all compounds except compound 6f.
However, K. pneumoniae was the most resistant Gram-negative bacteria.
Ciprofloxacin
Novobiocin
Table 1
MIC values of tested compounds 6a-f and 7a-f against Gram-positive, Gram-negative organisms and fungi.
Minimal Inhibitory Concentration (MIC) in µM
Compound No.
Gram-positive organisms
Gram-negative organisms
Fungi
B. subtilis
E. hirae
S. aureus
E. coli
K. pneumoniae
P. aeruginosa
C. albicans
6
6
6
6
6
6
7
7
7
7
7
7
a
b
c
d
e
f
6.25
12.5
3.12
6.25
12.5
6.25
12.5
12.5
na
25
3.12
na
12.5
12.5
6.25
12.5
25
25
12.5
12.5
6.25
6.25
12.5
25
na
na
na
na
na
25
na
na
na
na
25
na
nd
nd
12.5
6.25
3.12
12.5
3.12
12.5
6.25
6.25
6.25
25
na
12.5
50
50
12.5
6.25
6.25
na
12.5
na
3.12
3.12
6.25
3.12
12.5
6.25
6.25
12.5
6.25
nd
a
b
c
d
e
f
25
12.5
6.25
12.5
12.5
6.25
6.25
12.5
6.25
nd
25
12.5
na
12.5
6.25
12.5
12.5
12.5
6.25
nd
3.12
12.5
6.25
6.25
6.25
nd
na
6.25
6.25
6.25
6.25
nd
25
na
Sulfamethoxazole
Ciprofloxacin
Clotrimazole
6.25
6.25
nd
na, not active; nd, not determined
4

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
Fig. 2. Agarose gel electrophoresis of E-coli DNA gyrase supercoiling activity of compounds 6a-f and 7a-f, novobiocin and ciprofloxacin using a microplate assay kit
(
Inspiralis). 1U of DNA gyrase is incubated with 0.5 µg of relaxed pBR322 in a reaction volume of 30 µl at 37 ◦C for 30 min in Assay Buffer. Negatively supercoiled
plasmids form intermolecular triplex DNA more readily than do relaxed plasmids. Gels are run in the absence of ethidium bromide or chloroquine.
Fig. 3. SAR of the synthesized target compounds 6a-f and 7a-f.
5

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
the cell viability. Both compounds showed no cytotoxic effects and the
viability of the cells for the tested compounds was 93% and 89% for
2.4. Molecular modeling and docking study
compound 6c and 7c, respectively, at 50
.3. Structure activity relationship (SAR)
A novel series of compounds namely: 1,2,4-oxadiazole/chalcone
μ
M.
Discovery Studio 2.5 software was used to investigate the binbing
ability of compounds 6c, 7c along with ciprofloxacin and novobiocin
into the active site of E. coli DNA gyrase protein. The 3D co-crystal
structure (PDB ID: 4DUH) with benzimidazol-2-ylurea inhibitor was
downloaded from the Protein Data Bank. The virtually docked com-
pounds were built and energy minimized. The best obtained studied
poses were chosen for docking using CDOCKER energy and were
inspected in 3D and 2D styles.
2
hybrids 6a-f and 1,2,4-oxadiazole/oxime hybrids 7a-f, were synthe-
sized and tested for their antimicrobial activities (Tables 1), in addition
to DNA-Gyrase supercoiling inhibitory activity (Table 2, Figures and 2).
In general, there is no significant difference in potency between the
Firstly, redocking of the ligand, benzimidazol-2-ylurea, was carried
out to validate the docking protocol. The RMSD value was 0.825 (less
than 2) which indicates the validity and confidence in the obtained
docking results. As shown in Fig. 4A and 4B, benzimidazol-2-ylurea
(CDOCKER energy = ꢀ 45.0109 and CDOCKER interaction energy =
ꢀ 58.2929), incorporated in the formation of 2 hydrogen bonds with
Asp73 and Arg136. Also, benzimidazol-2-ylurea formed many hydro-
phobic interactions such as van der Waals, Carbon Hydrogen bond and
Pi-Alkyl interactions with Val43, Asn46, Val71, Asp73, Arg76, Gly77,
Ile78, Pro79, Lys103, Arg136 and Val167 amino acid residues.
Novobiocin, as illustrated in Fig. 5A and 5B, with CDOCKER energy
= ꢀ 11.1743 and CDOCKER interaction energy = ꢀ 69.805, engaged in 3
hydrogen bonds with Asp73, Arg136 and Thr165. In addition to other
hydrophobic interactions such as van der Waals, Salt Bridge, Attractive
Charge, Carbon Hydrogen bond, Pi-Cation, Alkyl and Pi-Alkyl in-
teractions with Arg76, Ile78, Pro79, Ile94, Lys103, Arg136 and Val120
amino acid residues.
1
,2,4-oxadiazole/chalcone hybrids (6a-f) and 1,2,4-oxadiazole/oxime
hybrids (7a-f) in potency. Moreover, the active compounds in both se-
ries have a broad-spectrum activity against the tested Gram-positive and
Gram-negative strains. Concerning the 1,2,4-oxadiazole/chalcone hy-
brids, substituent at the 3-phenyl-oxadiazole moiety proved to have a
significant role in activity. Compounds 6a (unsubstituted-phenyl) and
6
3
c (4-OCH -phenyl) showed a broad-spectrum antibacterial potency.
The introduction of 3,4-dimethoxy-phenyl (6d), electron withdrawing
chlorine (6b) or nitro function (6e) decreased the magnitude of activity.
The structure activity relationship (Fig. 3) can be summarized as fol-
lows: Replacement of hydrogen atom with the electron withdrawing Cl
atom as in compound 6b, resulted in increase the antibacterial activity
towards E. hirae, while retain the same activity against E. coli and P.
aeruginosa. Conversion of chalcone 6b into its oxime counterpart yiel-
ded compound 7b with increased antibacterial activity towards
S. aureus, E. coli, K. pneumoniae and P. aeruginosa. Introducing the
donating group OCH
B. subtilis, E. hirae, E. coli and P. aeruginosa where its oxime derivatives
c lead to increase the antibacterial activity towards E. coli. Increases
the electron donation by adding 3,4-di-OCH as in chalcone 6d increases
3
(6c) increases the antibacterial activity towards
Ciprofloxacin, as illustrated in Fig. 5C and 5D, with CDOCKER en-
ergy = ꢀ 26.2818 and CDOCKER interaction energy = ꢀ 54.2711,
engaged in 4 hydrogen bonds with Gly77, Arg136 (two hydrogen bonds)
and many other hydrophobic interactions such as van der Waals,
Attractive Charge, Carbon Hydrogen bond, Halogen (Fluorine), Pi-
Cation, Pi-anion, Alkyl and Pi-Alkyl interactions with Asn46, Glu50,
Arg76, Ile78, Pro79, Ile94, Lys103 and Arg136 amino acid residues.
The docking results of compound 6c (CDOCKER energy = ꢀ 24.1222
and CDOCKER interaction energy = ꢀ 50.4697), (Fig. 6A and 6B),
revealed that it formed 3 hydrogen bonds; the nitrogen atom of 1,2,4-
oxadizaole nucleous forms one hydrogen bond with Arg136, and the
oxygen atom 1,3-peopenone moiety engaged in two hydrogen bonds
with Arg67 and Gly77. Also 6c showed many hydrophobic interactions
such as van der Waals, Carbon Hydrogen bond, Pi-Cation, Pi-Sigma and
Pi-Alkyl interactions with Ala47, Ile78, Pro79, Ile82, Ala90 and Lys103
amino acid residues.
