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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

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Abstract

A series of 3,5-disubstituted-2-pyrazoline derivatives (2a–2t) were synthesized by reacting different aromatic/heteroaromatic aldehydes and ketones, in a two-step reaction through Claisen Schmidt condensation, followed by cyclization of the resulted chalcones with hydrazine hydrate in the presence of a base using conventional and microwave approaches. The synthesized derivatives were characterized by various physicochemical methods, and their chemical structures were established by IR, Mass, 1H-NMR, 13C-NMR spectroscopic data and elemental analysis. The antidepressant with tail suspension test and forced swim test and anti-anxiety with Elevated Plus Maze Test activities were evaluated using suitable animal models. Compounds 2i, and 2j showed noticeable antidepressant activity, by reducing the duration of immobility in both the tests, while compounds 2a and 2b were found to possess good anxiolytic activity, by increasing the number of arm entries and open arm exploratory time at the tested doses (50 and 100 mg/kg b.w.), when compared to the standard drugs imipramine and diazepam, respectively. In order to ascertain the binding interactions of the synthesized derivatives to the MAO-A target protein, molecular docking was employed which demonstrated the key interactions with the amino acid residues Asn181, Phe208, Tyr69, Tyr197, Tyr444 and Met445 at the binding site. In addition, the most active derivatives 2i and 2b showed some imperative conserved interactions of the PDB co-crystal ligand 2Z5X with the amino acid residues at the binding site of MAO-A protein. The results of the study also demonstrated that the Glide gscores of the synthesized derivatives were in close correlation with the in vivo biological activity data, in particular with the forced swim test of the antidepressant activity with a very good correlation coefficient of 0.754103. Furthermore, the ADME properties of the synthesized derivatives were predicted and found to be within the affirmed limits.

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References

  • Abdel-Wahab BF, Abdel-Aziz HA, Ahmed EM (2009) Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles. Eur J Med Chem 44:2632–2635

    Article  CAS  PubMed  Google Scholar 

  • Acharya BN, Saraswat D, Tiwari M, Shrivastava AK, Ghorpade R, Bapna S, Kaushik MP (2010) Synthesis and antimalarial evaluation of 1,3,5-trisubstituted pyrazolines. Eur J Med Chem 45:430–438

    Article  CAS  PubMed  Google Scholar 

  • Amrein R, Martin JR, Cameron AM (1999) Moclobemide in patients with dementia and depression. Adv Neurol 80:509–519

    CAS  PubMed  Google Scholar 

  • Bhat AR, Athar F, Azam A (2009) Bis-pyrazolines: synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica. Eur J Med Chem 44:426–431

    Article  CAS  PubMed  Google Scholar 

  • Bilgin AA, Palaska E, Sunal R (1993) Studies on the synthesis and antidepressant activity of some 1-thiocarbamoyl-3,5-diphenyl-2-pyrazolines. Arzneimittelforschung 43:1041–1044

    CAS  PubMed  Google 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 27:5–12

    Article  CAS  PubMed  Google Scholar 

  • Budakoti A, Bhat AR, Azam A (2009) Synthesis of new 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives and evaluation of their antiamoebic activity. Eur J Med Chem 44:1317–1325

    Article  CAS  PubMed  Google Scholar 

  • Cesura AM, Pletscher A (1992) The new generation of monoamine oxidase inhibitors. Prog Drug Res 38:171–297

    CAS  PubMed  Google Scholar 

  • Chawla R, Sahoo U, Arora A, Sharma PC, Radhakrishnan V (2010) Microwave assisted synthesis of some novel 2-pyrazoline derivatives as possible antimicrobial agents. Acta Polo Pharm 67:55–61

    CAS  Google 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 47:2071–2074

    Article  CAS  PubMed  Google Scholar 

  • Chimenti F, Carradori S, Secci D, Bolasco A, Bizzarri B, Chimenti P, Granese A, Yanez M, Orallo F (2010) Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives. Eur J Med Chem 45:800–804

    Article  CAS  PubMed  Google Scholar 

  • Congiu C, Onnis V, Vesci L, Castorina M, Pisano C (2010) Synthesis and in vitro antitumor activity of new 4,5-dihydropyrazole derivatives. