Design, synthesis, docking, and antidepressant activity evaluation of isatin derivatives bearing Schiff bases

Document Type : Original Article

Authors

1 Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

2 Isfahan Pharmaceutical Science Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

3 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Objective(s): Depression is a prevalent psychiatric disorder. Treatment of depression is still a challenge due to the lack of response of some patients to a variety of available medications and side effects. Isatin is an interesting molecule with diversified biological effects. It also participates in many synthetic reactions, as a precursor molecule. In this study, a new series of N-alkyl and N-benzyl isatin derivatives bearing Schiff bases were synthesized and screened for antidepressant activities in mice.
Materials and Methods: The synthesis was initiated by N-alkylation and N-benzylation of isatin by an alkylation reaction to give N-substituted isatins. 2-(Benzyloxy) benzohydrazide derivatives were synthesized by treating methyl2-hydroxybenzoate with benzyl bromide or 4-chlorobenzyl bromide which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. The final compounds were obtained by condensation of N-substituted isatins with 2-(benzyloxy) benzohydrazide derivatives as Shiff-base products. Compounds were evaluated for antidepressant activities in mice by the locomotor activity, marble burying test, and forced swimming test. Monoamine oxidase–A (MAO–A) enzyme has been used for molecular docking studies.
Results: Compounds 8b and 8e in both doses, and 8 c in the lower dose, reduced immobility time during the forced swimming test relative to the control group. All preparations reduced the number of marbles buried compared with the control group. The highest docking score was -11.01 kcal/mol for compound 8e.
Conclusion: N-Benzylated-isatin (8b, 8e) and N- acetic acid ethyl ester -isatin derivatives (8c) showed more effective antidepressant activity compared with N-phenyl acetamide isatin derivatives. Docking results relatively confirm the pharmacological results.