7
3
the antibacterial activity towards K. pneumoniae and P. aeruginosa, while
its oxime 7d increases the antibacterial activity towards B. subtilis and
2
S. aureus. Introducing the strongly deactivating NO group as in 6e in-
creases the antibacterial activity towards E. hirae, K. and pneumoniae
while its oxime 7e increases the antibacterial activity towards E. coli and
P. aeruginosa. Replacement of the phenyl group with the bulky 2-naph-
thyl group as in 6f lead to increase the antibacterial activity towards
E. hirae, E. coli, K. pneumoniae and C. albicans, while its oxime counter-
part 7f increases the antibacterial activity towards E. hirae, S. aureus and
P. aeruginosa.
The docking result of compound 7c, (Fig. 6C and 6D) (CDOCKER
Fig. 4. Binding mode of benzimidazol-2-ylurea inhibitor into DNA gyrase pocket (PDB code: 4DUH). (A) 3D structure of benzimidazol-2-ylurea (grey), (B) 2D
structure of benzimidazol-2-ylurea (grey).
6

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
Fig. 5. Binding mode of novobiocin and ciprofolxacin into DNA gyrase pocket (PDB code: 4DUH). (A) 3D structure of novobiocin (blue), (B) 2D structure of
novobiocin (blue), (C) 3D structure of ciprofloxacin (pink), (D) 2D structure of ciprofloxacin (pink). (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)
energy = ꢀ 16.0866 and CDOCKER interaction energy = ꢀ 46.169),
showed that it formed 3 hydrogen bonds; the oxygen atom of the
methylene group incorporated in one hydrogen bond with Lys103, the
proton of the oxime group formed one hydrogen bond with Arg136 and
the oxygen atom of the oxime group engaged in the third hydrogen bond
with Arg136. Further, 7c showed many hydrophobic interactions such
as van der Waals, Carbon Hydrogen bond, Pi-Cation and Pi-Alkyl in-
teractions with Arg76, Ile78, Pro79, Ile94, Lys103 and Val120 amino
acid residues.
elimination and toxic (ADMET) factors [44]. Thus, utilizing the online
application Pre-ADMET, theoretical calculations of the pharmacokinetic
parameters as well as the theoretical agreement of compounds 6c, 7c,
ciprofloxacin and novobiocin to both Lipinski’s Rule of Five [45] and
Veber’s standard [46] were carried out.
The obtained results as illustrated in Table 3, showed that com-
pounds 6c and 7c are in agreement with Lipinski’s rule with only one
violation Log P > 5). Moreover, all the tested compounds had TPSA
values <140 Å2 which used to calculate the percentage of oral absorp-
tion (%ABS) using the following equation: (%ABS = 109-(0.345 TPSA)
[47]. The tested compounds 6c and 7c exhibited better oral absorption
than than both ciprofloxacin and novobiocin with %ABS of 85.93, 80.32,
79.40 and 55.73, respectively.
From the docking results, it clear that hybrids 6c and 7c exhibited
binding patterns similar to that described for the majority of gyrase B
inhibitors. Thus, it could be concluded that compounds 6c and 7c are
entitled to be used as future lead template for identifying more potent
antibacterial candidates.
Absorption is the process by which the drug can reach the systemic
circulation through body organs via several routes such as oral ab-
sorption (human intestinal absorption, HIA), skin permeability (SP,
LogKp) and permeability through certain cells such as MDCK and Caco2
cells [48].
2
.5. In silico prediction of physicochemical properties and
pharmacokinetic profile
Moreover, compounds 6c (98.22%) and 7c (96.89%) displayed good
intestinal absorption with HIA values close to 1 (acceptable range:
0–100% absorption) which is similar to ciprofloxacin (96.27%) and
better than novobiocin (71.71%). Skin permeability (SP, LogKp) was
found to be slightly less than the acceptable range (ꢀ 2.5 LogKp)
2
.5.1. Lipinski rule calculations and ADMET analysis
Prediction of the physicochemical characters, pharmacokinetics and
toxicity is an important tool in drug discovery of biologically active
agents [32,43]. Many potential therapeutic candidates fail to reach the
clinic due to their unfavorable absorption, distribution, metabolism,
7

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
Fig. 6. Binding mode of compounds 6c and 7c into DNA gyrase pocket (PDB code: 4DUH). (A) 3D structure of 6c (cyan), (B) 2D structure of 6c (cyan), (C) 3D
structure of 7c (yellow), (D) 2D structure of 7c (yellow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article.)
Table 3
Calculated parameters of Veber’s and Lipinski’s rule of five for compounds 6c, 7c ciprofloxacin and novobiocin.
Comp.
MW
Log P
HBD
HBA
nVs
MolPSA
%ABS
Drug likeness score
Lipinski*
≤500
–
442.15
457.16
331.13
612.23
≤5
≤5
–
≤10
–
≤1
–
–
–
*
*
Veber
–
≤140
66.87 A
83.13 A
58.80 A
–
2
2
2
6
c
c
5.46
6.01
0.45
3.10
0
7
1
85.93
80.32
79.40
55.73
ꢀ 0.31
0.06
0.84
1.11
7
1
8
1
Ciprofloxacin
Novobiocin
2
4
0
2
6
11
1
154.40 A
*
Reference values of Lipinski;
*
*
Reference values of Veber; MW, Molecular weight; LogP, lipophilicity (O/W); HBD, Number of hydrogen bond donors; HBA, Number of hydrogen bond acceptors;
nVs, Number of Lipinski rule violations; MolPSA, molecular polar surface area (PSA) (Å2); %ABS, percentage of oral absorption.
(
Table 4).
Regarding distribution (Table 4), two parameters namely; blood
nervous system (CNS) drugs. Additionally, measurement of the per-
centage of a molecule bound to plasma protein (PPB%) is also helpful in
estimation of the novel target compounds distribution. Results exhibited
that compounds 6c (99.19) and 7c (97.29) showed strong plasm protein
binding values indicating prolonged half-lives more than ciprofloxacin
(31.05) and novobiocin (84.66). Moreover, compounds 6c (0.157) and
brain barrier (BBB) and plasma binding protein (PBP), were measured to
predict the distribution of molecules from one organ to another. BBB
allows the hydrophobic and small molecules to diffuse to the brain
which considered as an important predictor for the discovery of central
8

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
7
c (0.019) showed limited brain penetration (BBB; unbound brain -to-
plasma ratio) as well as both ciprofloxacin (0.014) and novobiocin
0.065).
Concerning metabolism (Table 4), the chemical modification(S) or
(
the biotransformation of xenobiotics or exogenous compounds to facil-
itate their excretion through increasing their water solublity either in
phase I or phase II. Cytochrome P450 isoforms predicts the ability of
compounds to be inhibitors for drug metabolizing enzymes such as
CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP1A2. Furthermore, glyco-
protein (P-gp) inhibition measurement is used to predict the excretion
property of the target compounds. In this study, compounds 6c and 7c
exhibited good inhibitory behavior towards CYP2C19, CYP2C9 and
CYP3A4, but they did not show inhibitory behavior towards CYP2D6.
Moreover, compound 6c had no inhibitory effect on P-gp, while 7c is P-
gp inhibitor.
