Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted-2-(4-phenylethynyl-phenyl)-1H-benzimidazoles and N-substituted 2[4-(4,4-dimethyl-thiochroman-6-yl-ethynyl)-phenyl)-1H-benzimidazoles

Article abstract of DOI:10.1016/j.ejmech.2007.06.013

Synthesis of a series of novel and functionalized benzimidazole derivatives by the condensation of OPDA with 4-bromobenzoic acid and subsequent reactions of the product obtained with phenylacetylene and 6-ethynyl-4,4-dimethylthiochroman utilising Sonogash

Full text of DOI:10.1016/j.ejmech.2007.06.013

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 986e995
http://www.elsevier.com/locate/ejmech
Original article
Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of
novel N-substituted-2-(4-phenylethynyl-phenyl)-1H-benzimidazoles and
N-substituted 2[4-(4,4-dimethyl-thiochroman-6-yl-ethynyl)-phenyl)-1H-
benzimidazoles
a,b
a
Ramanatham Vinodkumar a, , Sanjay Dashrath Vaidya , Bobba Venkata Siva Kumar ,
*
Umesh Nanasaheb Bhise a, Shekhar Bhaskar Bhirud a, Uday Chandrakant Mashelkar b,
*
a Glenmark Research Center, Plot No. A-607, T.T.C. Industrial Area, M.I.D.C. Mahape, Navi Mumbai 400 709, India
b Organic Research Laboratory, Patkar College, S.V. Road, Goregaon (West), Mumbai 400 062, India
Received 26 February 2007; received in revised form 16 June 2007; accepted 21 June 2007
Available online 10 July 2007
Abstract
Synthesis of a series of novel and functionalized benzimidazole derivatives by the condensation of OPDA with 4-bromobenzoic acid and
subsequent reactions of the product obtained with phenylacetylene and 6-ethynyl-4,4-dimethylthiochroman utilising Sonogashira coupling
has been reported. The Sonogashira coupling products were then alkylated at the benzimidazole eNH with different electrophilic reagents lead-
ing to functionalized derivatives. All the compounds synthesized were screened for their potential anti-bacterial, anti-asthmatic and anti-diabetic
properties, which exhibited moderate activities in screening studies in vitro.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Anti-bacterial; Anti-asthmatic; Anti-diabetic; Alkylations; Acylations; Benzimidazole; Sonogashira coupling
1. Introduction
releasing hormone receptor antagonists [16], non-nucleoside
HIV-1 reverse transcriptase inhibitors [17] and interestingly al-
kynylbenzimidazoles as modulators of metabotropic glutamate
receptors [18]. The biological activities exhibited by com-
pounds containing benzimidazole moiety has prompted chem-
ists to synthesis more and more benzimidazole libraries and
screen them for potential activities [19e21]. Owing to the im-
portance and in continuation of our ongoing project on bioac-
tive benzimidazole libraries [22e26], we now wish to describe
our efforts towards the synthesis of a novel class of alkynyl-
benzimidazole derivatives and their biological activity screen-
ing studies.
Benzimidazoles and their analogs are well known biologi-
cally active N-containing heterocycles [1], widely used as
drugs such as proton pump inhibitor Omeprazole [2,3], anti-
helmentic Albendazole [4,5], anti-dopaminergic Domperidone
[6,7], anti-psychotic Pimozide [8,9], etc. Some of their analogs
are the constitutional parts of the marine alkaloids, such as
kealiiquinone and anti-tumor agents such as pyrrolo[1,2-a]
benzimidazole quninone (APBI-A) [10,11] (Fig. 1). Specifi-
cally, the 2-substituted analogs of benzimidazoles are known
to be potent biologically active compounds [12e14].
Some of the important benzimidazole derivatives have been
reported as thyroid receptor agonists [15], gonadotropin
2. Results and discussion
To realize the synthesis of novel alkynylbenzimidazoles, ini-
tially we have carried out the condensation of o-phenylenedi-
amine (OPDA) (1) with 4-bromobenzoic acid (2) in
* Corresponding authors. Tel.: þ91 2227783700.
E-mail address: rvinodk@yahoo.com (R. Vinodkumar).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.06.013

R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
987
N
O
N
O
H
N
N
N
N
O
NH
O
S
N
H
N
H
S
N
H
Cl
N
O
O
O
Omeprazole
Albendazole
Domperidone
(Proton Pump Inhibitor)
(Anti-helmintic drug)
(antidopaminergic drug)
F
O
H
H3CO
H3CO
N
O
O
O
H3C
N
CH3
HN
N
O
N
R
O
F
N
H3C
O
O
N
OCH3
O
N
H
Kealiiquinone
(Marine Alkaloid)
pyrrolo[1,2-a]benzimidazole quninone
(APBI-A)
Pimozide
(Anti-Psychotic Drug)
Fig. 1. Some of the benzimidazole based drugs and natural products.
polyphosphoric acid (PPA) at 180 ꢀC for 4 h following a simple
work-up to obtain the known 2-(4-bromophenyl)-1H-benzimid-
azole (3) [27] (Scheme 1). It is noteworthy to mention here that
we have synthesized compound 3 alternatively by a couple of
other methods such as by microwave irradiation of a mixture
of 1 and 2 in presence of PPA and also via Eaton’s reagent
[28] in comparable yields, which gives scope for the alternate
routes either to synthesize benzimidazoles at low temperatures
or in less reaction times, unlike conventional methods which
involve high temperatures and long reaction times.
and Pd(Ph3P)2Cl2 as catalyst under Sonogashira coupling
conditions [29] to obtain 2-(4-(2-phenylethynyl)phenyl)-1H-
benzimidazole (4) based on its spectral data assignments
(Scheme 2).
To generate the analogs of 4, we then carried out the
alkylation, acylation and sulfonation reactions of 4 at the benz-
imidazole eNH and obtained the corresponding N-substituted
analogs 6aej, respectively (Scheme 3) (Table 1).