Keywords

References

1.    Réus GZ,  Fries GR, Stertz L, Badawy M,  IC Passos, Barichello T, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neurosci 2015; 300: 141-154.
2.    Kerzare DR, Menghani SS, Khedekar PB. Synthesis, characterization, antidepressant activity and docking studies of some novel indole bearing azetidinone derivatives. Indian J Pharm Educ Res 2018; 52: 110-121.
3.    Jupally VR, Eggadi V, Sheshagiri SB, Kulandaivelu U. Synthesis and evaluation of neuropharmacological profile of isatin-3-[N2-(2-benzalaminothiazol-4-yl)] hydrazones. Egypt Pharmaceut J 2015; 14: 130-138.
4.    Khan FA, Maalik A. Advances in pharmacology of isatin and its derivatives: A review. Trop J Pharm Res. 2015; 14: 1937-1942.
5.    Pakravan P, Kashanian S, Khodaei MM, Harding FJ. Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity. Pharmacol Rep 2013; 65: 313-335.
6.    Shruthi N, Poojary B, Kumar V, Prathibha A, Hussain MM, Revanasiddappa BC, et al. Synthesis and biological evaluation of N-(substituted phenyl)-2-(5H-[1, 2, 4] triazino [5, 6-b] indol-3-ylsulfanyl) acetamides as antimicrobial, antidepressant, and anticonvulsant agents. Russ J Bioorganic Chem 2015; 41: 223-230.
7.    Ramgalla  A, Chandra S, Kumar PH, Ankam S. Synthesis and biological evaluation of isatin Derivatives. Int J Innov Pharm Sci Res 2015; 3: 1305-1318.
8.    Zhen X, Peng Z, Zhao S, Han Y, Jin Q, Guan L. Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2, 3-dioxoindolin-1-yl) acetamide derivatives. Acta Pharm Sin B 2015; 5: 343-349.
9.    Hassanzadeh F, Jafari E, Khayambashi N, Hajhashemi V. Synthesis and anti-inflammatory effects evaluation of 1, 3 substituted isatin derivatives. Thai J Pharm Sci. 2021; 45: 248-252.
10.    Chandra PM, Venkateshwar J.  Biological evaluation of schiff bases of new isatin derivatives for anti alzheimer’s activity. Asian J Pharm Clin Res 2014; 7: 114-117.
11.    Sridhar SK, Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives. Biol Pharm Bull 2001; 24: 1149-1152.
12. Igosheva N, Lorz C, O’conner E, Glover V, Mehmet H. Isatin, an endogenous monoamine oxidase inhibitor, triggers a dose-and time-dependent switch from apoptosis to necrosis in human neuroblastoma cells. Neurochem Int 2005; 47: 216-224.
13. Pal M, Sharma NK, Priyanka P, Jha KK. Synthetic and biological multiplicity of isatin. Chem Inform 2011; 42: 35-44.
14. Diaz P, Xu J, Astruc-Diaz F, Pan HM, Brown DL, Naguib M. Design and synthesis of a novel series of N-alkyl isatinacylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of neuropathic pain. J Med Chem 2008; 51: 4932-4947.
15. Medvedev A, Buneeva O, Gnedenko O, Ershov P, Ivanov A. Isatin, an endogenous nonpeptidebiofactor: A review of its molecular targets, mechanisms of actions, and their biomedical implications. BioFactors 2018; 44: 95-108.
16 . Minami, M, Hamaue, N, Hirafuji, M, Saito, H., Hiroshige, T., et al. Isatin, an endogenous MAO inhibitor, and a rat model of Parkinson’s disease induced by the Japanese encephalitis virus. J Neural Transm Suppl. 2006;  71:87–89.
17. Kumar S, Nair AS, Abdelgawad MA, Mathew B. Exploration of the Detailed Structure–Activity Relationships of Isatin and Their Isomers As Monoamine Oxidase Inhibitors. ACS Omega 2022; 7: 16244-16259.
18. Xie C, Tang LM, Li FN, Guan LP, Pan CY, Wang SH. Structure-based design, synthesis, and anticonvulsant activity of isatin-1-N-phenylacetamide derivatives. Med Chem Res 2014; 23: 2161-2168.
19. Blanco MM, Dal Maso M, Shmidt MS, Perillo IA. Reaction of Isatin-1-acetamides with Alkoxides: Synthesis of Novel 1, 4-Dihydro-3-hydroxy-4-oxo-2-quinolinecarboxamides. Synthesis 2007; 6: 829-834.
20. Sharma PK, Balwani S, Mathur D, Malhotra S, Singh BK, Prasad AK, et al. Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids. J  Enzyme Inhib Med Chem 2016; 31: 1520-1526.
21. Eldehna WM, Abo-Ashour MF, Nocentini A, El-Haggar RS, Bua S, Bonardi A, et al. Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents. Eur J Med Chem 2019; 162: 147-160.
22. Saidugari S, Rao L, Vidya K, Ram B, Balram B. Synthesis, characterization and antibacterial activity of (E)-4-((3-methyl-4-(methylsulfonyl) pyridin-2-yl) methoxy)-N’ (substitutedbenzylidene) benzohydrazide derivatives. Indian J Chem 2017; 56B: 177-182.
23. Yan X, Lv Z, Wen J, Zhao S, Xu Z. Synthesis and in vitro evaluation of novel substituted isatin-propylene-1H-1, 2, 3-triazole-4-methylene-moxifloxacin hybrids for their anti-mycobacterial activities. Eur J Med Chem 2018; 143: 899-904.
24. Njung’e K, Handley SL. Evaluation of marble-burying behavior as a model of anxiety. Pharmacol Biochem Behav 1991; 38: 63-67.
25. Mesripour A,Payandekhah F. The Noradrenergic System is Partly Involved in Resveratrol Antidepressant and Anti-Obsessive Like Effects in Mice Model. Res J Pharmacogn 2021;8: 67-75.
26. Hassanzadeh F, Jafari E, Zarabi M, Khodarahmi G, Vaseghi G. Synthesis, cytotoxic evaluation, and molecular docking studies of some new 1, 3, 4-oxadiazole-based compounds. Res Pharml Sci 2020; 15:454.
27. Mesripour A, Alhimma F, Hajhashemi V. The effect of vitamin B6 on dexamethasone-induced depression in mice model of despair. NutrNeurosci 2019; 22: 744-749.
28. Mesripour A, Meshkati A, Hajhashemi V. A Synbiotic Mixture Augmented the Efficacy of Doxepin, Venlafaxine, and Fluvoxamine in a Mouse Model of Depression. Turk J Pharm Sci 2020; 17: 293-298.
29. Yankelevitch-Yahav R, Franko M, Huly A, Doron R. The forced swim testas a model of depressive-like behavior. J Vis Exp 2015; 97: 52587.
30. Deussing JM. Animal models of depression. Drug Discov Today Dis Models 2006; 3: 375-383.
 
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 4
April 2023
Pages 438-444

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