Finally, toxicity prediction (Table 4) of compounds 6c, 7c, cipro-
floxacin and novobiocin was obtained by measuring AMES test (for
mutagenicity prediction), carcino-Mouse/Rat (for carcinogenicity pre-
diction of the tested compounds) and hERG-inhibition (for checking the
cardiac toxicity). Compounds 6c and 7c, ciprofloxacin and novobiocin
showed mutagenic behavior in AMES test. All compounds had negative
carcinogenic effect in mouse and rats except novobiocin which had
positive carcinogenic effect in mouse. Compounds 6c and 7c showed
medium risk as cardiotoxic agents better than novobiocin which
exhibited high risk as cardiotoxic agents. From these predicted ADMET
parameters, we could conclude that compounds 6c and 7c have
acceptable physicochemical properties and reasonable drug-likeness,
hence, can be used as a promising drug candidate for development of
new antibacterial agents.
3
. Conclusion
In summary, a novel series of 1,2,4-oxadiazole appended chalcone
6
a-f and their oxime counterparts 7a-f were prepared and evaluated for
their in vitro quantitative (MIC) antimicrobial activity by the modified
agar diffusion method in Müller-Hinton Broth and Sabouraud Liquid
Medium. Among all, compounds, 6a, 6c-e, 7b and 7e proved to possess
broad spectrum antibacterial activity against the tested Gram-positive
and Gram-negative organisms. Compound 6a (against S. aureus), 6c
(
(
against B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c
against E. coli),7d (against B. subtilis) all with MIC value of 3.12
μM
were two-fold more active than the standard ciprofloxacin (MIC = 6.25
M). In comparison with novobiocin (IC50 = 12.3 µM) and ciprofloxacin
IC50 = 10.5 µM), E-coli gyrase inhibitory activity assessment of the
synthesized target compounds showed that compounds 6c, 7c, 7e and
b displayed a good inhibitory activity against E-coli gyrase with IC50
μ
(
7
values of 17.05 µM, 13.4 µM, 16.9 µM, and 19.6 µM, respectively. The
docking study exhibited that both compounds 6c and 7c showed binding
patterns similar to that described for the majority of gyrase B inhibitors.
Furthermore, hybrids 6c and 7c exhibited acceptable physicochemical
properties and good drug-likeness scores. Therefore, compound 6c and
7
c could be considered as promising leads as antibacterial candidate
which merit further optimization and development in future work for
potent derivatives.
4
. Experimental
4
4
.1. Chemistry
.1.1. General information
All commercially available reagents were purchased from Merck,
Aldrich and Fluka and were used without further purification. All re-
actions were monitored by thin layer chromatography (TLC) using
precoated plates of silica gel G/UV-254 of 0.25 mm thickness (Merck
6
0F254) using UV light (254 nm/365 nm) for visualization. Melting
points were detected with a Kofler melting points apparatus and
9

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
uncorrected. Infrared spectra were recorded with
a
FT-IR-
4.1.2.4. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-(3,4-dimethoxyphenyl)-
ꢀ
1
ALPHBROKER-Platinum-ATR spectrometer and are given as cm
using the attenuated total reflection (ATR) method. 1H NMR and 13C
NMR spectra for all new compounds were recorded in CDCl or DMSO‑d
1,2,4-oxadiazol-5-yl)metho-xy]phenyl}prop-2-en-1-one (6d). Yield 82%;
beige solid; m.p.: 146–148 ◦C. IR (ATR)
ν
max 3067, 3032 (C
H aro-
O), 1601
), 3.97 (s,
), 6.95–6.99 (m, 3H,
–
matic), 2990, 2964, 2913, 2839 (C
–
H aliphatic), 1651 (C–
–
3
6
–
ꢀ 1
1
on a Bruker Bio Spin AG spectrometer at 400 MHz and 100 MHz,
(C
–
N) cm . H NMR (400 MHz, CDCl
3 3
) δ3.87 (s, 3H, OCH
1
respectively. For H NMR, chemical shifts (δ) were given in parts per
3H, OCH
3
), 3.98 (s, 3H, OCH ), 5.43 (s, 2H, CH
3
2
million (ppm) with reference to tetramethylsilane (TMS) as an internal
standard (δ = 0); coupling constants (J) were given in hertz (Hz) and
data are reported as follows: chemical shift, integration, multiplicity (s
CHarom.), 7.14 (d, J = 7.1 Hz, 2H, CHarom.), 7.41 (d, J = 15.6 Hz, 1H,
CHarom.), 7.61 (br. s, 3H, CHarom.), 7.74 (d, J = 7.1 Hz, 1H, CHarom.), 7.80
(d, J = 15.6 Hz, 1H, CHarom.), 8.07 (d, J = 6.8 Hz, 2H, CHarom.); 13C NMR
1
3
=
singlet, d = doublet, m = multiplet). For C NMR, TMS (δ = 0), DMSO
3
(100 MHz, CDCl ) δ 55.4, 56.0, 56.1, 61.1, 110.2, 111.3, 114.5, 114.7,
(
δ = 39.51) or CDCl
3
(δ = 77.2) was used as internal standard and
118.8, 119.5, 121.2, 127.8, 130.1, 130.8, 132.9, 144.3, 149.4, 151.9,
spectra were obtained with complete proton decoupling. Elemental
analyses were obtained on a Perkin-Elmer CHN-analyzer model. Com-
pounds 3 [22], 4a-f and 5a-f [32,33,35] were prepared according to the
previously reported procedure.
160.9, 161.7, 168.5, 173.9, 188.7. Anal. Calcd. for C27H N O
24 2 6
(472.48): C, 68.63; H, 5.12; N, 5.93. Found: C, 68.47; H, 5.03; N, 5.77.
4.1.2.5. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-(4-nitrophenyl)-1,2,4-oxa-
diazol-5-yl)methoxy] phenyl}prop-2-en-1-one (6e). Yield 79%; yellow
◦
4
.1.2. General procedure for the synthesis of (2E)-3-(4-methoxyphenyl)-1-
solid; m.p.: 190–192 C. IR (ATR) νmax 3072, 3050 (C
–
–
H aromatic),
ꢀ
1 1
{
4-[(3-aryl-1,2,4-oxadiazol-5-yl)methoxy]phenyl}prop-2-en-1-one (6a-f)
2978, 2939, 2840 (C
–
H aliphatic), 1650 (C
–
O), 1599 (C N) cm . H
To a suspension of {4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]phe-
NMR (400 MHz, DMSO‑d ) δ 3.82 (s, 3H, OCH ), 5.79 (s, 2H, CH ), 7.01
6
3
2
′
noxy}acetic acid (3, 2 mmol, 0.624 g) in acetonitrile (30 mL), the N,N -
carbonyldiimidazole (CDI) (2.2 mmol, 0.36 g) was added and the
mixture was stirred at room temperature for 30 mins. The appropriate
amidoximes 4a-f (2 mmol) was then added and stirring was continued
for additional 2 h. The reaction mixture was heated under reflux over-
night (monitored with TLC). The reaction mixture was allowed to cool to
room temperature and the obtained precipitate was filtered, dried and
recrystallized from methanol to afford 6a-f.
(d, J = 8.6 Hz, 2H, CH
), 7.27 (d, J = 7.4 Hz, 2H, CH
), 7.67–7.85
arom.
arom.
1
3
(m, 4H, CH
arom.
