Abstract
Background: Benzimidazole and piperidine rings are important pharmacophore groups for drug design studies.
Objective: In this study, we aimed to investigate the antidepressant-like activity of some 2-(4- substituted-phenyl)-1-[2-(piperidin-1-yl)ethyl]-1H-benzimidazole derivatives.
Methods: Tail-suspension Test (TST) and Modified Forced Swimming Tests (MFST) were used to assess antidepressant-like activities of the test compounds. Moreover, locomotor activity performances of the animals were evaluated by an activity cage device.
Results: In the TST and MFST, compounds 2c-2h (10 mg/kg) and the reference drug fluoxetine (20 mg/kg) significantly reduced the immobility time of mice indicating the antidepressant-like activities of these compounds. Further, in MFST, the same compounds induced significant enhancement in the duration of active swimming behaviors without affecting the climbing performance of the animals. This prolongation in the swimming time, similar to fluoxetine, pointed out that antidepressant- like activity of the compounds 2c-2h might be related to the serotonergic rather than noradrenergic mechanisms. Besides, results of the activity cage tests demonstrated that none of the tested compounds caused an alteration in the locomotor activities of mice, signifying that antidepressantlike effects presented in this study were specific.
Conclusion: In conclusion, results of this present study supported the previous papers reporting the therapeutic potential of compounds carrying benzimidazole and/or piperidine rings in their structure and emphasized, once again, the importance of these pharmacophore groups in drug design studies.
Keywords: Activity cage test, benzimidazole, modified forced swimming test, piperidine, tail-suspension test, serotonergic.
Graphical Abstract
[1]
World Health Organization.Facts sheet No 369 – Depression.. http://www.who.int/en/news-room/fact-sheets/detail/depression (Accessed May 31, 2018).
[2]
Can, Ö.D.; Turan, N.; Demir Özkay, Ü.; Öztürk, Y. Antidepressant- like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems. Life Sci., 2017, 190, 110-117.
[3]
Gonçalves, A.E.; Bürger, C.; Amoah, S.K.; Tolardo, R.; Biavatti, M.W.; de Souza, M.M. The antidepressant-like effect of Hedyosmum brasiliense and its sesquiterpene lactone, podoandin in mice: Evidence for the involvement of adrenergic, dopaminergic and serotonergic systems. Eur. J. Pharmacol., 2012, 674(2-3), 307-314.
[4]
Khalafi-Nezhad, A.; Soltani Rad, M.N.; Mohabatkar, H.; Asrari, Z.; Hemmateenejad, B. Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives. Bioorg. Med. Chem., 2005, 13(6), 1931-1938.
[5]
Srivastava, R.; Gupta, S.K.; Naaz, F.; Singh, A.; Singh, V.K.; Verma, R.; Singh, N.; Singh, R.K. Synthesis, antibacterial activity, synergistic effect, cytotoxicity, docking and molecular dynamics of benzimidazole analogues. Comput. Biol. Chem., 2018, 76, 1-16.
[6]
Singh, A.; Yadav, D.; Yadav, M.; Dhamanage, A.; Kulkarni, S.; Singh, R.K. Molecular modeling, synthesis and biological evaluation of N-heteroaryl compounds as reverse transcriptase inhibitors against HIV-1. Chem. Biol. Drug Des., 2015, 85(3), 336-347.
[7]
Akhtar, M.J.; Khan, A.A.; Ali, Z.; Dewangan, R.P.; Rafi, M.; Hassan, M.Q.; Akhtar, M.S.; Siddiqui, A.A.; Partap, S.; Pasha, S.; Yar, M.S. Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors. Bioorg. Chem., 2018, 78, 158-169.
[8]
Kerimov, İ.; Ayhan-Kilcigil, G.; Özdamar, E.D.; Can-Eke, B.; Çoban, T.; Özbey, S.; Kazak, C. Design and one-pot and microwave-assisted synthesis of 2-amino/5-aryl-1,3,4-oxadiazoles bearing a benzimidazole moiety as antioxidants. Arch. Pharm. (Weinheim), 2012, 345(7), 549-556.
[9]
Noor, A.; Qazi, N.G.; Nadeem, H.; Khan, A.U.; Paracha, R.Z.; Ali, F.; Saeed, A. Synthesis, characterization, anti-ulcer action and molecular docking evaluation of novel benzimidazole-pyrazole hybrids. Chem. Cent. J., 2017, 11(1), 85.
[10]
Vinodkumar, R.; Vaidya, S.D.; Siva Kumar, B.V.; Bhise, U.N.; Bhirud, S.B.; Mashelkar, U.C. Synthesis, anti-bacterial, antiasthmatic 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)-1Hbenzimidazoles. Eur. J. Med. Chem., 2008, 43(5), 986-995.
