Derivatives of 4,5-dihydro (1H) pyrazoles as possible MAO-A inhibitors in depression and anxiety disorders: synthesis, biological evaluation and molecular modeling studies
- 27 Downloads
Abstract
A series of 1,3,5-trisubstituted-2-pyrazoline derivatives (3a–3t) were synthesized in appreciable yields by substituting N1 position of 2-pyrazoline nucleus with 4-nitrobenzenesulfonylchloride using conventional and microwave assisted synthetic approaches. The physicochemical and spectral characterization such as IR, Mass, 1H-NMR and 13C-NMR, and elemental analysis, assured the formation of proposed derivatives. Pharmacological studies revealed that compound 3d exhibited highest antidepressant activity however, compound 3l was found to be most effective anxiolytic agent at the tested doses (50 and 100 mg/kg b.w.), when compared to the control group. Molecular docking simulations established the possible mechanism of their neuropharmacological effects, with admirable affinity towards MAO-A protein. This was also evidenced from some of the key interactions of these compounds with the amino acid residues Ala68, Tyr69, Phe208, Tyr407 and Tyr444. Moreover, synthesized derivatives showed encouraging pharmacokinetic (ADME) and toxicological (neurotoxicity, carcinogenicity, mutagenicity, reproductive toxicity, irritancy and acute toxicity) parameters as predicted by computational programs. Some of these toxicity studies were further examined in wet laboratory by accomplishing behavioral neurotoxicity studies and acute toxicity studies as per OECD guidelines.
Key words
2-Pyrazoline Anxiolytic Antidepressant Locomotor and neuromuscular coordination studies Glide docking FST and TSTNotes
Acknowledgements
We express our sincere gratitude to Central Drugs Research Institute (CDRI), Lucknow, India and Department of Chemistry, Banasthali Vidyapith University, Banasthali, Rajasthan, India for providing the library and sophisticated analytical instrument facilities. Authors are thankful to the All India Council for Technical Education (AICTE), New Delhi, India, for providing grant under the Research Promotion Scheme (Grant No.: 8023/RID/RPS/30 (Pvt.) 2011-12), through which the computational software facility has been made available at the host institute. We also acknowledge the technical support team/application scientists of Schrodinger Inc. for their help during computational studies.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
References
- Amrein R, Martin JR, Cameron AM (1999) Moclobemide in patients with dementia and depression. Adv Neurol 80:509–519PubMedGoogle Scholar
- Bhandari S, Tripathi AC, Saraf SK (2013) Synthesis and anticonvulsant activity of some 2-pyrazoline derivatives. Med Chem Res 22:5290–5296CrossRefGoogle Scholar
- Brown CS, Kent TA, Bryant SG, Gevedon RM, Campbell JL, Felthous AR, Barratt ES, Rose RM (1989) Blood platelet uptake of serotonin in episodic aggression. Psychiatry Res 27:5–12CrossRefPubMedGoogle Scholar
- Cesura AM, Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Prog Drug Res 38:171–297PubMedGoogle Scholar
- Chimenti F, Bolasco A, Manna F, Secci D, Chimenti P, Befani O, Turini P, Giovannini V, Mondovi B, Cirilli R, La Torre F (2004) Synthesis and selective inhibitory activity of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives against monoamine oxidase. J Med Chem 47:2071–2074CrossRefPubMedGoogle Scholar
- Chimenti F, Bolasco A, Secci D, Chimenti P, Granese A, Carradori S, Yanez M, Orallo F, Ortuso F, Alcaro S (2010) Investigations on the 2-thiazolylhydrazyne scaffold: synthesis and molecular modeling of selective human monoamine oxidase inhibitors. Bioorg Med Chem 18:5715–5723CrossRefPubMedGoogle Scholar