To further extend the synthesis of alkynylbenzimidazoles,
we thought that it would be worth trying the Sonogashira cou-
pling of compound 3 with 6-ethynyl-4,4-dimethylthiochroman
[30], i.e., the key intermediate of Tazarotene [31], a well
Having obtained compound 3, we have carried out its reac-
tion with phenylacetylene in the presence of CuI, triethylamine
Br
NH2
N
PPA
180 oC / 4 h
Br
+
N
H
NH2
COOH
(2)
(3)
(1)
Scheme 1.
N
N
TEA / CuI
Br
+
(PPh3)2PdCl2/
NH
NH
DMSO/
140 - 150 oC
(3)
(4)
Scheme 2.

988
R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
Alkylation /
acylation /
N
N
sulfonation
NaH/DMF
N
H
N
R
0 oC - RT
(4)
(6a-6j)
6a, R = Methyl; 6b, R = Ethyl; 6c, R = Propyl; 6d, R = Butyl; 6e, R = Methyloxycarbonyl
6f, R = Ethyloxycarbonyl; 6g, R = Butyloxycarbonyl; 6h, R = Isobutyloxycarbonyl;
6i, R = Trifluoromethanesulfonyl; 6j, R = 4-Methylphenylsulfonyl.
Scheme 3.
N
N
TEA / CuI
Br
+
(PPh3)2PdCl2/
NH
N
S
DMSO/
H
S
140 - 150 oC
(3)
(5)
Scheme 4.
Alkylation /
acylation /
sulfonation
N
N
NaH/DMF
N
H
N
R
0 oC - RT
S
S
(5)
(7a-7h)
7a, R = Methyl; 7b, R = Ethyl; 7c, R = Propyl; 7d, R = Butyl; 7e, R = Methyloxycarbonyl;
7f, R = Ethyloxycarbonyl; 7g, R = Butyloxycarbonyl; 7h, R = Trifluoromethanesulfonyl.
Scheme 5.
known anti-acne drug used for psoriasis, i.e., to obtain
2-[4-(4,4-dimethylthiochroman-6-yl-ethynyl)-phenyl]-1H-
benzimidazole (5) (Scheme 4).
Compound 5 on alkylation, acylation and sulfonation reac-
tions yielded the corresponding N-substituted analogs 7aeh,
respectively (Scheme 5) (Table 1).
2.1. Biological activity
All the compounds prepared herein were screened for their
potential biological activities such as, anti-bacterial, anti-asth-
matic and anti-diabetic activities. The anti-bacterial activity
was carried out using both Staphylococcus aureus (Gram
positive) and Salmonella typhimurium (Gram negative) bacte-
ria. The compounds were added to the medium as dimethyl
Following numbering has been followed for NMR
assignment.
17'
18'
CH3
H3C
15'
3
4
12'
11'
3
2' 3'
9'
8'
8'
13'
4
2' 3'
9
9
N
5
6
14'
7'
2
N
5
6
2
10'
S
4'
7'
1'
5' 6'
4'
16'
10'
1
1'
5' 6'
N
8
1
N
9'
8
2' 3'
8'
9'
2' 3'
3''
7
7
O
O
2''
CH3
3''
1''
O
O
2''
1''
5''
4''
CH3
6''
(6e)
(7g)

R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
989
Table 1
Yields, m.p., 1H NMR, 13C NMR and EI-MS spectroscopic data for the compoundsa
Compound
Yield
(%)
M.p. (ꢀC)
1H NMR (d, ppm)
13C NMR (d, ppm)
EI-MS
(M þ 1)
295.5
4b
C21H14N2
92
282e283
7.23e7.26 (m, 2H, AreH), 7.45e7.48 (m, 3H,
AreH), 7.60e7.66 (m, 4H, AreH), 7.76 (d,
J ¼ 8.1 Hz, 2H, 30-AreH), 8.26 (d, J ¼ 8.1 Hz,
2H, 20-AreH), 13.10 (s, 1H, eNH)
89.29 (acetylenic carbon), 91.30
(acetylenic carbon), 122.29, 122.60,
123.65, 126.85, 129.04, 129.24, 130.33,
131.67, 132.17, 150.62 (aromatic
carbons)
2-(4-Phenylethynylphenyl)-
1H-benzimidazole
5b
C26H22N2S
90
272e274
153e155
98e99
85
1.30 (s, 6H, 170 and 180-CH3, 1.89e1.91 (m, 2H,
120-CH2), 3.06e3.07 (m, 2H, 110eCH2), 7.11
(d, J ¼ 8.1 Hz, 1H, AreH), 7.24e7.26 (m, 3H,
AreH), 7.63 (bs, 3H, AreH), 7.73 (d,
J ¼ 8.1 Hz, 2H, 30-AreH), 8.25 (d, J ¼ 8.1 Hz,
2H, 20-AreH), 13.10 (s, 1H, eNH)
3.91 (s, 3H, 100-CH3), 7.30e7.43 (m, 6H,
AreH), 7.55e7.58 (m, 2H, AreH), 7.69
(d, J ¼ 9 Hz, 2H, AreH), 7.78e7.85
(m, 3H, AreH)
22.66, 29.84, 32.84, 36.79 (aliphatic
carbons), 88.24 (acetylenic carbon),
91.91 (acetylenic carbon), 117.60,
122.60, 123.98, 126.75, 126.83, 129.01,
129.84, 130.05, 132.01, 133.78, 142.55,
150.69 (aromatic carbons)
395.5
2-[4-(4,4-Dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1H-benzimidazole
6a
C22H16N2
1-Methyl-2-(4-
87
90
95
31.76 (eCH3), 88.73 (acetylenic
carbon), 91.29 (acetylenic carbon),
109.62, 119.85, 122.55, 122.82, 122.95,
