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EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 3, c. 363-369
RAPID SYNTHESIS AND LIPASE INHIBITION ACTIVITY OF SOME NEW BENZIMIDAZOLE AND PERIMIDINE DERIVATIVES
© 2014 E. Mente§ e* #, F. Yilmaz*, N. Karaali*, S. Ulker**, B. Kahveci***
*Department of Chemistry, Art and Science Faculty, Recep Tayyip Erdo g an University, Rize, Turkey **Department of Biology, Faculty of Arts and Sciences, Recep Tayyip Erdo gan University, Rize, Turkey ***Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, Trabzon, Turkey
Recevied August 29, 2013; in final form, October 16, 2013
This study presents a synthesis of new series of some benzimidazole, bisbenzimidazole and perimidine derivatives via microwave technique, which, leads to the good product yields and short reaction times. The structure of newly synthesized compounds was confirmed by 1H-NMR and 13C-NMR spectra. These compounds were screened for their lipase inhibition activity. Then, all compounds were evaluated with regard to pancreatic lipase activity, and some of the 2-substituted perimidines, bisperimidine and bisbenzimidazole derivatives showed lipase inhibition at various concentrations.
Keywords: benzimidazole, perimidine, bisbenzimidazole, microwave synthesis, iminoester hydrochloride, lipase inhibition
DOI: 10.7868/S0132342314030099
INTRODUCTION
Obesity is a major health problem, both at national and international level [1, 2]. According to the 2008 World Health Organization report, nearly 300 million women and 200 million men were obese [3], and to this end, many drugs have been used to overcome obesity over the years. However, many anti-obesity drugs have now been withdrawn due to different adverse effects [4, 5]. Despite the suggested adverse effects, appropriate anti-obesity drugs can still produce sustained weight loss with minimal side effects. For this reason, the synthesis of new good anti-obesity drug canditates is of crucial significance for the coming generations all around the world.
Nitrogen-containing heterocyclic ring systems like benzimidazole, imidazole and perimidine have a wide spectrum of pharmacological activity [6, 7]. Especially, benzimidazole and perimidine derivatives have been of great interest due to their biological importance like antifungal, anticancer, anthelmintic, antimicrobial, antiallergic, antioxidant, antihistaminic, antitumor, lipase inhibition [8—17]. Also, some drugs have benzimidazole nucleus such as albendazole, thia-bendazole, omeprazole, astemizole, carbendazim, lan-soprazole, mebendazole, and timoprazole [18—21].
# Corresponding author (phone: +90 464 223-61-26; fax: +90 464 223-40-19; e-mail: emre.mentese@erdogan.edu.tr).
Development of new lipase inhibition agents is an important area of study in the fight against obesity. That is why, we have synthesized some benzimidazole derivatives which indicate great pancreatic lipase activity [17]. Earlier studies have shown that C(2)-sub-stituted benzimidazole derivatives include a good li-pase inhibition activity [17, 18, 22]. In this study, some perimidine derivatives as well as benzimidazole ones were synthesized, and their pancreatic lipase inhibition activity was investigated.
RESULTS AND DISCUSSION
Iminoester hydrochlorides are useful intermediates for microwave-assisted synthesis of potentional bioac-tive heterocyclic compounds such as benzimidazole, perimidine and triazole derivatives [16, 23, 24]. In this study, a rapid procedure was used for the synthesis of benzimidazole and perimidine derivatives. Iminoester hydrochlorides were prepared according to the known method [25]. To synthesize perimidine (2a)—(2g) and benzimidazole (3a)—(3e) derivatives, compounds (1a)—(1g) were allowed to react with 1,8-diamino-napthalene and 4,5-dichloro-1,2-phenylenediamine respectively, under microwave irradiation within short reaction times and with high yields (Scheme 1).
