Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of benzothiazole derivatives

Article abstract of DOI:10.1016/j.cclet.2015.09.004

New series of benzothiazole derivatives were designed and synthesized. The newly synthesized compounds were screened for their antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus cereus. Compounds 6j and 6o showed the highest activity against E. coli and S. aureus. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus fumigatus 293. Compounds 4c, 4g and 6j exhibited the highest activity against C. albicans. In addition, compounds 4a and 6j displayed promising activity against A. fumigatus 293. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds 4a, 6j and 6p showed moderate activity. The in vitro cytotoxicity testing of the synthesized compounds was performed against cervical cancer (Hela) and kidney fibroblast cancer (COS-7) cell lines. Results indicated that all tested compounds have IC₅₀ values >50 μmol/L against both cell lines. Molecular properties, toxicities, drug-likeness, and drug score profiles of compounds 4a-c, 5a, 6g,h, 6j, 6l, 6o and 7c,d were also assessed.

Full text of DOI:10.1016/j.cclet.2015.09.004

G Model
CCLET 3427 1–7
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Synthesis, antimicrobial, antiquorum-sensing and cytotoxic
activities of new series of benzothiazole derivatives
a
Q1 Moustafa T. Gabr a,b, Nadia S. El-Gohary a, , Eman R. El-Bendary ,
*
5
6
Mohamed M. El-Kerdawy a, Nanting Ni b, Mona I. Shaaban c,d
7
8
9
10
a Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
b Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
c Department of Microbiology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
d Department of Microbiology, College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia
A R T I C L E I N F O
A B S T R A C T
Article history:
New series of benzothiazole derivatives were designed and synthesized. The newly synthesized
compounds were screened for their antibacterial activity against Escherichia coli, Staphylococcus aureus
and Bacillus cereus. Compounds 6j and 6o showed the highest activity against E. coli and S. aureus. The
antifungal activity of these compounds was also tested against Candida albicans and Aspergillus fumigatus
293. Compounds 4c, 4g and 6j exhibited the highest activity against C. albicans. In addition, compounds
4a and 6j displayed promising activity against A. fumigatus 293. The same compounds were examined for
their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds
4a, 6j and 6p showed moderate activity. The in vitro cytotoxicity testing of the synthesized compounds
was performed against cervical cancer (Hela) and kidney fibroblast cancer (COS-7) cell lines. Results
Received 31 March 2015
Received in revised form 6 July 2015
Accepted 18 August 2015
Available online xxx
Keywords:
Benzothiazoles
Antimicrobial activity
Antiquorum-sensing activity
Cytotoxic activity
In silico studies
indicated that all tested compounds have IC50 values >50
mM against both cell lines. Molecular
properties, toxicities, drug-likeness, and drug score profiles of compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and
7c,d were also assessed.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
11
12
1. Introduction
virulence genes, antibiotic resistance and biofilm formation. QS 27
disruption is one of the emerging anti-virulence strategies that 28
13
14
15
16
17
18
19
20
21
22
23
24
25
26
The traditional antibacterial agents either kill bacteria (bacte-
ricidal)orinhibittheirgrowth(bacteriostatic). Typically, thetargets
for the conventional antibiotics are the essential cellular processes
such as bacterial cell wall biosynthesis, bacterial protein synthesis,
and bacterial DNA replication and repair [1]. The eventual growth
arrest and cell death can be followed by rapid expansion of resistant
subpopulations, making subsequent treatment difficult or impos-
sible [2]. Therefore, new antibacterial strategies are required. An
alternative to killing or inhibiting growth of pathogenic bacteria is
the specific attenuation of bacterial virulence, which could be
attained by targeting key regulatory systems that mediate the
expression of virulencefactors. Oneof thetargetregulatory systems
is quorum sensing (QS) [1]. QS is a phenomenon used by bacteria for
coordination of population-wide phenotypes, such as expression of
promises a lower risk of resistance development [3]. Many quorum 29
quenching methods have been developed against various clinically 30
significant bacterial pathogens [4].