), 8.18–8.42 (m, 6H, CH
DMSO‑d ) δ 55.9, 61.5, 114.9, 115.3, 120.0, 125.0, 127.9, 129.1, 131.2,
arom.
); C NMR (100 MHz,
6
131.3, 132.0, 132.4, 143.9, 149.9, 161.3, 161.8, 167.1, 176.7, 187.9.
Anal. Calcd. for C25H19N O (457.43): C, 65.64; H, 4.19; N, 9.19. Found:
3
6
C, 65.78; H, 4.00; N, 9.34.
4
.1.2.6. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-(2-naphthyl)-1,2,4-oxadia-
zol-5-yl)methoxy] phenyl}prop-2-en-1-one (6f). Yield 80%; beige solid;
◦
4
.1.2.1. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-phenyl-1,2,4-oxadiazol-5-
m.p.: 172–174 C. IR (ATR) νmax 3079, 3049 (C
–
–
H aromatic), 2962,
ꢀ 1 1
yl)methoxy]phenyl}prop-2-en-1-one (6a). Yield 78%; white crystal; m.p.:
2912, 2839 (C
–
H aliphatic), 1659 (C
–
O), 1594 (C N) cm . H NMR
◦
1
2
43–145 C. IR (ATR)
ν
max 3051 (C
–
H aromatic), 2957, 2934, 2906,
(400 MHz, DMSO‑d ) δ 3.83 (s, 3H, OCH ), 5.79 (s, 2H, CH ), 7.02 (d, J
6
3
2
ꢀ 1
1
836 (C
–
H aliphatic), 1661 (C
) δ 3.87 (s, 3H, OCH
H, CHarom.), 7.14 (d, J = 7.6 Hz, 2H, CHarom.), 7.42 (d, J = 15.5 Hz, 1H,
CHarom.), 7.51–7.53 (m, 3H, CHarom.), 7.61 (d, J = 7.4 Hz, 2H, CHarom.),
–
–
O), 1603 (C
–
–
N) cm . H NMR (400
= 8.1 Hz, 2H, CH
), 7.29 (d, J = 8.3 Hz, 2H, CH
), 7.61–7.78 (m,
arom.
arom.
MHz, CDCl
3
3
), 5.45 (s, 2H, CH
2
), 6.95 (d, J = 7.4 Hz,
4H, CH
), 7.84 (d, J = 8.5 Hz, 2H, CH
), 8.01–8.16 (m, 4H,
arom.
arom.
13
2
CHarom.), 8.20 (d, J = 8.3 Hz, 2H, CH
), 8.67 (s, 1H, CH
arom.
);
C
arom.
NMR (100 MHz, DMSO‑d ) δ 55.9, 61.6, 114.9, 115.3, 120.1, 123.6,
6
1
3
7
.80 (d, J = 15.5 Hz, 1H, CHarom.), 8.06–8.13 (m, 4H, CHarom.); C NMR
100 MHz, CDCl ) δ 55.4, 61.0, 114.5, 114.7, 119.6, 126.3, 127.6, 127.8,
28.9, 130.1, 130.8, 131.5, 133.0, 144.3, 160.9, 161.7, 168.7, 174.2,
88.7. Anal. Calcd. for C25 (412.43): C, 72.80; H, 4.89; N, 6.79.
123.8, 127.6, 127.9, 128.2, 128.3, 128.5, 129.4, 129.6, 131.1, 131.3,
(
3
132.4, 133.1, 134.8, 143.9, 161.4, 161.8, 168.4, 176.0, 187.9. Anal.
Calcd. for C29H22N O (462.49): C, 75.31; H, 4.79; N, 6.06. Found: C,
1
1
2
4
H
20
N
2
O
4
75.72; H, 4.55; N, 6.22.
Found: C, 72.67; H, 4.77; N, 6.86.
4
.1.3. General procedure for the synthesis of (2E)-3-(4-methoxyphenyl)-1-
4
.1.2.2. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-(4-chlorophenyl)-1,2,4-oxa-
{4-[(3-aryl-1,2,4-oxadiazol-5-yl)methoxy]phenyl}prop-2-en-1-one oxime
(7a-f)
diazol-5-yl)methoxy] phenyl}prop-2-en-1-one (6b). Yield 83%; white
◦
crystal; m.p.: 162–164 C. IR (ATR)
ν
max 3073, 3051 (C
–
H aromatic),
A mixture of 1,2,4-oxadiazole derivatives 6a-f (0.7 mmole) and hy-
droxylamine hydrochloride (2.1 mmole, 0.15 g) in 20 mL pyridine was
–
H aliphatic), 1652 (C
cm . H NMR (400 MHz, DMSO‑d ) δ 3.83 (s, 3H, OCH
CH
), 7.02 (d, J = 8.6 Hz, 2H, CHarom.), 7.26 (d, J = 8.7 Hz, 2H, CHarom.),
–
O), 1599 (C
–
N)
2
997, 2961, 2933, 2834 (C
ꢀ
1
1
◦
6
3
), 5.76 (s, 2H,
stirred at 70 C for 3 hrs. After cooling, the mixture was added onto ice
2
cold distilled water and acidified by conc. HCl. The formed crude
product 7a-f was then collected by filtration, washed with distilled
water, dried and recrystallized from methanol.
7
.66 (d, J = 8.6 Hz, 2H, CHarom.), 7.71–7.85 (m, 4H, CHarom.), 8.04 (d, J
=
8.5 Hz, 2H, CHarom.), 8.18 (d, J = 8.7 Hz, 2H, CHarom.); 13C NMR (100
6
MHz, DMSO‑d ) δ 55.9, 61.5, 114.9, 115.3, 120.0, 125.1, 127.9, 129.4,
1
1
6
30.0, 131.2, 131.3, 132.4, 137.1, 143.9, 161.4, 161.8, 167.5, 176.2,
87.9. Anal. Calcd. for C25 19ClN (446.88): C, 67.19; H, 4.29; N,
.27. Found: C, 67.57; H, 4.01; N, 6.13.
4.1.3.1. 3-(4-Methoxyphenyl)-1-{4-[(3-phenyl-1,2,4-oxadiazol-5-yl)
H
2
O
4
methoxy]phenyl}prop-2-en-1-one oxime (7a). Yield 72%; white solid; m.