R-CN
EtOH, HCl(g) Et2O '
R^
NH.HCl
OEt (1a)-(1g)
0-nh2
MW,
MeOH
ClT ^nh2
nh2
/
ri—NH (2a)-(2g)
N
R
Cl
N H
(3a)-(3e)
V-R
(1a), (2a), (3a) R = 3,4-Cl2C6H3CH2-; (1b), (2b), (3b) R = 2,4-Cl2C6H3CH2-; (1c), (2c), (3c) R = 2,6-Cl2C6H3CH2-; (1d), (2d), (3d) R = (1e), (2e), (3e) R = 3,4,5-(Me0)3C6H2CH2-; (1f), (2f), (3f) R = 3-BrC6H4CH2-(1g), (2g), (3g) R = 4-BrC6H4CH2-
Scheme 1. The synthesis of compound (2a)-(2g) and (3a)-(3e).
An efficient synthesis of compounds (4) and (5) was obtained from the reaction of 1,4-bisiminoester hydrochloride with 1,8-diaminonapthalene and 4,5-dichloro-1,2-phenylenediamine under microwave irradiation respectively (Scheme 2).
NH.HCl
Scheme 2. The synthetic route of compounds (4) and (5).
Also, a simple and rapid synthesis of bisbenzimida-zole derivatives (6a)-(6g) was performed with readily available 3,3'-diaminobenzidine and iminoester hydrochlorides of phenylacetic acids as starting materials. The synthetic path to the compounds (6a)-(6g) is shown in
Scheme 3. All the reactions provide a convenient and practical strategy for the synthesis of potential bioactive benzimidazole and perimidine derivatives. The structure of newly-synthesized compounds was confirmed by 1H-NMR, 13C-NMR spectra and elemental analyses.
H2N
h2n
NH NH.HCl
nh2 rh;
OEt
N
NH2
MW, MeOH
HN R N
-R
(6a) R = 3,4-Cl2C6H3CH2—; (6b) R = 2,4-Cl2C6H3CH2-; (6c) R = 2,6-Cl2C6H3CH2-; (6d) R = 3,4-(MeO)2C6H3CH2—; (6e) R = 3,4,5-(MeO)3C6H2CH2-; (6f) R = 3-BrC6H4CH2 (6g) R = 4-BrC6H4CH2-
Scheme 3. The synthetic path of the compounds (6a)—(6g).
Anti-Lipase Activity Results
All compounds were evaluated with regard to pancreatic lipase activity among which compounds (2b), (2f), (2g), (5), (6a) and (6g) showed anti-lipase activities at various concentrations (Table 1). No significant inhibitory effect was detected for other compounds (Table 2). Among the tested compounds, (2f) and (2b) showed the best anti-lipase activity. These compounds inhibited pancreatic lipase activity by 98.6 and 63.9% at concentration of 9.375 ^g/mL respectively. Orlistat, known pancreatic lipase inhibitor used as anti-obesity drug, showed inhibitory effect by 91.6% at concentration of 31.25 ng/mL. IC50 values for compounds (2b) and (2f) were calculated as 0.20 ^g/mL and 0.26 ^g/mL respectively. Also IC50 values for compounds (2g), (5) and (6g) were determined as 0.68, 1.24 and 1.46, respectively. Orlistat is the only approved anti-obesity medication [26], but it has some side effects, such as fecal incontinence, flatulence, and steatorrhea [27, 28]. Compared to Orlistat, synthesized (2b) and (2f) compounds have indicated slight inhibitory activity. Further investigation of their toxic-ity and side effects are needed.
EXPERIMENTAL
All the chemicals were purchased from Merck, Al-drich and Fluka. Melting points were determined on capillary tubes on Buchi oil heating melting point apparatus and uncorrected. 1H NMR and 13C NMR spectra were performed on Varian Mercury 400 MHz spectrometer in DMSO-af6 using TMS as internal standart. The elemental compositions were determined on a Carlo Erba 1106 CHN analyzer; the experimental values were in agreement (±0.4%) with the calculated ones. A mono-mode CEM-Discover microwave was used to carry out microwave reactions in 30 mL microwave process vials with temperature control by infrared detection temperature sensor. All reactions were monitored by TLC using precoated aluminum sheets (silica gel 60 F 2.54 0.2 mm thickness).
