Synthesis of novel derivatives of 4-Methylbenzimidazole and evaluation of their biological activities

Article abstract of DOI:10.1016/j.ejmech.2014.07.078

4-Methylbenzimidazole 1-28 novel derivatives were synthesized and evaluated for their antiglycation and antioxidant activities. Compounds 1-7 and 11 showed excellent activities ranged 140-280 μM, better than standard drug rutin (294.46 ± 1.50 μM). Compoun

Full text of DOI:10.1016/j.ejmech.2014.07.078

European Journal of Medicinal Chemistry 84 (2014) 731e738
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel derivatives of 4-methylbenzimidazole and
evaluation of their biological activities
,
b
,
,
Muhammad Taha a *, Nor Hadiani Ismail a b, Waqas Jamil c, Hesham Rashwan d,
Syed Muhammad Kashif c, Amyra Amat Sain e, Mohd Ilham Adenan a
,
, e, f
El Hassane Anouar a, Muhammad Ali g, Fazal Rahim i, Khalid M. Khan h
a Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 43200 Puncak Alam, Selonger,
Malaysia
b Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor D. E., Malaysia
c Institute of Advance Research Studies in Chemical Sciences, University of Sindh Jamshoro, Pakistan
d Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam 42300, Selangor, Malaysia
e Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation, Bangunan Pentadbiran, Blok 5-A, Halaman
Bukit Gambir,11700 Bayan Lepas, Penang, Malaysia
f Forest Research Institute Malaysia (FRIM), 52109 Kepong, Selangor, Malaysia
g Center for Advanced Drug Research, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, KPK, Pakistan
h H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
i Department of Chemistry, Hazara University, Mansehra, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Methylbenzimidazole 1e28 novel derivatives were synthesized and evaluated for their antiglycation
Received 18 July 2013
Received in revised form
18 July 2014
Accepted 22 July 2014
Available online 23 July 2014
and antioxidant activities. Compounds 1e7 and 11 showed excellent activities ranged 140e280
better than standard drug rutin (294.46 1.50 M). Compound 1e28 were also evaluated for DPPH
activities. Compounds 1e8 showed excellent activities, ranging 12e29 M, better than standard drug n-
0.40 M). For superoxide anion scavenging activity, compounds 1e7
mM,
m
m
propylgallate (IC50 ¼ 30.30
m
showed better activity than standard n-propylgallate (IC50 ¼ 106.34 1.6
mM), ranged 82e104 mM. These
compounds were found to be nontoxic to THP-1 cells.
Keywords:
© 2014 Elsevier Masson SAS. All rights reserved.
Benzimidazole
Antiglycation
Antioxidant
Antileishmanial
Stereoisomers
1. Introduction
acylhydrazone have been used as effective therapeutics for tuber-
culosis [10]. The hydrazones also reported for their bactericidal
[11,12], anti-convulsant [13], analgesic [14], anti-inflammatory [15]
and vasodilator [16] activities.
Benzimidazole is a versatile heterocyclic pharmacophore with
diverse range of medicinal properties as evaluated by numerous
research groups [1]. A number of commercially available drugs that
contain benzimidazole ring are proton pump inhibitors [2] anti-
helmintics [3] antidopaminergics [4] antipsychotics [5] ionodilators
[6] and anticancers [7].
Metal complexes of hydrazones also drew considerable atten-
tion due to their medicinal and catalytic properties [17,18].
Discovery of glycation inhibitor is a main advancement for the
treatment of late diabetic complications. At present, number of
efficient glycation inhibitors is few; the requirement of novel gly-
cation inhibitors is still unmet [19]. Horrible incident of type-2
diabetes is increasing; its harmful effects are mostly endorsed to
the formation of sugar derived substances called advanced glyca-
tion end products (AGEPs) [20]. AGEPs are important pathogenic
mediators of approximately all diabetic complications [21]. A lot of
efforts have been focused on reversing the glycation process by
discovering potential new glycation inhibitors [22]. These
Hydrazone derivatives are widely used in pharmaceutical in-
dustry [8,9], such as Isonicotinhydrazide and its N-isopropyl
* Corresponding author. Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 43200 Puncak Alam,
Selonger, Malaysia.