124.70, 128.38, 128.55, 129.29, 129.73,
131.64, 131.78, 136.61, 142.91, 152.96
(aromatic carbons)
309
phenylethynyl-phenyl)-1H-
benzimidazole
6b
C23H18N2
1-Ethyl-2-(4-phenylethynyl-
1.50 (t, J ¼ 7.2 Hz, 3H, 200-CH3), 4.32 (q,
J ¼ 7.2 Hz, 2H, 100-CH2), 7.31e7.46 (m, 6H,
AreH), 7.55e7.58 (m, 2H, AreH), 7.67e7.76
(m, 4H, AreH), 7.83e7.86 (m, 1H, AreH)
15.23 (eCH3), 39.63 (eCH2e), 88.69
(acetylenic carbon), 91.23 (acetylenic
carbon), 109.90, 119.97, 122.44, 122.83,
124.69, 128.36, 128.54, 129.09, 130.09,
131.61, 131.82, 135.42, 143.15, 152.61
(aromatic carbons)
323
phenyl)-1H-benzimidazole
6c
C24H20N2
0.88 (t, J ¼ 7.8 Hz, 3H, 300-CH3), 1.83e1.90 (m,
2H, 200-CH2). 4.22 (t, J ¼ 7.8 Hz, 2H, 100-CH2),
7.30e7.45 (m, 6H, AreH), 7.55e7.58 (m, 2H,
AreH), 7.67e7.74 (m, 4H, AreH), 7.82e7.85
(m, 1H, AreH)
11.06 (eCH3), 22.99 (eCH2e), 46.19
(eNeCH2e), 88.62 (acetylenic carbon),
91.13 (acetylenic carbon), 110.03,
119.80, 122.28, 122.68, 124.48, 128.25,
128.42, 129.06, 130.18, 131.49, 131.69,
135.58, 142.95, 152.77 (aromatic
carbons)
337
1-Propyl-2-(4-phenylethynyl-
phenyl)-1H-benzimidazole
6d
C25H22N2
92
89
90
88
0.88 (t, J ¼ 7.2 Hz, 3H, 400-CH3), 1.25e1.32 (m,
2H, 300-CH2), 1.76e1.83 (m, 2H, 200-CH2), 4.25
(t, J ¼ 7.5 Hz, 2H, 100-CH2), 7.26e7.44 (m, 6H,
AreH), 7.55e7.74 (m, 6H, AreH), 7.82e7.85
(m, 1H, AreH)
13.50 (eCH3), 19.85 (eCH2e), 31.79
(eCH2e), 44.55 (eNeCH2e), 88.71
(acetylenic carbon), 91.22 (acetylenic
carbon), 110.10, 119.96, 122.43, 122.81,
124.64, 128.38, 128.55, 129.20, 130.24,
131.63, 131.81, 135.63, 143.05, 152.88
(aromatic carbons)
351.1
1-Butyl-2-(4-phenylethynyl-
phenyl)-1H-benzimidazole
6e
C23H16N2O2
148e150
126e127
3.95 (s, 3H, 300-CH3), 7.36e7.43 (m, 5H,
AreH), 7.55e7.69 (m, 6H, AreH), 7.79e7.83
(m, 1H, AreH), 8.01e8.04 (m, 1H, AreH)
54.21 (eOCH3), 88.87 (acetylenic
carbon), 91.14 (acetylenic carbon),
114.81, 120.26, 122.85, 124.81, 125.32,
128.32, 128.46, 129.29, 130.99, 131.13,
131.59, 133.42, 142.63, 150.60, 153.06
(aromatic carbons and carbonyl
carbon)
353
2-(4-Phenylethynyl-phenyl)-
benzimidazole-1-
carboxylicacid methyl
ester
6f
1.28 (t, J ¼ 7.2 Hz, 3H, 400-CH3), 4.40 (q,
J ¼ 7.2 Hz, 2H, 300-CH2), 7.36e7.43 (m, 5H,
AreH), 7.55e7.69 (m, 6H, AreH), 7.79e7.82
(m, 1H, AreH), 8.03e8.06 (m, 1H, AreH)
13.80 (eCH3), 64.13 (eOeCH2e),
88.91 (acetylenic carbon), 91.06
(acetylenic carbon), 114.86, 120.25,
122.88, 124.75, 125.29, 128.34, 128.48,
129.35, 130.95, 131.40, 131.61, 133.56,
142.66, 150.04, 153.10 (aromatic
carbons and carbonyl
367
C24H18N2O2
2-(4-Phenylethynyl-phenyl)-
benzimidazole-1-
carboxylicacid ethyl ester
carbon)
6g
C26H22N2O2
91
134e135
0.89 (t, J ¼ 7.35 Hz, 3H, 600-CH3), 1.19e1.27
(m, 2H, 500-CH2), 1.54e1.64 (m, 2H, 400-CH2),
4.34 (t, J ¼ 6.6 Hz, 2H, 300-CH2), 7.35e7.45 (m,
5H, AreH), 7.54e7.68 (m, 6H, AreH), 7.79e
7.82 (m, 1H, AreH), 8.04e8.07 (m, 1H, AreH)
13.50 (eCH3), 18.88 (eCH2e), 30.17
(eCH2e), 67.99 (eOCH2e) 88.87
(acetylenic carbon), 91.02 (acetylenic
carbon), 114.85, 120.24, 122.90, 124.73,
125.30, 128.33, 128.46, 129.32, 130.96,
131.49, 131.61, 133.61, 142.65, 150.15,
153.07 (aromatic carbons and carbonyl
carbon)
395.1
2-(4-Phenylethynyl-phenyl)-
benzimidazole-1-
carboxylicacid butyl ester
(continued on next page)

990
R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
Table 1 (continued)
Compound
Yield
(%)
M.p. (ꢀC)
1H NMR (d, ppm)
13C NMR (d, ppm)
EI-MS
(M þ 1)
395
6h
C26H22N2O2
92
102e103
0.84 (d, J ¼ 7.2 Hz, 6H, 500-CH3), 1.86e1.95 (m,
1H, 400-CH), 4.13 (d, J ¼ 6.6 Hz, 2H, 300-CH2),
7.35e7.45 (m, 5H, AreH), 7.55e7.69 (m, 6H,
AreH), 7.80e7.83 (m, 1H, AreH), 8.05e8.08
(m, 1H, AreH)
18.76 (eCH3), 27.43 (eCHe), 74.15
(eOeCH2e), 88.89 (acetylenic carbon),