[11]
Navarrete-Vázquez, G.; Hidalgo-Figueroa, S.; Torres-Piedra, M.; Vergara-Galicia, J.; Rivera-Leyva, J.C.; Estrada-Soto, S.; León-Rivera, I.; Aguilar-Guardarrama, B.; Rios-Gómez, Y.; Villalobos-Molina, R.; Ibarra-Barajas, M. Synthesis, vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives. Bioorg. Med. Chem., 2010, 18(11), 3985-3991.
[12]
Shingalapur, R.V.; Hosamani, K.M.; Keri, R.S.; Hugar, M.H. Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur. J. Med. Chem., 2010, 45(5), 1753-1759.
[13]
Kwak, H.J.; Pyun, Y.M.; Kim, J.Y.; Pagire, H.S.; Kim, K.Y.; Kim, K.R.; Rhee, S.D.; Jung, W.H.; Song, J.S.; Bae, M.A.; Lee, D.H.; Ahn, J.H. Synthesis and biological evaluation of aminobenzimidazole derivatives with a phenylcyclohexyl acetic acid group as antiobesity and anti-diabetic agents. Bioorg. Med. Chem. Lett., 2013, 23(16), 4713-4718.
[14]
Alpan, A.S.; Parlar, S.; Carlino, L.; Tarikogullari, A.H.; Alptüzün, V.; Güneş, H.S. Synthesis, biological activity and molecular modeling studies on 1H-benzimidazole derivatives as acetylcholinesterase inhibitors. Bioorg. Med. Chem., 2013, 21(17), 4928-4937.
[15]
Sondhi, S.M.; Rajvanshi, S.; Johar, M.; Bharti, N.; Azam, A.; Singh, A.K. Anti-inflammatory, analgesic and antiamoebic activity evaluation of pyrimido[1,6-a]benzimidazole derivatives synthesized by the reaction of ketoisothiocyanates with mono and diamines. Eur. J. Med. Chem., 2002, 37(10), 835-843.
[16]
El-Nezhawy, A.O.; Gaballah, S.T.; Radwan, M.A.; Baiuomy, A.R.; Abdel-Salam, O.M. Structure-based design of benzimidazole sugar conjugates: Synthesis, SAR and in vivo anti-inflammatory and analgesic activities. Med. Chem., 2009, 5(6), 558-569.
[17]
Mute, V.M.; Bodhankar, S.L. Antidepressant like effect of newly synthesized compound 2[(N-benzylacetamido) mercapto] benzimidazole (vs 25) and its possible mechanism by inhibition of monoamine oxidase enzyme in mice. Int. J. Pharm. Pharm. Sci., 2015, 7(2), 407-410.
[18]
Khan, I.; Tantray, M.A.; Hamid, H.; Alam, M.S.; Kalam, A.; Dhulap, A. Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity. Bioorg. Med. Chem. Lett., 2016, 26(16), 4020-4024.
[19]
Tantray, M.A.; Khan, I.; Hamid, H.; Alam, M.S.; Dhulap, A.; Kalam, A. Synthesis of benzimidazole-based 1,3,4- oxadiazole-1,2,3-triazole conjugates as glycogen synthase kinase-3b inhibitors with antidepressant activity in in vivo models. SC. Adv., 2016, 6, 43345-43355.
[20]
Kamil, A.; Akhtar, S.; Khan, A.; Farooq, E.; Nishan, U.; Uddin, R.; Farooq, U. Synthesis, structure–activity relationship and antinociceptive activities of some 2-(2′-pyridyl) benzimidazole derivatives. Med. Chem. Res., 2016, 25(6), 1216-1228.
[21]
Jain, P.; Sharma, P.K.; Rajak, H.; Pawar, R.S.; Patil, U.K.; Singour, P.K. Design, synthesis and biological evaluation of some novel benzimidazole derivatives for their potential anticonvulsant activity. Arch. Pharm. Res., 2010, 33(7), 971-980.
[22]
Yuan, Y.P.; Wang, S.B.; Gong, G.H.; Quan, Z.S. Synthesis and studies on anticonvulsant and antibacterial activities of 1-alkyl-4- (4H-1,2,4-triazol-4-yl)piperidine derivatives. Lett. Drug Des. Discov., 2014, 11, 1070-1078.
[23]
Jiang, Z.; Gu, J.; Wang, C.; Wang, S.; Liu, N.; Jiang, Y.; Dong, G.; Wang, Y.; Liu, Y.; Yao, J.; Miao, Z.; Zhang, W.; Sheng, C. Design, synthesis and antifungal activity of novel triazole derivatives containing substituted 1,2,3-triazole-piperdine side chains. Eur. J. Med. Chem., 2014, 82, 490-497.