31
The benzothiazole nucleus is a unique scaffold for further 32
molecular exploration to synthesize novel compounds. Literature 33
survey revealed that benzothiazole analogs are assosciated with 34
diverse pharmacological effects, including antimicrobial activity 35
[5–9]. In addition, benzothiazoles incorporating pyrazole moiety 36
demonstrated remarkable antimicrobial activity [10,11]. On the 37
same line, benzothiazoles incorporating isatin moiety have 38
received considerable attention owing to their diverse chemother- 39
apeutic potentials, including antimicrobial activity [12,13]. In 40
addition, various Schiff bases of 2-hydrazinobenzothiazole deri- 41
vatives (Fig. 1) were previously synthesized and screened for their 42
antimicrobial activity [14–16]. Some of these derivatives displayed 43
promising activity.
44
Therefore, we found it interesting to design new compounds 45
within the scope of synthetic procedures using the benzothiazole 46
*
Corresponding author.
E-mail address: dr.nadiaelgohary@yahoo.com (N.S. El-Gohary).
http://dx.doi.org/10.1016/j.cclet.2015.09.004
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004

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M.T. Gabr et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
R1
cytotoxicity testing of compounds 4a–e, 5a–c, 6a–r and 7a–d was
76
77
78
79
80
81
performed against cervical cancer (Hela) and kidney fibroblast
cancer (COS-7) cell lines adopting MTT assay [23–25].
The synthetic details and related spectra of the compounds as
well as their biological testing are deposited in Supporting
information.
H3C
N
N
S
NH
R
3. Results and discussion
82
83
R = CH3; F
R1 = 2-F; 3-F; 2-Cl; 4-OH; 2,5-(OH)2; 3,4-(OCH3)2
3.1. Chemistry
Fig. 1. Schiff bases of 2-hydrazinobenzothiazole derivatives with reported
The structures of all the synthesized compounds were
confirmed by 1H NMR, 13C NMR and HRMS. 1H NMR spectra of
84
85
86
87
88
89
90
91
antimicrobial activity.
compounds 4a–e showed a characteristic singlet signal at
d 2.05–
2.50 ppm for the methyl protons at the 3-position of the pyrazole
ring. In the 1H NMR spectra of compounds 6a–r, a singlet signal at
d
47
48
49
50
51
scaffold followed by suitable modifications to generate new series
of compounds with expected antimicrobial activity. The manipu-
lation strategy embraces the incorporation of pyrazole, isatin and
arylidene moieties into the benzothiazole ring in order to verify the
importance of these moieties for the antimicrobial activity (Fig. 2).
7.95–8.83 ppm was due to CH55N proton. Regarding 1H NMR
spectra of compounds 7a–d, methyl protons were observed as a
singlet signal at
d 1.90–2.35 ppm.
3.2. Biological screening
92
52
2. Experimental
The antimicrobial screening results (Table 1) were determined
by measuring the average diameter of the inhibition zones,
expressed in millimeters (mm) [19,21]. The minimum inhibitory
93
94
95
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
A
general approach for the synthesis of the designed
compounds is outlined in Scheme 1. The starting compound, 2-
amino-6-fluorobenzothiazole (1) was reacted with hydrazine
hydrate in refluxing ethylene glycol in the presence of hydrochloric
concentration (MIC,
m
g/mL) of the most active compounds against
96
97
98
99
E. coli, S. aureus, C. albicans and A. fumigatus 293 was carried out by
broth microdilution method using 96-multiwell microtiter plates
[20]. As shown in the results (Table 2), compound 6j showed the
highest activity against E. coli with MIC value of 312
Furthermore, compound 6j exhibited good antibacterial activity
against S. aureus with MIC value of 156.25 g/mL. The results are
compared to ampicillin as reference antibacterial agent.
acid to produce the hydrazine derivative
2
[17]. Refluxing
compound 2 with ethyl 3-oxo-2-((2-substituted phenyl)hydrazo-
no)butanoates 3a–e [18] in glacial acetic acid yielded the
corresponding pyrazole analogs 4a–e. In addition, the reaction
of the key intermediate 2 with the appropriate isatin in ethanol in
the presence of glacial acetic acid gave compounds 5a–c. Reaction
of 2 with the appropriate aromatic aldehyde in ethanol under
microwave irradiation gave the corresponding Schiff bases 6a–r in
64–82% yields. Moreover, refluxing the hydrazine analog 2 with
the appopriate acetophenone in ethanol in the presence of glacial
acetic acid furnished compounds 7a–d in 61–73% yields. The
synthesized compounds, 4a–e, 5a–c, 6a–r and 7a–d were screened
for their in vitro antibacterial activity against two species of Gram-
positive bacteria (Staphylococcus aureus and Bacillus cereus) and
one Gram-negative bacterium (Escherichia coli) [19,20]. Antifungal
screening against Candida albicans and Aspergillus fumigatus
293 was also performed [20,21]. The same compounds were
examined for their antiquorum-sensing activity against Chromo-
bacterium violaceum ATCC 12472 [22]. Additionally, the in vitro
m
g/mL.