91.00 (acetylenic carbon), 114.83,
120.22, 122.84, 124.71, 125.28, 128.29,
128.43, 129.28, 130.99, 131.48, 131.57,
133.60, 142.62, 150.14, 153.04 (aromatic
carbons and carbonyl carbon)
2-(4-Phenylethynyl-phenyl)-
benzimidazole-1-
carboxylicacid isobutyl
ester
6i
C22H13F3N2O2S
92
80
188e189
169e170
7.36e7.39 (m, 3H, AreH), 7.50e7.58 (m, 4H,
AreH), 7.64e7.70 (m, 4H, AreH), 7.85e7.88
(m, 1H, AreH), 7.93e7.96 (m, 1H, AreH)
88.52 (acetylenic carbon), 91.90
427.5
449.3
(acetylenic carbon), 114.65, 117.22,
121.18, 121.54, 122.74, 126.27, 126.67,
126.79, 128.05, 128.39, 128.66, 130.43,
131.01, 131.69, 133.00, 142.33, 153.09
(aromatic carbons)
2-(4-Phenylethynyl-phenyl)-
1-trifluoromethanesulfonyl-
1H-benzimidazole
6j
2.31 (s, 3H, 500-CH3eAr), 7.10 (d, J ¼ 8.1 Hz,
2H, AreH), 7.32e7.44 (m, 7H, AreH), 7.56e
7.63 (m, 6H, AreH), 7.71e7.74 (m, 1H, AreH),
8.20e8.22 (m, 1H, AreH)
21.58 (eCH3), 88.83 (acetylenic
C28H20N2O2S
carbon), 91.53 (acetylenic carbon),
115.21, 120.39, 122.83, 125.37, 125.58,
126.88, 128.40, 128.61, 129.56, 129.72,
130.76, 130.85, 131.68, 133.90, 134.84,
142.66, 145.78, 153.48 (aromatic
carbons)
2-(4-Phenylethynyl-phenyl)-
1-(toluene-4-sulfonyl)-1H-
benzimidazole
7a
C27H24N2S
86
90
197e198
166e167
1.36 (s, 6H, 170 and 180-CH3), 1.95e1.99 (m,
2H, 120-CH2), 3.03e3.08 (m, 2H, 110-CH2), 3.90
(s, 3H, 100-CH3), 7.08 (d, J ¼ 8.4 Hz, 1H, Are
H), 7.20e7.42 (m, 4H, AreH), 7.55e7.56 (m,
1H, AreH), 7.67 (d, J ¼ 8.4 Hz, 2H, 30-AreH),
7.78 (d, J ¼ 8.4 Hz, 2H, 20-AreH), 7.82e7.85
(m, 1H, AreH)
23.16, 29.93, 31.75, 32.91, 37.12
(aliphatic carbons), 88.08 (acetylenic
carbon), 91.83 (acetylenic carbon),
109.60, 118.05, 119.83, 122.51, 122.90,
124.92, 126.53, 128.95, 129.25, 129.49,
129.70, 131.63, 133.50, 136.62, 142.06,
142.94, 153.01 (aromatic carbons)
15.19, 23.09, 29.87, 32.84, 37.03, 39.58
(aliphatic carbons), 88.00 (acetylenic
carbon), 91.75 (acetylenic carbon),
109.86, 117.98, 119.88, 122.37, 122.77,
124.86, 126.47, 128.88, 129.02, 129.64,
129.76, 131.63, 133.45, 135.37, 141.99,
143.09, 152.60 (aromatic carbons)
409
1-Methyl 2[4-(4,4-dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1H-benzimidazole
7b
C28H26N2S
1.36 (s, 6H, 170 and 180-CH3), 1.50 (t,
423.1
J ¼ 7.2 Hz, 3H, 200-CH3), 1.95e1.99 (m, 2H,
120-CH2), 3.04e3.08 (m, 2H, 110-CH2), 4.32
(q, J ¼ 7.2 Hz, 2H, 100-CH2), 7.08 (d, J ¼ 8.4 Hz,
1H, AreH), 7.20e7.23 (m, 1H, AreH), 7.29e
7.36 (m, 2H, AreH), 7.43e7.46 (m, 1H, AreH),
7.55e7.56 (m, 1H, AreH), 7.67 (d, J ¼ 8.4 Hz,
2H, 30-AreH), 7.73 (d, J ¼ 8.4 Hz, 2H,
1-Ethyl 2[4-(4,4-dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1H-benzimidazole
20-AreH), 7.81e7.85 (m, 1H, AreH)
7c
C29H28N2S
91
88
90
118e119
127e128
108e109
0.88 (t, J ¼ 7.2 Hz, 3H, 300-CH3), 1.36 (s, 6H, 170
and 180-CH3), 1.80e1.90 (m, 2H, 200-CH2), 1.97
(t, J ¼ 6.0 Hz, 2H, 120-CH2) 3.06 (t, J ¼ 6.0 Hz,
2H, 110-CH2), 4.21 (t, J ¼ 7.65 Hz, 2H, 100-CH2),
7.08 (d, J ¼ 8.1 Hz, 1H, AreH), 7.20e7.36 (m,
4H, AreH), 7.41e7.44 (m, 1H, AreH), 7.55e
7.61 (m, 1H, AreH), 7.65e7.73 (m, 3H, AreH),
7.81e7.84 (m, 1H, AreH)
0.88 (t, J ¼ 7.5 Hz, 3H, 400-CH3), 1.25e1.33 (m,
2H, 300-CH2), 1.36 (s, 6H, 170 and 180-CH3),
1.76e1.84 (m, 2H, 200-CH2), 1.95e1.99 (m, 2H,
120-CH2), 3.04e3.08 (m, 2H, 110-CH2), 4.25 (t,
J ¼ 7.5 Hz, 2H, 100-CH3), 7.08 (d, J ¼ 8.1 Hz,
1H), 7.20e7.35 (m, 4H), 7.41e7.44 (m, 1H),
7.55e7.56 (m, 1H), 7.66e7.74 (m, 3H), 7.82e
7.85 (m, 1H)
1.34 (s, 6H, 170 and 180-CH3), 1.93e1.97 (m,
2H, 120-CH2), 3.01e3.06 (m, 2H, 110-CH2), 3.93
(s, 3H, 300-CH3), 7.06 (d, J ¼ 8.1 Hz, 1H, Are
H), 7.19e7.22 (m, 1H, AreH), 7.36e7.43 (m,
2H, AreH), 7.54e7.55 (m, 1H, AreH), 7.60e
7.68 (m, 4H, AreH), 7.78e7.81 (m, 1H, AreH),
7.98e8.02 (m, 1H, AreH)
11.21, 23.17, 29.95, 32.92, 37.13, 46.38