General procedure for the synthesis of compounds (2a)—(2g) and (3a)—(3e). A mixture of 4,5-
dichloro-1,2-phenylenediamine (0.010 mol) or 1,8-diaminonapthalene (0.010 mol) and corresponding iminoester hydrochlorides (0.013 mol) (1a)—(1g) in dry methanol (10 mL) was irradiated in a closed vessel with the pressure control at 65°C for 10 min (hold time) at 300 W maximum power. After the completion of the reaction, (monitored by TLC, ethylacetate : hexane, 3 : 1), the mixture was poured onto water. The precipitate formed was filtered off and recrystallized from ethanol—water (1 : 3) to give pure product.
2-(3,4-Dichlorobenzyl)-1#-perimidine (2a). Yield: 2.35 g (72%); mp: 194-195°C; 1H-NMR 8 (ppm): 3.77 (2 H, s, CH2), 6.58 (2 H, d, J = 7.2 Hz, Ar-H), 7.11-7.19 (4 H, m, Ar-H), 7.50 (1 H d, J = 8.0 Hz, Ar-H), 7.62 (1 H, d, J = 8.0 Hz, Ar-H), 7.78 (1 H, s, Ar-H); 13C-NMR (DMSO-d6) 8 (ppm): 38.68 (CH2), 108.27, 120.20, 127.89, 121.44, 128.78, 129.90, 130.41, 131.14, 131.50, 131.61, 135.21, 136.96, 138.88, 157.28. Anal. calculated for C18H12Cl2N2: C, 66.07; H, 3.70 and N, 8.56; found: C, 66.15; H, 3.76 and N, 8.57.
2-(2,4-Dichlorobenzyl)-1#-perimidine (2b). Yield: 2.48 g (76%); mp: 178-179°C; 1H-NMR 8 (ppm): 3.74 (2 H, s, CH2), 6.80 (2 H, d, J = 7.2 Hz, Ar-H), 7.00 (2 H, d, J = 8.0 Hz, Ar-H), 7.11 (2 H, t, J = 8.2 Hz, Ar-H), 7.43 (1 H, d, J = 8.0 Hz, Ar-H), 7.51 (1 H, d, J = 8.2 Hz, Ar-H), 7.62 (1 H, s, Ar-H), 10.68 (1 H, br, NH); 13C-NMR (DMSO-d6) 8 (ppm): 38.04 (CH2), 121.86, 127.89, 128.80, 129.01, 132.65, 133.16, 134.07, 134.97, 135.54, 155.11. Anal. calculated for C18H12Cl2N2: C, 66.07; H, 3.70 and N, 8.56; found: C, 66.12; H, 3.74 and N, 8.59.
2-(2,6-Dichlorobenzyl)-1#-perimidine (2c). Yield: 2.52 g (77%); mp: 194-195°C; 1H-NMR 8 (ppm): 3.95 (2 H, s, CH2), 6.30 (2 H, dd, J = 1.2, Ar-H), 6.93-7.10 (4 H, m, Ar-H), 7.30-7.35 ( 1H, m, Ar-H), 7.48 (1 H, d, J = 1.6, Ar-H), 10.78 (1 H, s, NH); 13C-NMR (DMSO-d6) 8 (ppm): 38.45 (CH2), 119.18, 121.98, 128.89, 129.04, 130.17, 132.91, 135.67, 136.32, 154.83. Anal. calculated for C18H12Cl2N2: C, 66.07; H, 3.70 and N, 8.56; found: C, 66.12; H, 3.75 and N, 8.59.
2-(3,4-Dimethoxybenzyl)-1#-perimidine (2d). Yield: 2.29 g (72%); mp: 265°C (decomp); 1H-NMR 8
Table 1. Residual lipase activity of synthesized compounds. All compounds were screened at the concentration of 9.375 Mg/mL
Compound (9.375 Mg/mL) Residual activity, %
T+ 100.0
(2a) 46.4
(2b) 16.0
(2c) 40.8
(2d) 68.7
(2e) 73.0
(2f) 10.0
(2g) 7.4
(3a) 57.3
(3b) 49.6
(3c) 51.0
(3d) 84.9
(3e) 82.6
(4) 34.6
(5)
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