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
m
a
Regarding the antifungal activity, compounds 4c, 6g and 6j
displayed the highest activity against C. albicans with MIC value
of 312.5
strong antifungal activity against A. fumigatus 293 with MIC value
of 156.25 g/mL (Table 2). The results are compared to fluconazole
mg/mL. In addition, compounds 4a and 6j demonstrated
m
as a reference antifungal agent. A. fumigatus 293 was resistant to
fluconazole [26]. These observations may promote further
development of benzothiazole derivatives and may lead to
compounds with potent antibacterial and antifungal activities.
While antibiotics kill or slow down the growth of bacteria,
quorum sensing inhibitors (QSIs) or quorum quenchers (QQs)
attenuate bacterial virulence and appear to be a promising strategy
to control bacterial resistance to antibiotics [27]. Thus, the same
compounds were examined for antiquorum-sensing activity
Arylidene moieties
Benzothiazole scaffold
Pyrzole moiety
H
O
N
R
Ar
CH3
F
S
N
N
N
NH
N
S
N
S
N
H
NH
N
N
R
N
F
F
O
R
4a-e
5a-c
6a-r; 7a-d
Isatin moiety
Fig. 2. Designed strategy of the titled compounds.
Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004

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M.T. Gabr et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
CH3
N
S
N
R
COOC2H5
H
N
H
N
N
N
F
N
COCH3
3a-e
Glacial acetic acid
O
R
4a-e
R = a) 2-Cl-4-NO2 ; b) 4-NO2; c) 2,4-(Cl)2;
d) 2,5-(Cl)2; e) 2-CH3-5-NO2
H
O
N
O
R
O
N
H
N
N
S
NH
Glacial acetic acid/ethanol
R
F
N
S
N
S
5a-c
NH2NH2.H2O/ HCl
Ethylene glycol
NH2
NHNH2
R = a) H; b) Br; c) CH3
F
F
1
2
Ar
N
N
S
NH
Ethanol/MW
F
6a-r
R
H3C
R
O
N
NH
N
CH3
S
F
Glacial acetic acid/ethanol
7a-d
R = a) 2-OH-5-Br; b) 2-OCH3-3-OH;
c) 2-OH-5-CH3; d) 4-I
Comp. No.
Ar
Comp. No.
Ar
Comp. No.
Ar
6a
6b
6c
NO2
O
N
O
H
Cl
OCH3
OCH3
6d
6e
6f
6i
NO2
O2N
OH
Br
6g
6j
6h
6k
NC
OH
OH
N
6l
Cl
Cl
HO
6m
6p
N
6n
6q
6o
N
N
O
O
6r
N
Scheme 1. Synthesis of compounds 4a–e, 5a–c, 6a–r and 7a–d.
118
119
120
121
against Ch. violaceum ATCC 12472 [22]. The QS system of Ch.
violaceum was used for this assay. QS in this wild type strain of
bacteria produces violacein (a purple pigment) in response to
autoinducer molecules known as acyl HSLs [28,29]. Thus, drugs
that inhibit acyl HSL-mediated QS activity in Ch. violaceum would 122
prevent the production of this purple pigment. Screening results 123
for their ability to inhibit QS regulated violacein production against 124
Ch. violaceum (based on measuring the radius of pigment inhibition 125
Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004

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M.T. Gabr et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Table 1
Antimicrobial and antiquorum-sensing activities of compounds 4a–e, 5a–c, 6a–r and 7a–d.
Comp. No.
