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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Design, Synthesis, and Evaluation of Isoindoline Derivatives as New Antidepressant Agents

Author(s): Ai-Ling Sun, Chao-Chao Wang, Hao Zhou, Yi-Fei Lang, Shu-Yue Fu, Ren-Min Liu* and Kang Lei*

Volume 19, Issue 8, 2022

Published on: 13 May, 2022

Page: [769 - 777] Pages: 9

DOI: 10.2174/1570180819666220301141149

Price: $65


Background: Isoindoline derivatives exhibit a wide range of biological activities and have attracted considerable attention. However, few studies have been conducted on their antidepressant activity.

Objective: Here, we designed and synthesized a series of isoindoline derivatives and studied their antidepressant activities.

Methods: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mice brain by using ELISA. The biological activities of the compounds were verified by molecular docking studies. The pharmacokinetic properties of the target compounds were predicted by Discovery Studio (DS) 2020.

Results: The results of the pharmacological experiments showed that most isoindoline derivatives exhibited significant antidepressant activity. Among these compounds, compound 4j showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of isoindoline derivatives may be mediated by elevated 5-HT levels. Compound 4j was used in molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT1A receptor. The results demonstrated that compound 4j had a significant interaction with amino acids around the active site of the 5-HT1A receptor in the homology model.

Conclusion: Isoindoline derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

Keywords: Isoindoline, synthesis, antidepressant screening, in vivo, molecular docking studies, forced swimming test, tail suspension test.