◦
p.: 140–142 C. Spectral data for the major isomer: IR (ATR) νmax 3310
broad (O
aliphatic), 1604 (C
3H, OCH ), 5.66 (s, 2H, CH
– – –
H), 3058, 3004 (C H aromatic), 2958, 2931, 2836 (C H
–
ꢀ 1
6
N) cm . H NMR (400 MHz, DMSO‑d ) δ 3.78 (s,
1
4
.1.2.3. (2E)-3-(4-Methoxyphenyl)-1-{4-[(3-(4-methoxyphenyl)-1,2,4-
–
oxadiazol-5-yl)methoxy] phenyl}prop-2-en-1-one (6c). Yield 81%; beige
3
2
), 6.69 (d, J = 16.6 Hz, 1H, CHarom.),
◦
solid; m.p.: 169–171 C. IR (ATR)
ν
max 3069, 3019 (C
–
–
H aromatic),
6.88–6.97 (m, 2H, CHarom.), 7.27 (d, J = 8.5 Hz, 1H, CHarom.), 7.39–7.51
ꢀ 1
1
2
997, 2941, 2836 (C
NMR (400 MHz, DMSO‑d
.02–7.26 (m, 6H, CHarom.), 7.71–8.20 (m, 8H, CHarom.); C NMR (100
MHz, DMSO‑d ) δ 55.8, 55.9, 61.5, 114.9, 115.3, 118.5, 120.0, 127.9,
29.3, 131.2, 131.3, 132.4, 143.9, 161.4, 161.8, 162.4, 166.1, 168.0,
75.5, 187.9. Anal. Calcd. for C26 (442.46): C, 70.58; H, 5.01;
–
H aliphatic), 1652 (C
–
–
O), 1600 (C
–
N) cm . H
(m, 3H, CHarom.), 7.59–7.65 (m, 5H, CHarom.), 8.02–8.05 (m, 3H,
1
3
6
) δ 3.83 (s, 6H, 2OCH
3
), 5.72 (s, 2H, CH
2
),
6
CHarom.), 11.36 (s, 1H, OH); C NMR (100 MHz, DMSO‑d ) δ 55.7, 61.4,
1
3
7
114.7 (2C), 114.8 (2C), 115.0, 115.2, 126.3, 127.6 (2C), 128.5, 129.2
6
(2C), 129.8 (2C), 130.6 (2C), 132.2, 136.9, 152.7, 158.1, 159.9, 168.3,
1
1
176.2. Anal. Calcd. for C25
21 3 4
H N O (427.45): C, 70.25; H, 4.95; N, 9.83.
22 2 5
H N O
Found: C, 70.46; H, 4.74; N, 9.52.
N, 6.33. Found: C, 70.72; H, 4.92; N, 6.24.
1
0

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
155.4, 158.2, 160.4, 168.4, 176.3. Anal. Calcd. for C29H N O
23 3 4
4
.1.3.2. 3-(4-Methoxyphenyl)-1-{4-[(3-(4-chlorophenyl)-1,2,4-oxadia-
zol-5-yl)methoxy] phenyl}prop-2-en-1-one oxime (7b). Yield 77%; white
(477.51): C, 72.94; H, 4.85; N, 8.80. Found: C, 73.47; H, 4.93; N, 8.72.
◦
solid; m.p.: 190–192 C. Spectral data for the major isomer: IR (ATR)
ν
max 3263 broad (O
H aliphatic), 1605 (C
.78 (s, 3H, OCH ), 5.66 (s, 2H, CH
H), 3060, 3007 (C H aromatic), 2962, 2933, 2836
– –
C
–
–
N) cm . 1H NMR (400 MHz, DMSO‑d
ꢀ 1
) δ
(
6
4.2. Biological assays
3
6
7
3
2
), 6.68 (d, J = 17.6 Hz, 1H, CHarom.),
.93–6.95 (d, J = 8.4 Hz, 2H, CHarom.), 7.17 (d, J = 8.4 Hz, 2H, CHarom.),
.42–7.50 (m, 5H, CHarom.), 7.66 (d, J = 8.3 Hz, 2H, CHarom.), 8.05 (d, J
4.2.1. Antimicrobial activity
All the synthesized compounds 6a-f and 7a-f were estimated in vitro
for their antimicrobial activity against a board of standard strains of the
Gram-negative bacteria including Pseudomonas aeuroginosa (ATCC-
27953), Klebsiella pneumoniae (ATCC-13883), and Escherichia coli (ATCC
ꢀ 25922), the Gram-positive bacteria including Bacillus subtilis (ATCC-
19659), Staphylococcus aureus (ATCC-25923) and Enterococcus hirae
=
8.3 Hz, 2H, CHarom.), 11.36 (s, 1H, OH); 13C NMR (100 MHz,
DMSO‑d
6
) δ 55.7, 61.4, 114.8 (2C), 115.2 (2C), 116.0, 125.2, 129.1,
29.4 (2C), 129.8 (2C), 130.0 (2C), 130.6 (2C), 136.9, 137.0, 155.4,
58.1, 160.5, 167.5, 176.5. Anal. Calcd. for C25 20ClN (461.89): C,
5.01; H, 4.36; N, 9.10. Found: C, 64.87; H, 4.27; N, 9.03.
1
1
6
H
3 4
O
(
ATCC-10541), and the yeast-like fungal pathogen Candida albicans
4
.1.3.3. 3-(4-Methoxyphenyl)-1-{4-[(3-(4-methoxyphenyl)-1,2,4-oxadia-
(ATCC-10231). The antimicrobial activity of the tested compounds was
carried out by means of the agar disc-diffusion method using the Müller-
Hinton agar medium while a 24-hours bacterial culture was swabbed on
the surface of the Muller-Hinton agar plate using a sterile cotton swab.
The compounds were freshly dissolved in Dimethyl Sulfoxide (DMSO)
and the twofold dilutions were prepared. The sterile filter discs (9 mm)
were separately loaded with 100 ul of prepared compounds and left till
dryness and then positioned on a previously inoculated nutrient agar
zol-5-yl)methoxy] phenyl}prop-2-en-1-one oxime (7c). Yield 74%; beige
◦
solid; m.p.: 154–155 C. Spectral data for the major isomer: IR (ATR)
ν
max 3281 broad (O
H aliphatic), 1604 (C
.82 (s, 3H, OCH ), 3.83 (s, 3H, OCH
0H, CHarom.), 7.62 (d, J = 8.8 Hz, 1H, CHarom.), 7.94–7.97 (m, 3H,
) δ 55.7, 55.9,
1.3, 114.8 (2C), 115.1 (2C), 115.2 (2C), 115.8, 118.4, 127.5, 129.2
2C), 129.3 (2C), 130.7 (2C), 137.0, 152.9, 155.5, 158.1, 160.4, 162.3,
67.9, 175.8. Anal. Calcd. for C26 (457.47): C, 68.26; H, 5.07;
N, 9.19. Found: C, 68.58; H, 4.95; N, 9.04.
H), 3061, 3003 (C H aromatic), 2962, 2937, 2836
– –
N) cm . 1H NMR (400 MHz, DMSO‑d
) δ
–
–
ꢀ 1
(
C
6
3
1
3
3
), 5.61 (s, 2H, CH
2
), 6.63–7.49 (m,
CHarom.), 11.46 (s, 1H, OH); 13C NMR (100 MHz, DMSO‑d
6
◦
6
with the target microbial strain. After two hours of diffusion at 4 C, the
◦
(
plates were incubated at 37 C for 24 h regarding bacteria and 48 h
1
H
23
N
3
O
5
regarding Candida albicans. and the inhibition areas were measured and
compared to sulphamethoxazole (SXT) as the reference antibiotic. The
minimal inhibitory concentration (MIC) was estimated as the minimum
concentration of antimicrobial agent that totally inhibited the colony
formation via the modified agar diffusion method in Müller-Hinton
Broth and Sabouraud Liquid Medium [49–51].