- Dhingra D, Goyal PK (2008) The CNS depressant drugs such as barbiturates and alcohol reduce the motor activity while the stimulants such as caffeine and amphetamines increase the activity. Indian J Exp Biol 46:212–218PubMedGoogle Scholar
- Foley P, Gerlach M, Youdim MB, Riederer P (2000) MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? Park Relat Disord 6:25–47CrossRefGoogle Scholar
- Gareri P, Falconi U, De Fazio P, De Sarro G (2000) Conventional and new antidepressant drugs in the elderly. Prog Neurobiol 61:353–396CrossRefPubMedGoogle Scholar
- Gokhan-Kelekci N, Koyunoglu S, Yabanoglu S, Yelekci K, Ozgen O, Ucar G, Erol K, Kendi E, Yesilada A (2009) New pyrazoline bearing 4(3H)-quinazolinone inhibitors of monoamine oxidase: synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity. Bioorg Med Chem 17:675–689CrossRefPubMedGoogle Scholar
- Gokhan N, Yesilada A, Ucar G, Erol K, Bilgin AA (2003) 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: synthesis and evaluation as MAO inhibitors. Arch Pharm 336:362–371CrossRefGoogle Scholar
- Jagrat M, Behera J, Yabanoglu S, Ercan A, Ucar G, Sinha BN, Sankaran V, Basu A, Jayaprakash V (2011) Pyrazoline based MAO inhibitors: Synthesis, biological evaluation and SAR studies. Bioorg Med Chem Lett 21:4296–4300CrossRefPubMedGoogle Scholar
- Jayaprakash V, Sinha BN, Ucar G, Ercan A (2008) Pyrazoline-based mycobactin analogues as MAO-inhibitors. Bioorg Med Chem Lett 18:6362–6368CrossRefPubMedGoogle Scholar
- Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Altintop MD, Can OD (2010) New pyrazoline derivatives and their antidepressant activity. Eur J Med Chem 45:4383–4387CrossRefPubMedGoogle Scholar
- Karuppasamy M, Mahapatra M, Yabanoglu S, Ucar G, Sinha BN, Basu A, Mishra N, Sharon A, Kulandaivelu U, Jayaprakash V (2010) Development of selective and reversible pyrazoline based MAO-A inhibitors: synthesis, biological evaluation and docking studies. Bioorg Med Chem 18:1875–1881CrossRefPubMedGoogle Scholar
- Klebe G (2000) Recent developments in structure-based drug design. J Mol Med 78:269–281CrossRefPubMedGoogle Scholar
- Lidstrom P, Tierney J, Wathey B, Westman J (2001) Microwave assisted organic synthesis- a review. Tetrahedron 57:9225–9283CrossRefGoogle Scholar
- Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacol (Berl) 92:180–185Google Scholar
- Maccioni E, Alcaro S, Orallo F, Cardia MC, Distinto S, Costa G, Yanez M, Sanna ML, Vigo S, Meleddu R, Secci D (2010) Synthesis of new 3-aryl-4,5-dihydropyrazole-1-carbothioamide derivatives. An investigation on their ability to inhibit monoamine oxidase. Eur J Med Chem 45:4490–4498CrossRefPubMedGoogle Scholar
- Manna F, Chimenti F, Bolasco A, Secci D, Bizzarri B, Befani O, Turini P, Mondovi B, Alcaro S, Tafi A (2002) Inhibition of amine oxidases activity by 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. Bioorg Med Chem Lett 12:3629–3633CrossRefPubMedGoogle Scholar
- Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63:1209–1216CrossRefPubMedGoogle Scholar
- Mishra N, Sasmal D (2011) Development of selective and reversible pyrazoline based MAO-B inhibitors: virtual screening, synthesis and biological evaluation. Bioorg Med Chem Lett 21:1969–1973CrossRefPubMedGoogle Scholar
- Mitoma J, Ito A (1992) Mitochondrial targeting signal of rat liver monoamine oxidase B is located at its carboxy terminus. J Biochem 111:20–24CrossRefPubMedGoogle Scholar
- OECDGuidelines (2001) For testing of chemicals 423: acute oral toxicity—acute toxic class method 2001. Organization For Economic Corporation And Development, Paris, FranceGoogle Scholar