(aliphatic carbons), 88.04 (acetylenic
carbon), 91.75 (acetylenic carbon),
110.09, 118.06, 119.95, 122.41, 122.78,
124.87, 126.54, 128.94, 129.18, 129.72,
130.03. 130.78, 131.70, 131.94, 133.48,
135.69, 142.06, 143.07, 153.01 (aromatic
carbons)
437.1
451.1
453
1-Propyl 2[4-(4,4-dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1H-benzimidazole
7d
C30H30N2S
13.47, 19.85, 23.13, 29.91, 31.75, 32.88,
37.09, 44.50 (aliphatic carbons), 88.03
(acetylenic carbon), 91.75 (acetylenic
carbon), 110.07, 118.02, 119.90, 122.38,
122.75, 124.86, 126.51, 128.91, 129.15,
129.68, 129.94, 131.66, 133.48, 135.62,
142.03, 143.01, 152.90 (aromatic
carbons)
1-Butyl 2[4-(4,4-dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1H-benzimidazole
7e
C28H24N2O2S
23.14, 29.91, 32.89, 37.11 (aliphatic
carbons), 54.22 (eOeCH3), 88.21
(acetylenic carbon), 91.70 (acetylenic
carbon), 114.81, 118.09, 120.25, 124.82,
125.07, 125.32, 126.50, 128.93, 129.27,
129.68, 130.87, 133.41, 133.45, 142.02,
142.64, 150.64, 153.13 (aromatic
carbons and carbonyl carbon)
2[4-(4,4-Dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-benzimidazole-1-
carboxylicacid methyl
ester

R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
991
Table 1 (continued)
Compound
Yield
(%)
M.p. (ꢀC)
1H NMR (d, ppm)
13C NMR (d, ppm)
EI-MS
(M þ 1)
467.1
7f
88
98
90
102e103
1.26 (t, J ¼ 7.2 Hz, 3H, 400-CH3), 1.34 (s, 6H, 170
and 180-CH3), 1.92e1.97 (m, 2H, 120-CH2),
3.01e3.05 (m, 2H, 110-CH2), 4.37 (q,
J ¼ 7.2 Hz, 2H, 300-CH2), 7.06 (d, J ¼ 8.1 Hz,
1H, AreH), 7.19e7.22 (m, 1H, AreH), 7.38e
7.41 (m, 2H, AreH), 7.54e7.55 (m, 1H, AreH),
7.59e7.67 (m, 4H, AreH), 7.78e7.81 (m, 1H,
AreH), 8.02e8.05 (m, 1H, AreH)
13.78, 23.12, 29.89, 32.87, 37.09
(aliphatic carbons) 64.10 (OeCH2e),
88.23 (acetylenic carbon), 91.59
(acetylenic carbon), 114.81, 118.08,
120.19, 124.72, 124.97, 125.25, 126.48,
128.91, 129.30, 129.65, 130.79, 131.08,
133.39, 133.54, 142.00, 142.60, 150.01,
153.13 (aromatic carbons and carbonyl
carbon)
C29H26N2O2S
2[4-(4,4-Dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-benzimidazole-1-
carboxylicaci ethyl ester
7g
C31H30N2O2S
110e111
0.89 (t, J ¼ 7.2 Hz, 3H, 600-CH3), 1.19e1.29 (m,
2H, 500-CH2), 1.36 (s, 6H, 170 and 180-CH3),
1.54e1.64 (m, 2H, 400-CH2), 1.95e1.99 (m, 2H,
120-CH2), 3.03e3.08 (m, 2H, 110-CH2), 4.34 (t,
J ¼ 6.6 Hz, 2H, 300-CH2), 7.07 (d, J ¼ 8.1 Hz,
1H, AreH), 7.19e7.23 (m, 1H, AreH), 7.37e
7.44 (m, 2H, AreH), 7.54e7.55 (m, 1H, AreH),
7.59e7.67 (m, 4H, AreH), 7.79e7.82 (m, 1H,
AreH), 8.03e8.07 (m, 1H, AreH)
1.34 (s, 6H, 170 and 180-CH3), 1.93e1.97 (m,
2H, 120-CH2), 3.02e3.06 (m, 2H, 110-CH2), 7.07
(d, J ¼ 8.1 Hz, 1H, AreH), 7.19e7.25 (m, 1H,
AreH), 7.47e7.55 (m, 3H, AreH), 7.62e7.69
(m, 4H, AreH), 7.84e7.87 (m, 1H, AreH),
7.92e7.95 (m, 1H, AreH)
13.53, 18.91, 23.19, 29.95, 30.21, 32.94,
37.17 (aliphatic carbons) 68.03
495.1
2[4-(4,4-Dimethyl-
thiochroman-6-yl-
ethynyl)phenyl]-
(eOeCH2e), 88.24 (acetylenic carbon),
91.59 (acetylenic carbon), 114.88,
118.18, 120.27, 124.77, 125.06, 125.33,
126.54, 128.99, 129.33, 129.70, 130.88,
131.22, 133.41, 133.65, 142.06, 142.67,
150.22, 153.19 (aromatic carbons and
carbonyl carbons)
benzimidazole-1-
carboxylicacid butyl ester
7h
C27H21F3N2O2S2
158e159
23.15, 29.63, 29.90, 32.89, 37.09
(aliphatic carbons) 87.87 (acetylenic
carbon), 92.49 (acetylenic carbon),
114.62, 117.19, 117.92, 121.13, 121.50,
126.47, 126.53, 126.61, 126.75, 127.73,
128.96, 129.73, 130.39, 130.83, 132.97,
133.67, 142.04, 142.31, 153.13 (aromatic
carbons)
527
2[4-(4,4-Dimethyl-
thiochroman-6-yl-ethynyl)-
phenyl]-1-
trifluoromethanesulfonyl-
1H-benzimidazole
a
All the new compounds prepared gave satisfactory elemental analysis data.