4
.1.3.4. 3-(4-Methoxyphenyl)-1-{4-[(3-(3,4-dimethoxyphenyl)-1,2,4-
oxadiazol-5-yl)methoxy]phenyl}prop-2-en-1-one oxime (7d). Yield 70%;
◦
beige solid; m.p.: 155–157 C. Spectral data for the major isomer: IR
(
ATR)
936, 2838 (C
DMSO‑d ) δ 3.85 (s, 9H, 3OCH
H, CHarom.), 6.94 (d, J = 7.6 Hz, 2H, CHarom.), 7.09–7.16 (m, 4H,
ν
max 3277 broad (O
–
H), 3059, 3005 (C
–
H aromatic), 2964,
–
ꢀ 1
N) cm . H NMR (400 MHz,
1
2
–
H aliphatic), 1605 (C
–
4.2.2. DNA-Gyrase supercoiling inhibition assay
), 5.63 (s, 2H, CH
2
), 6.68 (d, J = 16.4 Hz,
All compounds were screened in vitro for their inhibitory activity of
E. coli DNA Gyrase supercoiling using E. coli DNA gyrase microplate
assay kit (Inspiralis, Norwich, UK) according to the manufacturer’s
protocol [52]. Two reference drugs; ciprofloxacin and novobiocin were
used. The whole tested compounds at concentrations of 100, 50, 25, 13
and 6 uM were used. The results are depicted as IC50 values.
6
3
1
1
3
CHarom.), 7.42–7.51 (m, 6H, CHarom.), 11.36 (s, 1H, OH); C NMR (100
MHz, DMSO‑d ) δ 55.7, 56.2 (2 OCH ), 61.5, 110.4, 112.6, 114.8 (2C),
15.2 (2C), 116.0, 118.6, 121.1, 127.7, 129.1, 129.8 (2C), 130.6 (2C),
36.9, 149.6, 152.2, 155.4, 158.2, 160.5, 168.1, 175.8. Anal. Calcd. for
(487.50): C, 66.52; H, 5.17; N, 8.62. Found: C, 66.67; H,
6
3
1
1
27 25 3 6
C H N O
5
.00; N, 8.69.
4.2.3. Cell viability and MTT assay
MTT assay was performed to explore the effect of the synthesized
compounds on the viability of mammary epithelial cells (MCF-10A)
according to previously reported procedures [42] (see Supporting
Information).
4
5
.1.3.5. 3-(4-Methoxyphenyl)-1-{4-[(3-(4-nitrophenyl)-1,2,4-oxadiazol-
-yl)methoxy] phenyl}prop-2-en-1-one oxime (7e). Yield 72%; yellow
◦
solid; m.p.: 162–164 C. Spectral data for the major isomer: IR (ATR)
ν
max 3347 broad (O
H aliphatic), 1604 (C
.78 (s, 3H, OCH ), 5.70 (s, 2H, CH
.88–7.50 (m, 9H, CHarom.), 8.31–8.45 (m, 4H, CHarom.), 11.36 (s, 1H,
–
H), 3072, 3036 (C
–
H aromatic), 2958, 2934, 2838
–
–
N) cm . 1H NMR (400 MHz, DMSO‑d
ꢀ 1
6
) δ
4.2.4. Docking methodology
(
C
For molecular docking analysis, Discovery Studio 2.5 software
3
6
3
2
), 6.68 (d, J = 16.8 Hz, 1H, CHarom.),
(
Accelrys Inc., San Diego, CA, USA) was used for docking analysis. Fully
1
3
automated docking tool using “Dock ligands (CDOCKER)” protocol
running on Intel (R) core (TM) i32370 CPU @ 2.4 GHz 2.4 GHz, RAM
Memory 2 GB under the Windows 7.0 system. The co-crystal structure of
E. coli DNA gyrase B with a thiazole inhibitor (PDB code: 4DUH) was
retrieved from protein data bank (https://www.rcsb.org/struc
ture/4DUH). The docked compounds were built using Chem. 3D ultra
OH); C NMR (100 MHz, DMSO‑d
6
) δ 55.7, 61.5, 114.7 (2C), 114.8
2C), 115.0, 115.2, 116.0, 125.0, 125.3 (2C), 128.5 (2C), 129.0, 129.1
2C), 130.7 (2C), 132.1, 133.9, 136.9, 149.8, 167.1, 177.0. Anal. Calcd.
(472.45): C, 63.56; H, 4.27; N, 11.86. Found: C, 63.74;
H, 4.19; N, 11.81.
(
(
20 4 6
for C25H N O
1
2.0 software [Chemical Structure Drawing Standard; Cambridge Soft
4
.1.3.6. 3-(4-Methoxyphenyl)-1-{4-[(3-(2-naphthyl)-1,2,4-oxadiazol-5-
corporation, USA (2010)], and copied to Discovery Studio 2.5 software.
Automatic protein preparation module was used applying MMFF94
force field. The binding site sphere has been defined automatically by
the software. Now the above prepared receptor is given as input for
yl)methoxy] phenyl}prop-2-en-1-one oxime (7f). Yield 75%; beige solid;
◦
m.p.: 180–182 C. Spectral data for the major isomer: IR (ATR)
ν
max
3
299 broad (O
H aliphatic), 1604 (C
.77 (s, 3H, OCH ), 5.70 (s, 2H, CH
.92 (d, J = 8.7 Hz, 2H, CHarom.), 7.19–7.68 (m, 9H, CHarom.), 8.02 (d, J
7.6 Hz, 1H, CHarom.), 8.08–8.16 (m, 3H, CHarom.), 8.68 (s, 1H,
CHarom.), 11.37 (s, 1H, OH); 13C NMR (100 MHz, DMSO‑d
) δ 55.7, 61.5,
14.8 (2C), 115.2 (2C), 116.0, 123.7, 123.8, 127.6, 128.2, 128.3, 128.4,
28.5, 129.1, 129.4, 129.6, 129.8, 130.7 (2C), 133.1 (2C), 134.8, 136.9,
H), 3056, 3026 (C H aromatic), 2999, 2957, 2836
– –
1
–
ꢀ 1
(
C
–
N) cm
.
H NMR (400 MHz, DMSO‑d
6
) δ
“
input receptor molecule” parameter in the CDOCKER protocol param-
3
6
3
2
), 6.69 (d, J = 16.8 Hz, 1H, CHarom.),
eter explorer. Force fields are applied on compounds to get the minimum
lowest energy structure. The obtained poses were studied and the poses
showing best ligand interactions were selected and used for CDOCKER
energy (protein-ligand interaction energies) calculations. Recep-
tor–ligand interactions of the complexes were examined in 2D and 3D
styles bank
=
6
1
1
1
1

T.S. Ibrahim et al.
Bioorganic Chemistry 111 (2021) 104885
4
.2.5. In silico prediction of physicochemical properties and
[17] P.M. Sivakumar, S.K. Geetha Babu, D. Mukesh, QSAR studies on chalcones and
flavonoids as anti-tuberculosis agents using genetic function approximation (GFA)
method, Chem. Pharm. Bull. 55 (1) (2007) 44–49.
pharmacokinetic profile.
For Lipinski’s rule (rule of five) and molecular property prediction,
the free accesses to website (https://www.molsoft.com/servers.html)
was used. Also, for Pre-ADMET estimation, the free access of website
[
18] P. Yadav, K. Lal, L. Kumar, A. Kumar, A. Kumar, A.K. Paul, R. Kumar, Synthesis,
crystal structure and antimicrobial potential of some fluorinated chalcone-1,2,3-
triazole conjugates, Eur. J. Med. Chem. 155 (2018) 263–274.
[
19] R. Li, X. Chen, B. Gong, P.M. Selzer, Z. Li, E. Davidson, G. Kurzban, R.E. Miller, E.
O. Nuzum, J.H. McKerrow, R.J. Fletterick, S.A. Gillmor, C.S. Craik, I.D. Kuntz, F.
E. Cohen, G.L. Kenyon, Structure-based design of parasitic protease inhibitors,
Bioorg. Med. Chem. 4 (9) (1996) 1421–1427.