E-mail addresses: taha_hej@yahoo.com, muhamm9000@puncakalam.uitm.edu.
my (M. Taha).
http://dx.doi.org/10.1016/j.ejmech.2014.07.078
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

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M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
molecular inhibitors can cleave AGEPs cross-links and possibly
opens the opportunity to reverse the steady process of diabetic
complications [23]. On the other hand, AGEPs receptor binding
induces the production of reactive oxygen species (ROS), which
results in the activation of pleiotropic transcription factor nuclear
benzimidazole was formed by refluxing arylester of benzimidazole
with methanolic hydrazine hydrate (Scheme 1).
The synthesis of benzimidazole benzohydrazide Schiff bases
(1e28) was accomplished by reacting different aldehydes with
benzimidazole benzohydrazide in n-butanol in the presence of
catalytic amount of acetic acid as shown in Scheme 1.
factor NF-kB, thus causing multiple pathological alterations in gene
expression [24].
Results suggest that oxidative stress has significant role in the
development of diabetic complications, both microvascular and
cardiovascular. It has been shown that the metabolic abnormalities
associated with diabetes results in mitochondrial superoxide
overproduction. This increased superoxide production is vital
mediator of diabetes tissue damage, which is involved in the acti-
vation of 5 pathways leading to the pathogenesis of complications
and direct inactivation of 2 antiatherosclerotic enzymes, eNOS and
prostacyclin synthase [25].
In the continuation of our research on medicinal chemistry, we
have synthesized a series of benzimidazoles 1e28 with benzohy-
drazide moiety. Our previous studies suggested that benzohy-
drazide moiety has potent antioxidant, antiglycation and
antileishmanial activities [26]. In view of the potential of these
classes of organic compounds we proposed if benzimidazole ring
and benzohydrazide moieties are combined in a single molecule to
see whether it improves their efficacy or not.
2.2. DFT study over configuration (Z/E)
The stereochemical configuration of double bond eN]CH-R in
4-methylbenzimidazoles 1e28 (Scheme 1) may be assigned as Z or
E. Electronic energies and vibration modes i.e, nC¼O, nN¼C and nCH
(CH in eN]CH-R), have been calculated for randomly selected five
compounds (3, 5, 8, 16 and 25) using DFT calculations at the b3lyp/
6-311þþG(d,p) level to determine the configuration. The calculated
electronic energies showed that the E configuration is relatively
more stable than Z by (5, 9, and 8 kcal/mol) for 3, 5 and 8 com-
pounds, respectively. However, for compound 16 and 25, the
hydrogen bond formation between eCOeNHe group and (i) ni-
trogen atom of pyridine ring in 16 (d ¼ 1.93 Å) and (ii) oxygen atom
of furan moiety in 25 stabilize the Z configuration by 7 and 2 kcal/
mol with regard to E configuration, respectively (Fig. 1).
To confirm these results, the vibration modes of nC¼O, nN¼C and
nCH (CH in eN]CH-R) were calculated at the same level of theory
Antiglycation agents with antioxidant properties may serve as
viable lead compounds for the development of new antidiabetic
drugs which will possibly not only reverse the glycation process but
will also assist to eradicate glycation induced oxidative stress.
