Novel substituted oxadiazole - piperazine derivatives as potential MAO inhibitors: Design, synthesis, in vitro and in silico studies

Year 2022, Volume: 26 Issue: 1, 20 - 27, 28.06.2025

Harun Uslu , Begüm Nurpelin Saglik , Derya Osmaniye , Kadriye Benkli

https://izlik.org/JA54SA65LH

Abstract

Recent studies have shown that there are many piperazine and oxadiazole derivatives with MAO-A and/or MAO-B inhibitory activity. For this reason in our recent study, a new compound series of oxadiazole - piperazine derivatives (4a-e) were designed, synthesized, characterized and screened their hMAOs inhibitory activities. When the in silico studies were examined, it was seen that the pharmacokinetic properties and interactions with the receptor of synthesized compounds were suitable. Compound 4e, with a NO2 group on the 4-position of the phenyl ring, found showing significant MAO-A inhibitory activity. Compound 4e, was the most effective agent against MAO-A enzyme with IC50 value of 0.116 ± 0.004 μM. The newly synthesized oxadiazole - piperazine derivatives appears to be supported studies to design MAO inhibitors to obtain more suitable drugs, against diseases such as depression and anxiety due to MAO-A.

Keywords

hMAOs inhibition , oxadiazole , piperazine , ADME , molecular docking

References

• [1] Youdim MBH, Bakhle YS. Monoamine oxidase: Isoforms and inhibitors in Parkinson's disease and depressive illness. Br J Pharmacol. 2006; 147(SUPPL. 1): S287-S296. [CrossRef]
• [2] Carradori S, D'Ascenzio M, De Monte C, Secci D, Yáñez M. Synthesis and Selective Human Monoamine Oxidase B Inhibition of Heterocyclic Hybrids Based on Hydrazine and Thiazole Scaffolds. Arch Pharm (Weinheim). 2013; 346(1): 17-22. [CrossRef]
• [3] Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal LJ, Masliah E. Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease. J Neural Transm. 2003; 110(7): 789-801. [CrossRef]
• [4] Patil PO, Bari SB, Firke SD, Deshmukh PK, Donda ST, Patil DA. A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer’s disease. Bioorg Med Chem. 2013; 21(9): 2434-2450. [CrossRef]
• [5] Yu PH. Pharmacological and clinical implications of MAO-B inhibitors. Gen Pharmacol: Vasc S. 1994; 25(8): 15271539. [CrossRef]
• [6] Evranos-Aksöz B, Yabanoğlu-Çiftçi S, Uçar G, Yelekçi K, Ertan R. Synthesis of some novel hydrazone and 2pyrazoline derivatives: monoamine oxidase inhibitory activities and docking studies. Bioorg Med Chem Lett. 2014; 24(15): 3278-3284. [CrossRef]
• [7] DeMaagd G, Philip A. Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis. P T. 2015; 40(8): 504-532.
• [8] Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD. The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease: A Mini Review. Oxid Med Cell Longev. 2016; 8590578; 1-15. [CrossRef]
• [9] Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 2008; 1147: 180-195. [CrossRef]
• [10] Ankur V, Shweta J, Priyanka J, Prachi J, Nidhi T, Roshni J, Rashi J, Abhishek KJ, Ram KA. Synthesis and Biological Activities of Oxadiazole Derivatives: A Review. Mini Rev Med Chem. 2016; 16(10): 825-845. [CrossRef]
• [11] Ke S, Li Z, Qian X. 1,3,4-Oxadiazole-3(2H)-carboxamide derivatives as potential novel class of monoamine oxidase (MAO) inhibitors: Synthesis, evaluation, and role of urea moiety. Bioorg Med Chem. 2008; 16(16): 7565-7572. [CrossRef]
• [12] Maccioni E, Alcaro S, Cirilli R, Vigo S, Cardia MC, Sanna ML, Meleddu R, Yanez M, Costa G, Casu L, Matyus P, Distinto S. 3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: A New Scaffold for the Selective Inhibition of Monoamine Oxidase B. J Med Chem. 2011; 54(18): 6394-6398. [CrossRef] https://dx.doi.org/10.29228/jrp.99