1H NMR spectra for compounds 4 and 5 were recorded in DMSO-d6 and for the rest of the compounds in CDCl3.
b
sulfoxide solutions. No inhibition zone was observed in
controls (i.e., for DMSO). The concentrations used were as fol-
lows: 500, 200, 100, 10, 1.0 and 0.1 mg/ml. Minimum Inhibi-
tory Concentration values were determined after incubation
at 37 ꢀC for 48 h and was determined using tube dilution
method according to the standard procedure [32]. Cephalexin
was used as the anti-bacterial standard and dimethyl sulfoxide
was used both as a solvent and as a control (see Tables 2 and 3).
The anti-asthmatic activity studies were carried out using
Phosphodiesterase IV enzyme (PDE-IV) [33] and the primary
screening of the compounds was done at 1 nM concentration
using human PDE-IV enzyme, where Rolipram and Ariflo
were used as standard compounds. (Table 4).
The anti-diabetic activity screening was carried out with di-
peptidyl peptidase (DPP-IV) [34] enzyme and the primary
screening of the compounds was carried out at 300 nM
concentration using recombination human DPP-IV enzyme
by the use of 1-(2-amino-3,3-dimethylbutanoyl) pyrrolidine-2-
carbonitrile as the standard compound at 100 nM. (see Table 4).
Similarly, the PTP-1B (in-house compound, also for anti-dia-
betic) activity was done using the test compounds at 30 mM
with the standard compound N-[5-[N-acetyl-4-[N-(2-carboxy-
phenyl)-N-(2-hydroxyoxalyl)amino]-3-ethyl-DL-phenylalany-
lamino] pentanoyl]-L-methionine at a concentration of 0.3 mM.
(Table 4).
Phosphodiesterase IV present. The [3H] 50-AMP then was
quantitatively converted to free [3H] adenosine and phosphate
by the action of snake venom 50-nucleotidase hence the
amount of [3H] adenosine liberated is proportional to Phos-
phodiesterase IV activity.
The assay was performed at 34 ꢀC in a 200 ml total reaction
mixture. The reaction mixture contained 25 mM of tris buffer,
10 mM MgCl2, 1 mM cAMP (cold) and [3H] cAMP (0.1 mCi).
Stock solutions of the compounds to be investigated were
prepared in dimethyl sulfoxide in concentrations such that
the dimethyl sulfoxide content in the test samples did not
exceed 0.05% by volume to avoid affecting the Phosphodies-
terase IV activity. Compounds were then added in the reaction
mixture (25 ml/tube). The assay was initiated by addition of
enzyme mix (75 ml) and the mixture was incubated for
20 min at 34 ꢀC. The reaction was stopped by boiling the tubes
for 2 min at 100 ꢀC in a water bath. After cooling on ice for
5 min and addition of 50 mg 50-nucleotidase snake venom
from Crotalus atrox, incubation was carried out again for
20 min at 34 ꢀC. The unreacted substrate was separated from
(3H) adenosine by addition of Dowex AG 1X-8 (400 ml), which
was pre-equilibrated in (1:1) water:ethanol. Reaction mixture
was then thoroughly mixed, placed on ice for 15 min, vortexed
and centrifuged at 14,000 rpm. for 2 min. After centrifugation,
a sample of the supernatant (150 ml) was taken and added in 24-
well optiplates containing scintillant (1 ml) and mixed well.
The samples in the plates were then determined for radio-
activity in a Top Counter and the Phosphodiesterase IVactivity
was calculated. Phosphodiesterase IV enzyme was present in
2.1.1. Protocol for PDE-IV inhibition assay
Phosphodiesterase IV enzyme converts [3H] cAMP to the
corresponding [3H] 50-AMP in proportion to the amount of

992
R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
Table 2
Anti-bacterial activity of compounds against Staphylococcus aureus
Compound no.