and compared the corresponding experimental data (Table 1). The
variation of vibrational modes DnC¼O (DnN¼C) between the calcu-
lated and experimental values was very small for E and Z configu-
rations, respectively. However, the large variation of vibration
modes of nCH (CH in eN]CH-R) between the E and Z configuration
allow a better assignment of absolute configuration. On one hand,
the E configurations for the compounds 3, 5 and 8 showed a vari-
ation of 3e15 cmꢀ1 to experimental mode; while for Z configura-
tion the variation vary from 105 to 132 cmꢀ1. These results are in
good agreement with electronic energies obtained above. There-
fore, the stereochemistry of eN]CHe double bond for 3, 5 and 8 is
E configuration. On the other, based on the electronic energy, the Z
configurations of 16 and 25 are more stable than E ones. The stable
configuration of 16 and 25 is confirmed by nCH (CH in eN]CH-R)
2. Results and discussion
2.1. Chemistry
The synthesis of novel derivatives of 4-benzimidazole are
commenced with the synthesis of sodium metasulfite adduct ac-
cording to literature protocol [27]. The resulting sulfite adduct was
refluxed with 3-methyl-1,2-diaminobenzene in DMF for 6 h to give
the arylester substituted benzimidazole. The benzohydrazide of
Scheme 1. synthesis of benzimidazole benzohydrazide 1e28.

M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
733
Fig. 1. Optimized structures of Z configurations of 16 and 25 compounds.
(Table 1). Therefore, the stereochemistry of eN]CHe double bond
in 16 and 25 are Z. Based on these results we compare the nCH (CH in
eN]CH-R) of all other compounds (1, 2, 4, 6, 7, 9e15, 17e24,
26e28) and they are in the range of 2910e2930 so they all have E
configuration.
hydroxy is the second most active compound amongst current
series. It is worth mentioning that compound 22 with a p-methoxy
group found to be completely inactive which proved that for a
compound to be active among the current series it should possess a
p-hydroxy substituent.
Compound 3 (IC50 ¼ 190.12 1.70
compound having 3,4-dihydroxy moiety. Comparing analogue 3
M, p-hydroxyl group), we came across
the conclusion that intramolecular hydrogen bonding in 3 has
resulted in somewhat reduced activity as compared to analogue 6.
mM), is the third most active
2.3. Antiglycation activity
and 6 (IC50 ¼ 150.45 1.30
m
We have reported hydrazones as potent inhibitor of glycation of
proteins previously [26]. In continuation to our efforts for devel-
oping novel antiglycation agents associated with antioxidant po-
tentials to combat diabetes and its complications. We synthesize
novel series of hydrazones 1e28 and evaluated them for their
antiglycation potential as well as antioxidant potential. They
showed varying degree of antiglycation activities, with IC50 values
Compound 4 (IC50 ¼ 195.12 1.58
mM), with 3,5-dihydroxy moi-
eties showed good activity but lesser than 4-hydroxy analogues.
Comparing compounds 2 (IC50 ¼ 205.52
dihydroxyl moieties and 14 (IC50 ¼ 400.15
1.92
3.86
m
M), with 2,5-
mM) with 2-
hydroxy-5-methoxy moieties, it is revealed that activity is mainly
dependent upon 5-hydroxy substituent. Protection of 5-hydroxy
substituent into methoxy group resulted in two folds downfall in
activity.
ranging between 140.40 and 500
mM, when compared to standard
rutin (294.46 1.50 M). Compounds 5, 6, 3, 4, 2, 1, 7, and 11
m
(IC50
(IC50
(IC50
¼
¼
¼
140.40
190.12
205.52
1.20
1.70
1.92
m
m
m
M), (IC50
M), (IC50
M), (IC50
¼
¼
¼
150.45
195.12
220.15
1.30
1.58
1.95
mM),
mM),
mM),
The compound 1 (IC50 ¼ 220.15 1.95
mM), having 2,3dihydroxy
is the least active compound among the dihydroxy analogues,
because it has strong intramolecular hydrogen bonding which
decreased its interactions with active constituent methylglyoxal.