Inhibition zone diameter (mm)a,b
QS inhibition (mm)c
E. coli
B. cereus
S. aureus
C. albicans
A. fumigatus
Ch. violaceum
4a
6
8
–
–
28
–
11
6
4b
3
6
4
17
28
–
4c
4
8
4
–
–
4d
4
4
–
5
4
4e
4
4
–
–
5
4
5a
–
–
–
2
26
14
–
–
5b
2
2
2
2
4
5c
–
–
–
–
4
6a
2
3
–
–
–
–
6b
5
7
–
–
–
–
6c
–
–
–
–
–
–
6d
5
3
14
–
–
–
–
6e
–
14
2
7
–
–
6f
–
3
10
19
8
–
6
6g
14
–
10
8
11
–
–
–
6h
17
–
–
6i
5
4
3
10
28
4
–
6j
18
–
14
–
26
3
32
–
14
–
6k
6l
2
4
4
6
20
–
–
6m
4
8
10
–
6
–
6n
–
4
8
–
5
6o
16
–
12
5
19
5
12
7
–
–
6p
–
14
–
6q
–
3
–
–
–
6r
5
4
15
–
–
–
–
7a
–
–
–
11
–
–
7b
4
2
–
–
–
7c
–
–
–
–
26
30
nt
–
–
7d
–
2
–
2
–
Ampicillin
Fluconazole
Catechin
26
nt
nt
12
nt
nt
30
nt
nt
nt
22
nt
nt
nt
4
nt
Bold values point out the best results. nt, not tested.
a
Results are calculated after substraction of DMSO activity.
b
Not active (–, inhibition zone <2 mm); weak activity (2–9 mm); moderate activity (10–15) mm; strong activity (16–25 mm); very strong activity (26–35 mm).
QS inhibition (radius of pigment inhibition in mm) = radius of growth and pigment inhibition (r2) – radius of bacterial growth inhibition (r1).
c
Table 2
3.3. Structure–activity relationship (SAR) studies
134
MIC values of the most active compounds.
Compounds 4a–e: Removal of the 2-chloro substituent from the
phenyl ring of compound 4a increasedthe activityagainst C. albicans
but abolished the activity against A. fumigatus 293 (compound 4b).
Moreover, replacement of the 4-nitro substituent in the same
compound with 4-chloro substituent resulted in excellent activity
against C. albicans (compound 4c) but abolished activity against
A. fumigatus 293. Compounds bearing 2,4-disubstituted phenyl and
4-substituted phenyl moieties exhibited stronger activity against C.
albicans compared to compounds bearing 2,5-disubstituted phenyl
moiety (compounds 4b,c vs. 4d,e).
Compounds 5a–c: Replacement of 2-oxoindolin-3-ylidene
moiety (compound 5a) with 5-bromo-2-oxoindolin-3-ylidene
(compound 5b) resulted in decreased antifungal activity against
A. fumigatus 293, while its replacement with 5-methyl-2-oxoin-
dolin-3-ylidene abolished the antifungal activity against both of
the tested fungi (compound 5c).
Compounds 6a–r: Compounds 6a,b bearing (furan-2-yl)methy-
lene moiety were inactive as antifungal agents and revealed weak
activity against E. coli and B. cereus. Replacement of (furan-2-
yl)methylene moiety with (1H-pyrrol-2-yl)methylene moiety
completely abolished the antibacterial activity against E. coli
and B. cereus (compound 6c vs. 6a,b). The presence of 2-
nitrobenzylidene moiety resulted in acceptable antibacterial
activity against the three tested microorganisms as well as
antifungal activity against C. albicans (compound 6g), while its
replacement with 2-bromobenzylidene or 2-cyanobenzylidene
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
Comp. No.
MIC (m
g/mL)a
E. coli
S. aureus
C. albicans
A. fumigatus
4a
nt
nt
nt
156.25
nt
4b
nt
nt
625
312.5
nt
4c
nt
nt
nt
5a
nt
nt
312.5
nt
6g
nt
nt
312.5
nt
6h
nt
nt
625
156.25
625
nt
6j
312.5
nt
156.25
nt
312.5
nt
6l
6o
625
nt
625
nt
nt
7c
nt
312.5
312.5
nt
7d
nt
nt
nt
Ampicillin
Fluconazole
19.531
nt
312.5
nt
nt
1250
–
a
–, MIC > 2500 mg/mL. nt, not tested.
126
127
128
129
130
131
132
133
in mm) are presented in Table 1 and revealed that compounds 4a,
6j and 6p have moderate antiquorum-sensing activity. The rest of
the tested compounds were found to be less active or completely
inactive. The results are compared to catechin as a positive control.