[24]
Wang, P.; Cai, J.; Chen, J.; Ji, M. Synthesis and anticancer activities of ceritinib analogs modified in the terminal piperidine ring. Eur. J. Med. Chem., 2015, 93, 1-8.
[25]
Kim, J.H.; Shyam, P.K.; Kim, M.J.; Lee, H.J.; Lee, J.T.; Jang, H.Y. Enantioselective synthesis and antioxidant activity of 3,4,5-substituted piperidine derivatives. Bioorg. Med. Chem. Lett., 2016, 26(13), 3119-3121.
[26]
Ahmad Bhat, M.; Al-Omar, M.A.; Naglah, A.M. Synthesis and in vivo anti-ulcer evaluation of some novel piperidine linked dihydropyrimidinone derivatives. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 978-988.
[27]
Chen, X.; Zhan, P.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of piperidinesubstituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors. Eur. J. Med. Chem., 2012, 51, 60-66.
[28]
Imaeda, Y.; Tawada, M.; Suzuki, S.; Tomimoto, M.; Kondo, M.; Tarui, N.; Sanada, T.; Kanagawa, R.; Snell, G.; Behnke, C.A.; Kubo, K.; Kuroita, T. Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors. Bioorg. Med. Chem., 2016, 24, 5771-5780.
[29]
El Ahmad, Y.; Maillet, P.; Laurent, E.; Talab, A.; Teste, J.F.; Cédat, M.J.; Fiez-Vandal, P.Y.; Dokhan, R.; Ollivier, R. New N-(benzhydryloxyalkyl)-4-(carboxy/carbamoylmethyl) piperidine derivatives with antidepressant activity. Eur. J. Med. Chem., 1997, 32, 205-218.
[30]
Köksal, M.; Bilge, S.S. Synthesis and antidepressant-like profile of novel 1-Aryl-3- [(4-benzyl)piperidine-1-yl]propane derivatives. Arch. Pharm. Chem. Life Sci, 2007, 340, 299-303.
[31]
Trabanco, A.A.; Aerts, N.; Alvarez, R.M.; Andrés, J.I.; Boeckx, I.; Fernández, J.; Gómez, A.; Janssens, F.E.; Leenaerts, J.E.; De Lucas, A.I.; Matesanz, E.; Steckler, T.; Pullan, S. 4-Phenyl-4-[1Himidazol-2-yl]-piperidine derivatives as non-peptidic selective delta-opioid agonists with potential anxiolytic/antidepressant properties. Part 2. Bioorg. Med. Chem. Lett., 2007, 17, 3860-3863.
[32]
Wang, J.; Mack, A.L.; Coop, A.; Matsumoto, R.R. Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice. Eur. Neuropsychopharmacol., 2007, 17, 708-716.
[33]
Zheng, Y.Y.; Guo, L.; Zhen, X.C.; Li, J.Q. Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors. Eur. J. Med. Chem., 2012, 54, 123-136.
[34]
Garner, R.; Gopalakrishnan, S.; McCauley, J.A.; Bednar, R.A.; Gaul, S.L.; Mosser, S.D.; Kiss, L.; Lynch, J.J.; Patel, S.; Fandozzi, C.; Lagrutta, A.; Briscoe, R.; Liverton, N.J.; Paterson, B.M.; Vornov, J.J. Mazhari, R3. Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist. Pharmacol. Res. Perspect., 2015, 3(6), e00198.
[35]
Sadek, B.; Kuder, K.; Subramanian, D.; Shafiullah, M.; Stark, H.; Lażewska, D.; Adem, A.; Kieć-Kononowicz, K. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists. Behav. Pharmacol., 2014, 25, 245-252.
[36]
Tripathi, P.; Tripathi, A.C.; Chawla, V.; Saraf, S.K. Syntheses, characterization and evaluation of novel 2,6-diarylpiperidin-4-ones as potential analgesic-antipyretic agents. Eur. J. Med. Chem., 2014, 82, 439-448.
[37]
Jahan, S.; Akhtar, S.; Kamil, A.; Mushtaq, N.; Saify, Z.S.; Arif, M. Analgesic activity of alkyl piperidine derivatives. Pak. J. Pharm. Sci., 2016, 29(1), 77-82.
[38]
Huang, L.; Zhang, W.; Zhang, X.; Yin, L.; Chen, B.; Song, J. Synthesis and pharmacological evaluation of piperidine (piperazine)- substituted benzoxazole derivatives as multi-target antipsychotics. Bioorg. Med. Chem. Lett., 2015, 25(22), 5299-5305.