(IC50 ¼ 270.60 2.20
m
M), and (IC50 ¼ 280.12 2.45
m
M) showed
M). The com-
pounds 8e10 and 12e14 showed good activities ranged
340e400 M. The compounds 27 and 28 showed moderate activ-
activities better than standard rutin (294.46 1.50
m
Compound 7 (IC50 ¼ 270.60 2.20
mM) having 4-hyrdoxy-3-
methoxy showed good activity but less as compare to compound
6 this may be due to the large size of methyl which created steric
hindrance for methylglyoxal to interact. This trend can further be
m
ities. The compounds 15e26 showed inhibition less than 50%
therefore they were not evaluated for IC50 (Table 2).
seen in compounds
8
(IC50
¼
350.30
3.45
m
M), 12
Preliminary SAR suggests the activity is mainly dependent upon
the number as well as position of hydroxyl groups. Five compounds
(1e5) having dihydroxy substituent's showed excellent activity
while variation in their activity is depending upon the position of
hydroxyl group. Compound 5 which showed highest activity
(IC50 ¼ 405.25 3.96
m
M) and 13 (IC50 ¼ 360.30 3.20
mM) having
4-hydroxy and 3-hydroxy groups, respectively, but activity
decreased due to bromine, methoxy, and iodine groups, respec-
tively. Compound 11 (IC50 ¼ 280.12 2.45
showed better activity than standard on the other hand com-
M) having 2-hydroxy showed very
mM) having 3-hydroxy
(IC50 ¼ 140.40 1.20
mM), has 2,4 dihydroxy substituent's on aro-
pound 9 (IC50 ¼ 380.20 3.60
m
matic ring. The activity mainly depends upon p-hydroxy substitu-
ent which can be proved by the compound 10 having 2-hydroxy-4-
methoxy substituents. It has been observed that activity is dropped
by factor of 2.5 approximately with respect to compound 5.
weak activity as compare to its other analogues due to steric hin-
drance. Compounds 27 and 28 showed very weak activities due to
the weak interaction of ester and nitro group respectively with
methylglyoxal.
Furthermore the compound 6 (IC50 ¼ 150.45 1.30
mM), having 4-
Additionally compounds 15e26 showed less than 50% inhibi-
tion; therefore they were not further evaluated for their IC50 values.
Table 1
Calculated and experimental vibrational modes (cmꢀ1) for selected compounds.
2.4. DPPH scavenging activity
Nꢁ
nC¼O
nN¼C
nCH
Calculated
Exp
Calculated
Exp
Calculated
Exp
4-Methylbenzimidazoles (1e28) were also evaluated for their
in vitro DPPH radical scavenging activity. They showed a varying
degree of DPPH radical scavenging activity with IC50 values be-
E
Z
E
Z
E
Z
3
5
8
16
25
1698
1696
1702
1709
1712
1706
1705
1708
1701
1705
1692
1690
1696
1705
1708
1623
1615
1619
1618
1626
1614
1613
1610
1588
1607
1628
1618
1621
1602
1609
2909
2935
2917
2910
2928
3033
3052
3035
3047
3054
2915
2920
2930
3050
3046
tween 12.0 and 180
values 12.05 0.45, 14.20
25.23 0.94, 26.15 1.05, 27.45
respectively, proved better than the standard antioxidant n-
m
M. Compounds 1, 3, 4, 2, 8, 7, 5, and 6 with IC50
0.55, 17.30 0.62, 18.52 0.60,
1.02, and 29.01 1.05
mM

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M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
Table 2
In vitro various biological activities of benzimidazole derivatives 1e28.
Comp. no.
R
IC50
(m
M
SEMa)
Antiglycation
DPPH
Superoxide anion
82 1.2
Antileishmanial
37.80 2.5
1.
220.15 1.95
12.05 0.45
2.
3.
205.52 1.92
190.12 1.70
18.52 0.60
14.20 0.55
86.12 1.5
81.02 1.7
NAb
NAb
4.
5.
195.12 1.58
140.40 1.20
17.30 0.62
27.45 1.02
90.01 2.1
92.12 3.2
NAb
NAb
6.
7.
8.
150.45 1.30
270.60 2.20
350.30 3.45
29.01 1.10
26.15 1.05
25.23 0.94
101.12 3.5
104.12 3.8
190.10 3.9
NAb
NAb
NAb
9.