Concentration
0.1 mg/ml
1 mg/ml
10 mg/ml
100 mg/ml
200 mg/ml
500 mg/ml
APP. MICa (mg/ml)
4
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þþ
þ
P
ꢁ
ꢁ
P
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
200
200
500
500
500
500
500
500
500
500
500
200
200
200
500
200
200
500
500
500
10
5
6a
P
þþ
þþ
þþ
þ
þ
6b
6c
þþ
þ
þ
P
6d
6e
þ
P
þ
P
P
6f
6g
þ
þ
P
þþ
þþ
þþ
þ
þþ
þþ
þþ
þ
þ
þ
P
6h
6i
6j
7a
ꢁ
ꢁ
ꢁ
P
þ
P
7b
7c
þþ
þþ
þ
þ
þ
7d
7e
P
ꢁ
ꢁ
P
þþ
þþ
þþ
þþ
þþ
þ
þ
7f
7g
þþ
þ
þ
þ
P
7h
Cephalexin
þþ
ꢁ
þ
þ
ꢁ
ꢁ
a
Approximate Minimum Inhibitory Concentration.
quantities that yield <30% total hydrolysis of substrate (linear
assay conditions). Rolipram and Cilomilast were used as stan-
dards in all assays.
coumarin (AMC) from synthetic substrate Gly-Pro-AMC. In
brief, the assay was conducted by adding 10 ng of human re-
combinant dipeptidyl peptidase IV enzyme (DPP-IV, available
commercially from R&D Systems) in 50 ml of the assay buffer
(25 mM tris, pH 7.4, 140 mM NaCl, 10 mM KCl, 1% BSA) to
96-well black flat bottom microtiter plates. The reaction was
initiated by adding 50 ml of 100 mM substrate Gly-Pro-AMC.
2.1.2. Protocol for the DPP-IV assay
DPP-IV inhibition measurement in vitro: DPP-IV activity
was determined by the cleavage rate of 7-amino-4-methyl
Table 3
Anti-bacterial activity screening results of compounds against Salmonella typhimurium
Compound no.
Concentration
0.1 mg/ml
1 mg/ml
10 mg/ml
100 mg/ml
200 mg/ml
500 mg/ml
APP. MIC (mg/ml)
4
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
P
ꢁ
ꢁ
ꢁ
þ
P
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
200
200
200
500
500
500
500
500
500
500
500
200
200
200
500
200
200
500
500
200
200
5
6a
þþ
þþ
þ
P
6b
6c
þþ
þ
þ
þ
P
6d
6e
þ
P
þþ
þ
P
6f
6g
P
þþ
þþ
þþ
þþ
þ
þþ
þþ
þ
P
P
6h
6i
þ
P
6j
7a
ꢁ
ꢁ
ꢁ
P
P
7b
7c
þþ
þþ
þ
P
þ
P
7d
7e
ꢁ
ꢁ
þ
P
þ
þ
þ
þ
P
7f
7g
þþ
þ
7h
Cephalexin
þþ
ꢁ
þ
P
ꢁ
Symbols: total inhibition, no growth of organism ¼ ꢁ; Poor growth compared to control ¼ P; medium growth compared to controls ¼ þ; confluent growth, no
inhibition ¼ þþ.

R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
993
Table 4
Anti-diabetic and anti-asthmatic activity screening results of compounds
Calculations: activity ¼ % of control;
% inhibition ¼ 100 ꢁ activity
Compound no.
PTP-1B (30 mM)
PDE-IV (1 mM)
DPP-IV (0.3 mM)
% Inhibition
% Inhibition
% Inhibition
2.1.4. Standard compound assay
4
1.64
2.42
8.42
2.2
0
3.40
0
0
0
9
0
0
3
0
0
0
0
0
0
0
0
0
5
5
7
0
9
5
1. PTP-1B:
N-[5-[acetyl]-4-[N-(2-carboxypheyl)-N-(2-hy-
6a
6b
6c
6d
6e
6f
22.29
13.52
8.91
droxalyl)amino]-3-ethyl-DL-phenylalanylamino]pentanoyl]-
L-methionine is used as a standard in all assays and shows
percentage inhibition of 49.09% at a concentration of
0.3 mM.
0
29
19.45
18.22
16.50
16.25
17.21
16.88
22.56
18.20
15.84
17.28
19.85
17.89
16.89
21.03
22.56
27.67
5.84
17.43
0
2. PDE-IV: Rolipram and Cilomilast were used as standards
in all assays. Rolipram shows percentage inhibition of
67.41% at a concentration of 2 mM. Cilomilast shows per-
centage inhibition of 45.28% at a concentration of
0.075 mM.
3. DPP-IV: 1-(2-amino-3,3-dimethylbutyryl) pyrrolidine-2-
carbonitrile is used as a standard in all assays and shows
percentage inhibition of 96% at a concentration of 0.1 mM.
6g
6h
6i
6j
0
7a
7b
7c
7d
7e
7f
0
0
7.38
0.15
0.97
0
7g
7h
1.94
0.52
3. Experimental section
Melting points are uncorrected and were recorded on
a MRVIS Series, Lab India Instrument. TLC analysis was
done using pre-coated silica gel plates and visualization was
done using iodine/UV lamp. IR spectra were recorded on a Per-
The incubation was carried out in the kinetic mode at 30 ꢀC
for 30 min. Fluorescence was measured using Fluorostar at
the excitation filter of 380 nm and the emission filter of
460 nm. Test compounds and solvent controls were added as
1 ml additions. Test compounds were dissolved in DMSO
and tested at 300 nM concentration. Percentage inhibition
was calculated with respect to the solvent control sample
(no test compound added). Dipeptidyl peptidase (i.e., anti-
diabetic).
1
kineElmer Spectrum One FT-IR spectrometer. H NMR and
13C NMR spectra were recorded on a Varian Mercury Vx
SWBB 300 MHz spectrometer. Elemental analysis was carried
out on a PerkineElmer SerieseII CHNS/O Analyzer 2400.
The EI-MS spectra were recorded using a Thermo Finnigan
UK Navigator Sr. No. 30019. The starting materials o-phenyl-
enediamine, alkylating, acylating, aroylating agents and
phenylacetylene were obtained from commercial suppliers,
6-ethynyl-4,4-dimethylthiochroman was prepared by using
a patented procedure [30].
2.1.3. Protocol for PTB-1B assay
In-house generated human recombinant enzyme: w35 ng
in assay.
Paranitrophenyle phosphate (SRL144916): 25 mM.
Buffer: Hepes 25 mM, 3 mM DTT, 0.15 M NaOH, 1 mM
EDTA, pH 7.4.