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Ferrari, A.J.; Charlson, F.J.; Norman, R.E.; Patten, S.B.; Freedman, G.; Murray, C.J.; Vos, T.; Whiteford, H.A. Burden of depressive disor-ders by country, sex, age, and year: Findings from the global burden of disease study 2010. PLoS Med., 2013, 10(11), e1001547.
[] [PMID: 24223526]
Ohno, Y. Therapeutic role of 5-HT1A receptors in the treatment of schizophrenia and Parkinson’s disease. CNS Neurosci. Ther., 2011, 17(1), 58-65.
[] [PMID: 21091640]
Reeves, R.R.; Ladner, M.E. Antidepressant-induced suicidality: An update. CNS Neurosci. Ther., 2010, 16(4), 227-234.
[PMID: 20553304]
Fournier, J.C.; DeRubeis, R.J.; Hollon, S.D.; Dimidjian, S.; Amsterdam, J.D.; Shelton, R.C.; Fawcett, J. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA, 2010, 303(1), 47-53.
[] [PMID: 20051569]
Abdel-Aziz, A.A.M.; El-Azab, A.S.; Abu El-Enin, M.A.; Almehizia, A.A.; Supuran, C.T.; Nocentini, A. Synthesis of novel isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones as selective inhibitors of the tumor-associated carbonic anhydrase IX. Bioorg. Chem., 2018, 80, 706-713.
[] [PMID: 30064081]
Kamiński, K.; Obniska, J.; Wiklik, B.; Atamanyuk, D. Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs. Eur. J. Med. Chem., 2011, 46(9), 4634-4641.
[] [PMID: 21840629]
Al-Qaisi, J.A.; Alhussainy, T.M.; Qinna, N.A.; Matalka, K.Z.; Al-Kaissi, E.N.; Muhi-Eldeen, Z.A. Synthesis and pharmacological evalua-tion of aminoacetylenic isoindoline-1,3-dione derivatives as anti-inflammatory agents. Arab. J. Chem., 2014, 7(6), 1024-1030.
Rani, A.; Johansen, M.D.; Roquet-Banères, F.; Kremer, L.; Awolade, P.; Ebenezer, O.; Singh, P.; Sumanjit, V.K.; Kumar, V. Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads as potential anti-mycobacterials. Bioorg. Med. Chem. Lett., 2020, 30(22), 127576.
[] [PMID: 32980514]
Muller, G.W.; Chen, R.; Huang, S.Y.; Corral, L.G.; Wong, L.M.; Patterson, R.T.; Chen, Y.; Kaplan, G.; Stirling, D.I. Amino-substituted thalidomide analogs: Potent inhibitors of TNF-α production. Bioorg. Med. Chem. Lett., 1999, 9(11), 1625-1630.
[] [PMID: 10386948]
Palumbo, A.; Rajkumar, S.V. Treatment of newly diagnosed myeloma. Leukemia, 2009, 23(3), 449-456.
[] [PMID: 19005483]
Wen, H.; Shi, Y.; Dong, J.W.Y.; Guo, Y.S.; Zang, J.J.; Yang, G.Z. Design, synthesis and pharmacological investigation of isoindoline de-rivatives as 5-HT/NE double reuptake inhibitors. Yao Xue Xue Bao, 2015, 50(9), 1148-1155.
[PMID: 26757552]
Afzal, O.; Altamimi, A.S.A.; Shahroz, M.M.; Sharma, H.K.; Riadi, Y.; Hassan, M.Q. Analgesic and anticancer activity of benzoxazole clubbed 2-pyrrolidinones as novel inhibitors of monoacylglycerol lipase. Molecules, 2021, 26(8), 2389.
[] [PMID: 33924091]
Gupta, M.; Ojha, M.; Yadav, D.; Pant, S.; Yadav, R. Novel benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) derivatives as potential anti-Alzheimer’s agents: Synthesis and pharmacological investigations. ACS Chem. Neurosci., 2020, 11(18), 2849-2860.
[] [PMID: 32816447]
Malawska, K.; Rak, A. Gryzło, B.; Sałat, K.; Michałowska, M.; Żmudzka, E.; Lodarski, K.; Malawska, B.; Kulig, K. Search for new poten-tial anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one. Pharmacol. Rep., 2017, 69(1), 105-111.
[] [PMID: 27915183]
Sapa, J.; Filipek, B.; Kulig, K.; Malawska, B. Antidepressant-like activity of the phenylpiperazine pyrrolidin-2-one derivatives in mice. Pharmacol. Rep., 2011, 63(1), 71-78.
[] [PMID: 21441613]
Porsolt, R.D.; Bertin, A.; Jalfre, M. Behavioral despair in mice: A primary screening test for antidepressants. Arch. Int. Pharmacodyn. Ther., 1977, 229(2), 327-336.
[PMID: 596982]
Zomkowski, A.D.; Santos, A.R.; Rodrigues, A.L. Evidence for the involvement of the opioid system in the agmatine antidepressant-like effect in the forced swimming test. Neurosci. Lett., 2005, 381(3), 279-283.
[] [PMID: 15896484]
Steru, L.; Chermat, R.; Thierry, B.; Simon, P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology (Berl.), 1985, 85(3), 367-370.
[] [PMID: 3923523]
Sairanen, M.; Lucas, G.; Ernfors, P.; Castrén, M.; Castrén, E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J. Neurosci., 2005, 25(5), 1089-1094.
[] [PMID: 15689544]
Elliott, P.J.; Chan, J.; Parker, Y.M.; Nemeroff, C.B. Behavioral effects of neurotensin in the open field: structure-activity studies. Brain Res., 1986, 381(2), 259-265.
[] [PMID: 3756503]
Tokgöz, G.; Demir Özkay, Ü.; Osmaniye, D.; Turan Yücel, N.; Can, Ö.D. Kaplancıklı Z.A.; Jeong, S.J.; Jeong, M.J. Synthesis of novel benzazole derivatives and evaluation of their antidepressant-like activities with possible underlying mechanisms. Molecules, 2018, 23(11), 2881.
[] [PMID: 30400609]
Galdino, P.M.; Nascimento, M.V.; Sampaio, B.L.; Ferreira, R.N.; Paula, J.R.; Costa, E.A. Antidepressant-like effect of Lafoensia pacari A. St.-Hil. ethanolic extract and fractions in mice. J. Ethnopharmacol., 2009, 124(3), 581-585.
[] [PMID: 19439172]
Sakakibara, H.; Ishida, K.; Grundmann, O.; Nakajima, J.; Seo, S.; Butterweck, V.; Minami, Y.; Saito, S.; Kawai, Y.; Nakaya, Y.; Terao, J. Antidepressant effect of extracts from Ginkgo biloba leaves in behavioral models. Biol. Pharm. Bull., 2006, 29(8), 1767-1770.
[] [PMID: 16880641]
Meyer, J.H.; McMain, S.; Kennedy, S.H.; Korman, L.; Brown, G.M.; DaSilva, J.N.; Wilson, A.A.; Blak, T.; Eynan-Harvey, R.; Goulding, V.S.; Houle, S.; Links, P. Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am. J. Psychiatry, 2003, 160(1), 90-99.
[] [PMID: 12505806]
Sherin, D.R.; Geethu, C.K.; Prabhakaran, J.; Mann, J.J.; Dileep Kumar, J.S.; Manojkumar, T.K. Molecular docking, dynamics simulations and 3D-QSAR modeling of arylpiperazine derivatives of 3,5-dioxo-(2H,4H)-1,2,4-triazine as 5-HT1AR agonists. Comput. Biol. Chem., 2019, 78, 108-115.
[] [PMID: 30502727]

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