380.20 3.60
340. 3.10
54.12 2.12
47.5 1.85
208.99 5.41
201.99 5.41
NAb
NAb
10.
11.
12.
280.12 2.45
405.25 3.96
60.23 2.45
40.12 1.58
211.99 5.55
210.10 4.41
NAb
NAb
13.
360.30 3.20
49.12 1.82
222.01 5.41
NAb

M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
735
Table 2 (continued )
Comp. no.
R
IC50
(
mM
SEMa)
Antiglycation
DPPH
Superoxide anion
215.30 6.41
Antileishmanial
14.
15.
400.15 3.86
74.21 2.65
NAb
NAb
N.A
90.21 3.12
320.30 6.15
16.
17.
18.
N.A
N.A
N.A
94.31 3.21
105 3.85
350.30 6.70
310.30 6.41
340.15 6.41
NAb
NAb
NAb
88.41 3.18
19.
N.A
120.21 3.60
360.30 7.50
NAb
20.
21.
N.A
N.A
150.01 4.12
158.12 4.10
345.30 7.10
340.30 6.88
NAb
NAb
22.
N.A
140.21 3.82
340.15 6.41
NAb
23.
24.
N.A
N.A
145.12 4.01
120.12 3.84
345.30 6.92
330.30 6.20
NAb
NAb
25.
26.
N.A
N.A
180.12 4.50
110.12 3.48
310.30 6.30
320.15 6.41
NAb
NAb
(continued on next page)

736
M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
Table 2 (continued )
Comp. no.
R
IC50
(m
M
SEMa)
Antiglycation
DPPH
Superoxide anion
322.30 6.52
Antileishmanial
27.
28.
500.65 6.12
160.12 4.15
NAb
450.12 5.20
138.45 3.84
312.30 6.10
NAb
Standard drug
IC50
(m
M
SEMa)
Rutin (antiglycation)
n-propylgallate (DPPH)
n-propylgallate (Superoxide anion)
294.46 1.50 mM
30.30 0.40
106.34 1.6
m
m
M
M
Pentamidine (antileishmanial)
7.02 0.12 mM
a
SEM is the standard error of the mean.
NA: Not active.
b
propylgallate (IC50 value ¼ 30.30
0.40
m
M). Compounds 9e13
2.5. Superoxide scavenging activity
showed good activity ranging between 40e60
mM and the com-
pounds 14e18 showed moderate activity ranging 74e105
compound 19e28 show weak activity ranging 110e180
(Table 2).
m
M. The
The synthetic compounds 1e30 also evaluated for superoxide
anion scavenging activity. The compounds 1e7 showed IC50 values
82 1.2, 86.12 1.5, 81.02 1.7, 90.01 2.1, 92.12 3.2,101.12 3.5,
mM
This is a well established and known fact; the antioxidant ac-
tivity mainly depends upon the number and position of hydroxy
[28,29]. The compound 1 is the most active compound among the
active compounds its activity is so high due to adjacent hydroxy
groups. Which is also proved by other researchers; adjacent hy-
droxy has better stabilizing potential than isolated [29]. The sec-
ond most active compound is compound 3 which is also having
adjacent hydroxy group but less active than compound 1 due to
the hydroxy group are not close to C]N. The compound 4 is the
third most active compound its activity is due to the resonance
stabilizing potential of the 3,5-dihyroxy position and a slight dif-
ference is seen when the hydroxy shift from 3 to 2 as in compound
2. The compound 5 having 2,4-dihyrdoxy showed better activity
than standard drug but least active among the dihydroxy
analogue. The compound 8 having 3-bromo-4-hydroxy showed
very good activity this may be due to the bromine which can
stabilize the intermediate form in bioassay by induct effect.