• [13] Tok F, Uğraş Z, Sağlık BN, Özkay Y, Kaplancıklı ZA, Koçyiğit-Kaymakçıoğlu B. Novel 2,5-disubstituted-1,3,4oxadiazole derivatives as MAO-B inhibitors: Synthesis, biological evaluation and molecular modeling studies. Bioorg Chem. 2021; 112: 104917. [CrossRef]
• [14] Çeçen M, Oh JM, Özdemir Z, Büyüktuncel SE, Uysal M, Abdelgawad MA, Musa A, Gambacorta N, Nicolotti O, Mathew B. Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors. Molecules. 2020; 25(22): 5371. [CrossRef]
• [15] Pessoa‐Mahana H, Gajardo GR, Araya‐Maturana R, Cárcamo JK, Pessoa‐Mahana CD. Synthesis of 4‐Arylpiperazine Derivatives of Moclobemide: Potential Antidepressants with a Dual Mode of Action. Synth Commun. 2004; 34(14): 2513-2521. [CrossRef]
• [16] Sağlık BN, Cebeci O, Acar Çevik U, Osmaniye D, Levent S, Kaya Çavuşoğlu B, Ilgın S, Özkay Y, Kaplancıklı ZA. Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors. Molecules. 2020; 25(18). [CrossRef]
• [17] Gumnick JF, Nemeroff CB. Problems with currently available antidepressants. The Journal of clinical psychiatry. 2000; 61 Suppl 10: 5-15.
• [18] Prashanth MK, Revanasiddappa HD, Lokanatha Rai KM, Veeresh B. Synthesis, characterization, antidepressant and antioxidant activity of novel piperamides bearing piperidine and piperazine analogues. Bioorg Med Chem Lett. 2012; 22(23): 7065-7070. [CrossRef]
• [19] Can NÖ, Osmaniye D, Levent S, Sağlık BN, Inci B, Ilgın S, Özkay Y, Kaplancıklı ZA. Synthesis of new hydrazone derivatives for MAO enzymes inhibitory activity. Molecules. 2017; 22(8): 1381. [CrossRef]
• [20] Can NÖ, Osmaniye D, Levent S, Sağlık BN, Korkut B, Atlı Ö, Özkay Y, Kaplancıklı ZA. Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors. Eur J Med Chem. 2018; 144: 68-81. [CrossRef]
• [21] Can ÖD, Osmaniye D, Özkay ÜD, Sağlık BN, Levent S, Ilgın S, Baysal M, Özkay Y, Kaplancıklı ZA. MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains. Eur J Med Chem. 2017; 131: 92-106. [CrossRef]
• [22] Ilgın S, Osmaniye D, Levent S, Sağlık BN, Acar Çevik U, Çavuşoğlu BK, Özkay Y, Kaplancıklı ZA. Design and synthesis of new benzothiazole compounds as selective hMAO-B inhibitors. Molecules. 2017; 22(12): 2187. [CrossRef]
• [23] Sağlık BN, Çavuşoğlu BK, Osmaniye D, Levent S, Çevik UA, Ilgın S, Özkay Y, Kaplancıklı ZA, Öztürk Y. In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors. Bioorg Chem. 2019; 85: 97-108. [CrossRef]
• [24] Tok F, Sağlık BN, Özkay Y, Ilgın S, Kaplancıklı ZA, Koçyiğit-Kaymakçıoğlu B. Synthesis of new hydrazone derivatives and evaluation of their monoamine oxidase inhibitory activity. Bioorg Chem. 2021; 114: 105038. [CrossRef]
• [25] QikProp, version 4.8, Schrödinger, LLC, New York, NY, 2016. [26] Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliver Rev. 2002; 54(3): 355-366. [CrossRef]
• [27] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings (Reprinted from Advanced Drug Delivery Reviews, vol 23, pg 3-25, 1997). Adv Drug Deliver Rev. 2001; 46(1-3): 3-26. [CrossRef]
• [28] Son S-Y, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T. Structure of human monoamine oxidase A at 2.2Å resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A. 2008; 105(15): 57395744. [CrossRef]
• [29] Kaya B, Özkay Y, Temel HE, Kaplancıklı ZA. Synthesis and biological evaluation of novel piperazine containing hydrazone derivatives. J Chem. 2016: 1-7. [CrossRef]
• [30] Kaya B, Kaplancıklı ZA, Yurttaş L, Çiftçi GA. Synthesis and biological evaluation of some new pyrimidine bearing 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives as cytotoxic agents. Turkish J Biochem. 2017; 42(2): 131-137. [CrossRef]