[39]
Więckowska, A.; Więckowski, K.; Bajda, M.; Brus, B.; Sałat, K.; Czerwińska, P.; Gobec, S.; Filipek, B.; Malawska, B. Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo. Bioorg. Med. Chem., 2015, 23(10), 2445-2457.
[40]
Schwartz, J.C. The histamine H3 receptor: From discovery to clinical trials with pitolisant. Br. J. Pharmacol., 2011, 163, 713-721.
[41]
Sadek, B.; Khan, N.; Darras, F.H.; Pockes, S.; Decker, M. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats. Physiol. Behav., 2016, 165, 383-391.
[42]
Liu, J.; Huang, D.; Xu, J.; Tong, J.; Wang, Z.; Huang, L.; Yang, Y.; Bai, X.; Wang, P.; Suo, H.; Ma, Y.; Yu, M.; Fei, J.; Huang, F. Tiagabine protects dopaminergic neurons against neurotoxins by inhibiting microglial activation. Sci. Rep., 2015, 5, 15720.
[43]
Statnick, M.A.; Chen, Y.; Ansonoff, M.; Witkin, J.M. Rorick- Kehn, L.; Suter, T.M.; Song, M.; Hu, C.; Lafuente, C.; Jiménez, A.; Benito, A.; Diaz, N.; Martínez-Grau, M.A.; Toledo, M.A.; Pintar, J.E. A novel nociceptin receptor antagonist LY2940094 inhibits excessive feeding behavior in rodents: A possible mechanism for the treatment of binge eating disorder. J. Pharmacol. Exp. Ther., 2016, 356(2), 493-502.
[44]
Demir Özkay, Ü.; Can, Ö.D.; Turan, N.; Kaya Cavuşoğlu, B. Synthesis and antinociceptive activities of some novel enzimidazolepiperidine derivatives. Turk. J. Chem., 2017, 41, 672-684.
[45]
Demir Özkay, Ü. Yurttas ̧, L.; Özkay, Y.; Üçel, U.I.; Can, Ö.D.; Öztürk, Y. Synthesis of new 1-phenyl-2-(4- substituted-piperazin-1-yl)-propanol derivatives and evaluation of their antidepressantlike effects. Arch. Pharm. Res., 2013, 36, 802-811.
[46]
Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology, (Berl.), 1985, 85, 367-370.
[47]
Demir Özkay, Ü.; Kaya, C.; Acar Çevik, U.; Can, Ö.D. Synthesis and antidepressant activity profile of some novel benzothiazole derivatives. Molecules, 2017, 22(9), E1490.
[48]
Cryan, J.F.; Markou, A.; Lucki, I. Assessing antidepressant activity in rodents: Recent developments and future needs. Trends Pharmacol. Sci., 2002, 23, 238-245.
[49]
Can, O.D.; Demir Ozkay, U.; Ucel, U.I. Anti-depressant-like effect of vitexin in BALB/c mice and evidence for the involvement of monoaminergic mechanisms. Eur. J. Pharmacol., 2013, 699, 250-257.
[50]
Votava, M.; Hess, L.; Slíva, J.; Krsiak, M.; Agová, V. Dexmedetomidine selectively suppresses dominant behavior in aggressive and sociable mice. Eur. J. Pharmacol., 2005, 523, 79-85.
[51]
Can, N.Ö.; Can, Ö.D.; Osmaniye, D.; Demir Özkay, Ü. Synthesis of some novel thiadiazole derivative compounds and screening their antidepressant-like activities. Molecules, 2018, 23(4), E716.
[52]
Patel, S.S.; Ray, R.S.; Sharma, A.; Mehta, V.; Katyal, A.; Udayabanu, M. Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice. Metab. Brain Dis., 2018. in press
[53]
Amoateng, P.; Kukuia, K.K.E.; Mensah, J.A.; Osei-Safo, D.; Adjei, S.; Eklemet, A.A.; Vinyo, E.A.; Karikari, T.K. An extract of Synedrella nodiflora (L) Gaertn exhibits antidepressant properties through monoaminergic mechanisms. Metab. Brain Dis., 2018. in press
[54]
da Silva, D.M.; Sanz, G.; Vaz, B.G.; de Carvalho, F.S.; Lião, L.M.; de Oliveira, D.R.; Moreira, L.K.D.S.; Cardoso, C.S.; de Brito, A.F.; da Silva, D.P.B.; da Rocha, F.F.; Santana, I.G.C.; Galdino, P.M.; Costa, E.A.; Menegatti, R. Tert-butyl 4-((1-phenyl-1H-pyrazol-4-yl) methyl) piperazine-1-carboxylate (LQFM104)- New piperazine derivative with antianxiety and antidepressant-like effects: Putative role of serotonergic system. Biomed. Pharmacother., 2018, 103, 546-552.
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