Furthermore the compound 7 having 3-methoxy-4-hydroxy shows
very good activity but almost half if we compare with 3,4-
dihydroxy compound 3 which proves that the adjacent position
of dihydroxy group is important for the molecule to be potent
active. Interestingly 4-hyroxy analogue showed better than stan-
dard drugs but showed less activity than other substituted 4-
hydroxy analogues 7 and 8 its mean the activity mainly depend
upon 4-hydroxy but further can be improve by other substitution
on the ring. The compounds 9e14 are monohydroxy analogue and
showed good activity but not like 4-hydroxy analogues, which
prove that 4-position is important for this kind of molecules to
show potent antioxidant potential. Furthermore the ortho 9 po-
sition show slightly better activity then meta 11, this may be due
to the closeness of ortho hydroxy to the N]C bridge. From our
previous studies [26] simple halogen, methoxy, pyridine ring, nitro
and ester groups were inactive for antioxidant activity of benzo-
hydrazide this moderate to weak activities of these may be due to
the present of benzimidazole activity that's way we have enhance
activity of dihydroxy analogues.
and 104.12 3.8
propylgallate (IC50 value ¼ 106.34 1.6
showed moderate activity ranges between 190 and 215
compounds 15e28 showed weak activity ranges between 310 and
360 M (Table 2).
The superoxide anion activity depends open number of hydroxy
and slightly on their position the most active compound 1 having
2,3-dihyroxy like it the compound 3 having 3,4-dihyroxy showed
almost same scale of activity. The third active compound 2 having
2,5-dihyroxy and activity slightly decrease as the hydroxy at posi-
tion 2 shift to position 3 in compound 4. Same way when the 5
hydroxy shift to 4 its activity further decreased as in compound 5.
This prove that the changing the position of hydroxy shifts its ac-
tivity and adjacent dihydroxy group has better activity then iso-
lated dihydroxy this may be due to the stabilizing power of adjacent
dihydroxy group is more than isolated dihydroxy.
m
M respectively, better activity than standard n-
M). The compounds 8e14
M. The
m
m
m
The compound 6 is 4-hydroxy and showed better activity than
standard drug its other analogues compound 7 having additional
methoxy at 3 position showed almost same activity but surprisingly
compound 8 having bromine at 3 positions instead of methoxy
dropped the active a lot. Nevertheless the ortho and meta sub-
mitted analogues showed very constant value ranges 190e215 mM
its mean that the para position is important for the superoxide
anion activity and ortho and meta derivatives give moderate ac-
tivity. All other compounds 15e28 which do not have any hydroxy
group showed weak activity ranging between 310 and 360 mM. This
activity may be due to the benzimidazole ring and varied according
to the electron dispersion potential of the molecules. So we
concluded that in superoxide anion activity mainly depends upon
the number of hydroxy groups and as well as their proper
arrangement.
2.6. Antileishmanial and cytotoxicity activity
As we have reported benzohydrazide, Benzohydrazones,
morphine and disulfide derivatives [30] as potent antileishmanial

M. Taha et al. / European Journal of Medicinal Chemistry 84 (2014) 731e738
737
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3. Conclusion
We reported the synthesis of novel derivatives of benzimidazole
(1e28) having benzohydrazone moiety. The Compounds 1e7 and
11 showed excellent antiglycation activity. The compounds 1e8
showed excellent antioxidant activity. These compounds were
found to be nontoxic to THP-1 cells. Compounds with both anti-
glycation and antioxidant potentials may serve as lead compounds
for the development of new antidiabetic drugs. This dual potential
of the current series will possibly not only reverse the glycation
process but will also assist to eradicate glycation induced oxidative
stress.
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AGEPs advanced glycation end products
ROS
NF-
reactive oxygen species
nuclear factor kappa-light-chain-enhancer of activated B
cells
k
B
eNOS
DMF
E
endothelial nitric oxide synthase
dimethylsulfoxide
entgegen
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Z
Zusammen
DFT
DPPH
THP-1
density functional theory
2,2-diphenyl-1-picrylhydrazyl
TammeHorsfall protein 1
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.07.078.
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