- Ozdemir Z, Kandilci HB, Gumusel B, Calis U, Bilgin AA (2008) Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-thienyl)pyrazoline derivatives. Arch Pharm 341:701–707CrossRefGoogle Scholar
- Palaska E, Aytemir M, Uzbay IT, Erol D (2001) Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines. Eur J Med Chem 36:539–543CrossRefPubMedGoogle Scholar
- Parasuraman S (2011) Toxicological screening. J Pharmacol Pharmacother 2:74–79CrossRefPubMedPubMedCentralGoogle Scholar
- Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167CrossRefPubMedGoogle Scholar
- Pletscher A (1991) The discovery of antidepressants: a winding path. Experientia 47:4–8CrossRefPubMedGoogle Scholar
- Porsolt RD (1981) Antidepressants. In: Enna SJ, Malick JB, Richelson E (eds) Neurochemical, Behavioural and Clinical Perspectives.. Raven Press, New York, NY, p 129–139Google Scholar
- Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
- Prasad YR, Rao AL, Prasoona L, Murali K, Kumar PR (2005) Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2ʹʹ-hydroxy naphthalene-1ʹ-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 15:5030–5034CrossRefGoogle Scholar
- Ruhoglu O, Ozdemir Z, Calis U, Gumusel B, Bilgin AA (2005) Synthesis of and pharmacological studies on the antidepressant and anticonvulsant activities of some 1,3,5-trisubstituted pyrazolines. Arzneimittelforschung 55:431–436PubMedGoogle Scholar
- Sahoo A, Yabanoglu S, Sinha BN, Ucar G, Basu A, Jayaprakash V (2010) Towards development of selective and reversible pyrazoline based MAO-inhibitors: synthesis, biological evaluation and docking studies. Bioorg Med Chem Lett 20:132–136CrossRefPubMedGoogle Scholar
- Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacol (Berl) 85:367–370CrossRefGoogle Scholar
- Thase ME (2012) The role of monoamine oxidase inhibitors in depression treatment guidelines. J Clin Psychiatry 73(Suppl 1):10–16CrossRefPubMedGoogle Scholar
- Tripathi AC, Upadhyay S, Paliwal S, Saraf SK (2016) An expeditious one-pot microwave facilitated versus conventional syntheses, in-vivo biological screening and molecular docking studies of some 3,5-disubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Med Chem Res 25:390–406CrossRefGoogle Scholar
- Tripathi AC, Upadhyay S, Paliwal S, Saraf SK (2018a) Monoamine oxidase inhibitors: Retrospects and prospects. Eur J Med Chem. https://doi.org/10.1016/j.ejmech.2018.01.003
- Tripathi AC, Upadhyay S, Paliwal S, Saraf SK (2018b) N1-benzenesulfonyl-2-pyrazoline hybrids in neurological disorders: Syntheses, biological screening and computational studies. EXCLI J 17:126–148Google Scholar
- Upadhyay S, Tripathi AC, Paliwal S, Saraf SK (2017a) 2-Pyrazoline derivatives in neuropharmacology: Synthesis, ADME prediction, molecular docking and in-vivo biological evaluation. EXCLI J 16:628–649PubMedPubMedCentralGoogle Scholar
- Upadhyay S, Tripathi AC, Paliwal S, Saraf SK (2017) Facile one-pot synthetic methodologies for nitrogen containing heterocyclic derivatives of 3,5-disubstituted 4,5-dihydro-1H-pyrazole, their biological evaluation and molecular docking studies. Pharm Chem J 51:536–547CrossRefGoogle Scholar
- Vogel HG (2002) Drug discovery and evaluation: pharmacological assays, 2 edn. Springer-Verlag, Berlin, Heidelberg, GermanyCrossRefGoogle Scholar
- Volz HP, Gleiter CH (1998) Monoamine oxidase inhibitors. A perspective on their use in the elderly. Drugs Aging 13:341–355CrossRefPubMedGoogle Scholar
- Willner P, Mitchell PJ (2002) The validity of animal models of predisposition to depression. Behav Pharmacol 13:169–188CrossRefPubMedGoogle Scholar
- Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309CrossRefPubMedGoogle Scholar