The results of in vitro cytotoxicity testing against cervical cancer
(Hela) and kidney fibroblast cancer (COS-7) cell lines indicated that
all tested compounds have IC50 values >50
lines.
mM against both cell
Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004

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Table 3
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
resulted in decreased antibacterial and antifungal activities
(compounds 6i and 6k). Furthermore, the presence of 3-hydro-
xybenzylidene moiety revealed strong antifungal activity against
A. fumigatus 293 (compound 6h). Incorporation of 3,4-dihydrox-
ybenzylidene moiety into the benzothiazole nucleus resulted in
promising activity against E. coli, S. aureus, C. albicans and A.
fumigatus 293 as well as moderate antiquorum-sensing activity
(compound 6j). Replacement of 4-N,N-dimethylaminobenzylidene
moiety with 4-N,N-diethylamino-2-hydroxybenzylidene in-
creased the antibacterial activity against the three tested micro-
organisms but abolished the antifungal activity against A.
fumigatus 293 (compound 6m vs. 6l). Replacement of (pyridin-
2-yl)methylene moiety with (3,5-dichloropyridin-4-yl)methylene
increased the antibacterial activity against the three tested
microorganisms as well as antifungal activity against C. albicans
(compound 6o vs. 6n). Incorporation of (isoquinolin-5-yl)methy-
lene moiety into the benzothiazole nucleus improved the
antiquorum-sensing activity (compound 6p), while incorporation
of (pyren-2-yl)methylene moiety enhanced the antibacterial
activity against S. aureus (compound 6r).
Topological polar surface area, number of rotatable bonds and calculated Lipinski’s
rule of five for compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and 7c,d.
Comp.
No.
Molecular properties
TPSAa
Nrotbb miLogPc OH–NH O–N
interact interact
MW
No. of
violations
4a
118.04
118.00
72.18
4
4
3
2
4
3
3
4
3
3
3
4
5
4.406
3.800
5.125
3.695
3.838
3.424
2.958
4.029
4.286
4.738
5.456
À0.87
À0.118
1
1
1
2
1
2
3
1
1
2
1
4
1
9
9
6
5
6
4
5
4
4
4
3
7
7
432.8
398.39
422.7
312.2
316.3
287.3
303.3
314.4
341.1
315.3
411.2
349.4
306.2
0
0
1
0
0
0
0
0
0
0
1
0
0
4b
4c
5a
70.145
83.107
57.511
77.739
40.521
50.175
57.511
37.283
112.73
6g
6h
6j
6l
6o
7c
7d
Ampicillin
Fluconazole 81.664
a
TPSA, topological polar surface area.
Nrotb, number of rotatable bonds.
miLogP, the parameter of lipophilicity.
b
c
Compounds 7a–d: The presence of 2-hydroxy-5-methylphenyl
and 4-iodophenyl moieties resulted in promising anifungal activity
against A. fumigatus 293 (compounds 7c,d), while incorporation of
5-bromo-2-hydroxyphenyl moiety into the benzothiazole nucleus
resulted in moderate antifungal activity against the same
microrganism (compound 7a). On the other hand, incorporation
of 3-hydroxy-2-methoxyphenyl moiety abolished the antifungal
activity against the same microrganism (compound 7b).
compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and 7c,d which exhibited the 205
highest antibacterial and/or antifungal activity, were analyzed for 206
the prediction of solubility and Lipinski’s rule of five [30] as well as 207
other properties (Tables 3 and 4) for filtering compounds for 208
subsequent synthesis and antimicrobial screening.