(
https://preadmet.bmdrc.kr/) was utilized for estimation.
[
[
20] J.C. Trivedi, J.B. Bariwal, K.D. Upadhyay, Y.T. Naliapara, S.K. Joshi, C.
C. Pannecouque, E. De Clercq, A.K. Shah, Improved and rapid synthesis of new
coumarinyl chalcone derivatives and their antiviral activity, Tetrahedron Lett. 48
Declaration of Competing Interest
(
48) (2007) 8472–8474.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
21] N. Tiwari, B. Dwivedi, Synthesis of some pyrazoline and isoxazolin derivatives as
possible fungicides, Boll. Chim. Farm. 128 (11) (1989) 332–335.
[22] M.F.A. Mohamed, M.S.A. Shaykoon, M.H. Abdelrahman, B.E.M. Elsadek, A.
S. Aboraia, G.-D. Abuo-Rahma, Design, synthesis, docking studies and biological
evaluation of novel chalcone derivatives as potential histone deacetylase
inhibitors, Bioorg. Chem. 72 (2017) 32–41.
Acknowledgments
[
23] H.A. Abou-Zied, B.G. Youssif, M.F. Mohamed, A.M. Hayallah, M. Abdel-Aziz, EGFR
inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and
docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid
molecules, Bioorg. Chem. 89 (2019), 102997.
This project was funded by the Deanship of Scientific Research
◦
(
DSR), King Abdulaziz University, Jeddah, under grant N . (DF-452-
66-1441). The authors, therefore, gratefully acknowledge DSR tech-
1
[24] M.F.A. Mohamed, G.-D. Abuo-Rahma, Molecular targets and anticancer activity of
quinoline–chalcone hybrids: literature review, RSC Adv. 10 (52) (2020)
nical and financial support.
3
1139–31155.
[
25] K.J. Jarvill-Taylor, R.A. Anderson, D.J. Graves, A hydroxychalcone derived from
cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes, J. Am. Coll.
Nutr. 20 (4) (2001) 327–336.
Appendix A. Supplementary material
[
[
26] W. Dan, J. Dai, Recent developments of chalcones as potential antibacterial agents
in medicinal chemistry, Eur. J. Med. Chem. 187 (2020), 111980.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104885.
27] K. Biernacki, M. Da ´s ko, O. Ciupak, K. Kubi n´ ski, J. Rachon, S. Demkowicz, Novel
1
,2,4-Oxadiazole Derivatives in Drug Discovery, in: Pharmaceuticals (Basel,
Switzerland), 2020.
[
28] N.P. Rai, V.K. Narayanaswamy, T. Govender, B.K. Manuprasad, S. Shashikanth, P.
N. Arunachalam, Design, synthesis, characterization, and antibacterial activity of
References
{
5-chloro-2-[(3-substitutedphenyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-
[
1] W. Zhang, W. Liu, X. Jiang, F. Jiang, H. Zhuang, L. Fu, Design, synthesis and
antimicrobial activity of chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)
propanoic acid derivatives, Eur. J. Med. Chem. 46 (9) (2011) 3639–3650.
2] F. Prestinaci, P. Pezzotti, A. Pantosti, Antimicrobial resistance: a global
multifaceted phenomenon, Pathog. Glob. Health 109 (7) (2015) 309–318.
3] G. Sanyal, P. Doig, Bacterial DNA replication enzymes as targets for antibacterial
drug discovery, Expert Opin. Drug Discov. 7 (4) (2012) 327–339.
(
phenyl)-methanones, Eur. J. Med. Chem. 45 (6) (2010) 2677–2682.
[
[
29] N. Zidar, H. Macut, T. Toma ˇs i ˇc , L.P. Ma ˇs i ˇc , J. Ila ˇs , A. Zega, P. Tammela, D. Kikelj,
New N-phenyl-4, 5-dibromopyrrolamides as DNA gyrase B inhibitors,
MedChemComm 10 (2019) 1007–1017.
[
[
[
ˇ
ˇ
ˇ
´
30] Z. Jakopin, J. Ilas, M. Barancokova, M. Brvar, P. Tammela, M. Sollner Dolenc,
T. Toma ˇs i ˇc , D. Kikelj, Discovery of substituted oxadiazoles as a novel scaffold for
DNA gyrase inhibitors, Eur. J. Med. Chem. 130 (2017) 171–184.
4] P.F. Chan, V. Srikannathasan, J. Huang, H. Cui, A.P. Fosberry, M. Gu, M.M. Hann,
M. Hibbs, P. Homes, K. Ingraham, J. Pizzollo, C. Shen, A.J. Shillings, C.
E. Spitzfaden, R. Tanner, A.J. Theobald, R.A. Stavenger, B.D. Bax, M.N. Gwynn,
Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug
etoposide and moxifloxacin, Nat. Commun. 6 (2015) 10048.
5] A. Kolari ˇc , T. Germe, M. Hrast, C.E.M. Stevenson, D.M. Lawson, N.P. Burton,
J. V o¨ r o¨ s, A. Maxwell, N. Minovski, M. Anderluh, Potent DNA gyrase inhibitors bind
asymmetrically to their target using symmetrical bifurcated halogen bonds, Nat.
Commun. 12 (2021) 150.
[
[
31] S.N. Dighe, T.A. Collet, Recent advances in DNA gyrase-targeted antimicrobial
agents, Eur. J. Med. Chem. 199 (2020), 112326.
32] M.F.A. Mohamed, A.A. Marzouk, A. Nafady, D.A. El-Gamal, R.M. Allam, G.E.
A. Abuo-Rahma, H.I. El Subbagh, A.H. Moustafa, Design, synthesis and molecular
modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived
from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors, Bioorg.
Chem. 105 (2020), 104439.
33] B.G.M. Youssif, M.F.A. Mohamed, M.M. Al-Sanea, A.H. Moustafa, A.
A. Abdelhamid, H.A.M. Gomaa, Novel aryl carboximidamide and 3-aryl-1,2,4-
oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors:
Design, synthesis and docking studies, Bioorg. Chem. 85 (2019) 577–584.
34] S.M. El-Messery, E.-S. Habib, S.T.A. Al-Rashood, G.S. Hassan, Synthesis,
antimicrobial, anti-biofilm evaluation, and molecular modelling study of new
chalcone linked amines derivatives, J. Enzyme Inhib. Med. Chem. 33 (1) (2018)
[
[
[
[
[
6] M. Durcik, T. Toma ˇs i ˇc , N. Zidar, A. Zega, D. Kikelj, L.P. Ma ˇs i ˇc , J. Ila ˇs , ATP-
competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents,
Expert Opin. Ther. Pat. 29 (3) (2019) 171–180.
7] A. Kolari ˇc , M. Anderluh, N. Minovski, Two Decades of Successful SAR-Grounded
Stories of the Novel Bacterial Topoisomerase Inhibitors (NBTIs), J. Med. Chem. 63
(
11) (2020) 5664–5674.
8
18–832.
[
[
8] C. Zhuang, W. Zhang, C. Sheng, W. Zhang, C. Xing, Z. Miao, Chalcone: A Privileged
Structure in Medicinal Chemistry, Chem. Rev. 117 (2017) 7762–7810.