3.1. Synthesis of 2-(4-bromo-phenyl)-1H-benzimidazole (3)
Dilution buffer (for enzyme): 2ꢂ reaction buffer (3 mM
A mixture of o-phenylenediamine (OPDA) (1) (5.40 g,
50 mmol), 4-bromobenzoic acid (2) (12.06 g, 60 mmol) and
polyphosphoric acid (50 ml) was heated slowly to 180 ꢀC for
4 h. The reaction mixture was then cooled and neutralized
with ice-cold concentrated potassium hydroxide solution
(200 ml) to obtain neutral pH. The solid separated out was fil-
tered, washed with water (3 ꢂ 100 ml) and dried under vac-
uum to afford an off-white solid (2.45 g, 90%). The crude
product was recrystallized from hot aq. ethanol to obtain the
pure compound 3. M.p. 295e297 ꢀC (lit. [27] 296e298 ꢀC).
DTT).
DMSO (Calbiochem).
Test compound in DMSO.
DMSO concentration not to exceed 1% in the assay.
Evaluation of the study observation
Protocol
Blank (ml)
Control (ml)
Test (ml)
DMSO
Compound
Buffer
1
e
1
e
e
1
89
e
10
88
1
88
1
3.2. Synthesis of compound 3 via microwave irradiation
Enzyme
PNPP
10
10
A mixture of o-phenylenediamine (1.08 g, 10 mmol), 4-
bromobenzoic acid (2) (2.01 g, 10 mmol) and polyphosphoric
acid (10 ml) was stirred and irradiated in a microwave oven at
100 W for 3 min at 170 ꢀC. The reaction mixture was then
Incubate and continuously monitor at 30 ꢀC for 30 min at 405 nm
NaOH
Read at 405 nm
100
100
100

994
R. Vinodkumar et al. / European Journal of Medicinal Chemistry 43 (2008) 986e995
cooled to room temperature and neutralized with ice-cold po-
tassium hydroxide solution (50 ml) to obtain neutral pH. The
solid separated out was filtered, washed with water
(3 ꢂ 25 ml) and dried under vacuum to afford an off-white
solid (2.48 g, 91%). The crude product was recrystallized
from hot aq. ethanol to obtain the pure compound 3. M.p.
295e296 ꢀC.
extracted with ethyl acetate (3 ꢂ 25 ml), washed with water
(2 ꢂ 25 ml), brine (10 ml) and dried over anhydrous magne-
sium sulfate. Ethyl acetate layer was evaporated under vacuum
to yield the corresponding N-substituted derivatives. The crude
products were purified by silica gel flash column chromato-
graphy to obtain the pure products (Table 1).
3.3. Synthesis of compound 3 via Eaton’s reagent
4. Conclusion
A mixture of o-phenylenediamine (1.08 g, 10 mmol), 4-
bromobenzoic acid (2) (2.01 g, 10 mmol) and Eaton’s reagent
(15 ml, 1:10 mixture of P2O5eMSA) was heated with stirring
at 100 ꢀC for 5 h. The reaction was then quenched with aque-
ous saturated bicarbonate solution till neutral pH and extracted
with ethyl acetate (3 ꢂ 50 ml). The organic layer was washed
with water (2 ꢂ 25 ml), brine (2 ꢂ 25 ml) and dried over anhy-
drous magnesium sulfate and concentrated under vacuum to
obtain compound 3 (2.42 g, 89%), which was recrystallized
from hot aq. ethanol to obtain pure compound 3 (m.p. 295e
296 ꢀC).
In conclusion, we have demonstrated the synthesis of a se-
ries of novel substituted benzimidazole derivatives by the con-
densation of OPDA with 4-bromobenzoic acid followed by
Sonogashira couplings and alkyl, acyl and sulfonylation reac-
tions to obtain corresponding substituted benzimidazole deriv-
atives. All the compounds prepared in the present work have
been screened for potential anti-bacterial, anti-asthmatic and
anti-diabetic activities. The activity studies showed that the
compounds exhibited moderate activities towards the testing
bacterial stains and enzymes in vitro. Some of the compounds
4, 5, 6j, 7a, 7b, 7d and 7e showed complete inhibition against
both S. aureus and S. typhimurium. However, compounds 6a,
7h showed complete inhibition only against S. typhimurium.
These compounds were also tested against PDE-IV for poten-
tial anti-asthmatic effect, and against DPP-IV and PTP-1B for
potential anti-diabetic effects. Unfortunately, the results were
disappointing.
3.4. General procedure for the synthesis of 4 and 5 by
Sonogashira coupling
A mixture of triphenylphosphine (0.067 g, 0.255 mmol)
and palladium chloride (0.022 g, 0.124 mmol) in dimethyl
sulfoxide (10 ml) was heated to 140e150 ꢀC for 10 min under
argon atmosphere to obtain a clear solution. The reaction mix-
ture was then allowed to cool to room temperature and then
slowly added to this solution, a mixture of 3 (1.265 g,
4.65 mmol) and, respectively, acetylene (5.58 mmol), triethyl-
amine (0.79 g, 7.82 mmol), copper iodide (0.032 g,
0.168 mmol) in dimethyl sulfoxide (20 ml). The resulting mix-
ture was heated with stirring at 90 ꢀC for 1e3 h. The reaction
mixture was then cooled to room temperature and filtered on
a celite pad, followed by washing with ethyl acetate
(2 ꢂ 50 ml). The filtrate was then washed with water
(2 ꢂ 25 ml), brine (2 ꢂ 10 ml) and dried over anhydrous mag-
nesium sulfate. Evaporation of the solvent under vacuum
yielded the crude products, which were recrystallized from
acetone to obtain pure products (for details see Table 1).
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sodium hydride (60%) (2.4 mmol) in small portions at 0 ꢀC.
After completion of addition, the temperature of the reaction
was slowly raised to room temperature and stirred at this tem-
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