209
189
3.4. Molecular properties and drug-likeness
3.4.1. Molinspiration calculations
210
As a part of our study; the compliance of compounds to the 211
Lipinski’s rule of five was evaluated [30], this simple rule is based 212
on the observation that most biologically active drugs have 213
molecular weight of 500 or less, logP values not higher than 5, 214
hydrogen bond donor sites not higher than 5 and hydrogen bond 215
acceptor sites not higher than 10. In addition, topological polar 216
surface area (TPSA) and number of rotatable bonds have been 217
linked to drug bioavailability [31]. Molecular properties (TPSA, 218
nrotb, miLogP, OH–NH interaction, O–N interaction, molecular 219
weight and number of violations from Lipinski’s rule) of the newly 220
synthesized compounds were calculated using molinspiration 221
software and compared to the values of the standard drugs, 222
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
A molecular property is a complex balance of various structural
features which determine whether a particular molecule is similar
to the known drugs. It generally means ‘‘molecules which contain
functional groups and/or have physical properties consistent with
most of the known drugs’’. Hydrophobicity, molecular size,
flexibility and presence of various pharmacophoric features are
the main physical properties that influence the behavior of
molecules in a living organism. Computational chemists have a
wide array of tools and approaches available for the assessment of
molecular diversity. Diversity analysis has been shown to be an
important ingredient in designing drugs. So, computational
sensitivity and structural analyses have been used to study the
drug-likeness of the candidate drug. As good bioavailability can be
achieved with an appropriate balance between solubility and
partitioning properties. Thus, in order to achieve good oral drugs,
ampicillin and fluconazole (Table 3).
223
Topological polar surface area (TPSA) and number of rotatable 224
bonds are two important properties for the prediction of oral 225
bioavailability of drug molecules [32–35]. TPSA is calculated based 226
Table 4
Toxicity risks, drug-likeness and drug score of compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and 7c,d.
Comp. No.
Toxicity risks
Mutagenicity
Drug-likeness
Drug score
Tumorogenicity
Irritancy
Reproductive effects
4a
1.13
À6.99
4.83
3.92
0.94
1.49
2.35
0.45
1.45
À0.27
0.93
10.72
1.99
0.08
0.18
0.20
0.62
0.15
0.52
0.60
0.25
0.40
0.35
0.31
0.91
0.87
4b
4c
5a
6g
6h
6j
6l
6o
7c
7d
Ampicillin
Fluconazole
Bold values point out the best drug score values.
low risk; high risk.
Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004

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on the methodology published by Ertl et al. [35] as the surface
areas that are occupied by oxygen and nitrogen atoms and by
hydrogen atoms attached to them. Thus, it is closely related to the
hydrogen bonding potential of a compound [32–35]. TPSA has been
shown to be a very good descriptor characterizing drug absorption,
antiquorum-sensing activity. These active compounds were
proved to be good scaffolds for the development of new potent
antibacterial and antifungal agents.
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Conflict of interest
293
including intestinal absorption, bioavailability and blood–brain
2
˚
barrier penetration. Molecules with TPSA values around 140 A or
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
294
295
more are expected to exhibit poor intestinal absorption
[31]. Results shown in Table 3 indicated that all of the analyzed
2
˚
compounds have TPSA values <140 A ; thus, they are expected to
Acknowledgments
296
have good intestinal absorption. Molecules with more than
10 rotatable bonds may have problems with bioavailability
[31]. All the tested compounds have 2 to 4 rotatable bonds and
they might not have problems with bioavailability (Table 3).
MiLogP is calculated adopting the methodology developed by
Molinspiration as a sum of fragment-based contributions and
correction factors (http://www.molinspiration.com). It has been
shown that for the compound to have a reasonable probability of
being well absorbed, miLogP value must be in the range of À0.4 to
+5 [31]. On this basis, all compounds under investigation (except
4c and 7d) were found to have miLogP values under the acceptable
criteria and they are expected to have reasonable oral absorption
(Table 3). It is worth mentioning that all of the analyzed
compounds have one or zero violation of Lipinski’s rule; therefore,
they are expected not to have problems with bioavailability
(Table 3). Molecules violating more than one may have problems
with bioavailability [36].
The authors thank Professor Binghe Wang at Georgia State
University, USA, for providing all required facilities and carrying
out the spectral analyses as well as the cytotoxicity testing.
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Appendix A. Supplementary data
300
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cclet.2015.09.
004.
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3.4.2. Osiris calculations
Toxicity risks (mutagenicity, tumorogenicity, irritancy and
reproductive effects) and physicochemical properties (drug-
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drugs, ampicllin and fluconazole. Compounds 5a, 6h and 6j possess
good drug score values (Table 4).
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4. Conclusion
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In a summary, compounds 6j and 6o are good antibacterial
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Please cite this article in press as: M.T. Gabr, et al., Synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of
benzothiazole derivatives, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.004