[
[
35] M.R. Albayati, M.F. Mohamed, A.H. Moustafa, Optimization of the synthesis of
het/aryl-amidoximes using an efficient green chemistry, Synth. Comm. (2020)
9] G. Viana, M. Bandeira, F. Matos, Analgesic and antiinflammatory effects of
chalcones isolated from Myracrodruon urundeuva Allem ˜a o, Phytomedicine 10
1
–15.
36] P. Thapa, S.P. Upadhyay, W.Z. Suo, V. Singh, P. Gurung, E.S. Lee, R. Sharma,
M. Sharma, Chalcone and its analogs: Therapeutic and diagnostic applications in
Alzheimer’s disease, Bioorg. Chem. 108 (2021), 104681.
(
2003) 189–195.
10] S.H. Lee, D.H. Sohn, X.Y. Jin, S.W. Kim, S.C. Choi, G.S. Seo, 2 , 4 , 6 -Tris
methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced
colitis and blocks tumor necrosis factor- -induced intestinal epithelial
′
′
′
[
(
[
[
37] Z. Rozmer, P. Perj ´e si, Naturally occurring chalcones and their biological activities,
Phytochem. Rev. 15 (1) (2016) 87–120.
α
inflammation via heme oxygenase 1-dependent and independent pathways,
Biochem. Pharmacol. 74 (6) (2007) 870–880.
38] A.R. Saundane, K.N. Mathada, Synthesis, characterization, and biological
evaluation of some new chalcones containing indole moiety and their derivatives,
Monatsh. Chem. 147 (7) (2016) 1291–1301.
[
[
11] M. Liu, P. Wilairat, S.L. Croft, A.-C. Tan, M.-L. Go, Structure–activity relationships
of antileishmanial and antimalarial chalcones, Bioorg. Med. Chem. 11 (13) (2003)
[
[
[
39] A. Alejo-Armijo, A.J. Parola, F. Pina, pH-Dependent Multistate System Generated
by a Synthetic Furanoflavylium Compound: An Ancestor of the Anthocyanin
Multistate of Chemical Species, ACS Omega 4 (2019) 4091–4100.
40] H.I. el-Subbagh, M.A. el-Sherbeny, M.N. Nasr, F.E. Goda, F.A. Badria, Novel
diarylsulphide derivatives as potential cytotoxic agents, Boll. Chim. Farm. 134
2
729–2738.
12] T. Narender, Shweta, K. Tanvir, M. Srinivasa Rao, K. Srivastava, S.K. Puri,
Prenylated chalcones isolated from Crotalaria genus inhibits in vitro growth of the
human malaria parasite Plasmodium falciparum, Bioorg. Med. Chem. Lett. 15 (10)
(
2005) 2453–2455.
(
1995) 80-84.
[
[
13] I.S. Arty, H. Timmerman, M. Samhoedi, H. van der Goot, Synthesis of
benzylideneacetophenones and their inhibition of lipid peroxidation, Eur. J. Med.
Chem. 35 (2000) 449–457.
41] Y.I. El-Gazzar, H.H. Georgey, S.M. El-Messery, H.A. Ewida, G.S. Hassan, M.
M. Raafat, M.A. Ewida, H.I. El-Subbagh, Synthesis, biological evaluation and
molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-
derivatives of quinazolin-4(3H)-one as DHFR inhibitors, Bioorg. Chem. 72 (2017)
14] S. Mukherjee, V. Kumar, A.K. Prasad, H.G. Raj, M.E. Bracke, C.E. Olsen, S.C. Jain,
V.S. Parmar, Synthetic and biological activity evaluation studies on novel 1, 3-
diarylpropenones, Bioorg. Med. Chem. 9 (2) (2001) 337–345.
15] Z. Nowakowska, A review of anti-infective and anti-inflammatory chalcones, Eur.
J. Med. Chem. 42 (2) (2007) 125–137.
2
82–292.
42] H.-L. Qin, J. Leng, C.-P. Zhang, I. Jantan, M.W. Amjad, M. Sher, M. Naeem-ul-
Hassan, M.A. Hussain, S.N.A. Bukhari, Synthesis of
, β-Unsaturated Carbonyl-
Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents
[
[
[
α
16] M. Go, X. Wu, X. Liu, Chalcones: an update on cytotoxic and chemoprotective
properties, Curr. Med. Chem. 12 (2005) 483–499.
1
2

T.S. Ibrahim et al.
for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in
Bioorganic Chemistry 111 (2021) 104885
[48] P.F. Lamie, J.N. Philoppes, 2-Thiopyrimidine/chalcone hybrids: design, synthesis,
ADMET prediction, and anticancer evaluation as STAT3/STAT5a inhibitors,
J. Enzyme Inhib. Med. Chem. 35 (2020) 864–879.
Tumor Cells, J. Med. Chem. 59 (7) (2016) 3549–3561.
[
43] N.A. Qandeel, A.K. El-Damasy, M.H. Sharawy, S.M. Bayomi, N.S. El-Gohary,
Synthesis, in vivo anti-inflammatory, COX-1/COX-2 and 5-LOX inhibitory activities
of new 2,3,4-trisubstituted thiophene derivatives, Bioorg. Chem. 102 (2020),
[49] M. Rbaa, S. Jabli, Y. Lakhrissi, M. Ouhssine, F. Almalki, T. Ben Hadda, S. Messgo-
Moumene, A. Zarrouk, B. Lakhrissi, Synthesis, antibacterial properties and
bioinformatics computational analyses of novel 8-hydroxyquinoline derivatives,
Heliyon 5 (10) (2019) e02689, https://doi.org/10.1016/j.heliyon.2019.e02689.
[50] A. Radman Kastelic, R. Odzak, I. Pezdirc, K. Sovic, T. Hrenar, A. Cipak Gasparovic,
M. Skocibusic, I. Primozic, New and Potent Quinuclidine-Based Antimicrobial
Agents, Molecules 24 (14) (2019) 2675, https://doi.org/10.3390/
molecules24142675.
1
03890.
[
44] S.T. Al-Rashood, G.S. Hassan, S.M. El-Messery, M.N. Nagi, E.E. Habib, F.A.M. Al-
Omary, H.I. El-Subbagh, Synthesis, biological evaluation and molecular modeling
study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)-quinazolin-4-ones
as a new class of DHFR inhibitors, Bioorg. Med. Chem. Lett. 24 (18) (2014)
4
557–4567.
[
[
[
45] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and
computational approaches to estimate solubility and permeability in drug
discovery and development settings, Adv. Drug Deliv. Rev. 46 (1–3) (2001) 3–26.
46] D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple,
Molecular properties that influence the oral bioavailability of drug candidates,
J. Med. Chem. 45 (12) (2002) 2615–2623.
[51] X. Jiang, W. Liu, W. Zhang, F. Jiang, Z. Gao, H. Zhuang, L. Fu, Synthesis and
antimicrobial evaluation of new benzofuran derivatives, Eur. J. Med. Chem. 46 (8)
(2011) 3526–3530.
[52] M. Durcik, P. Tammela, M. Baran ˇc okov ´a , T. Toma ˇs i ˇc , J. Ila ˇs , D. Kikelj, N. Zidar,
Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors,
ChemMedChem 13 (2018) 186–198.
47] R. Wang, Y. Fu, L. Lai, A new atom-additive method for calculating partition
coefficients, J. Chem. Inf. Comput. Sci. 37 (3) (1997) 615–621.
1
3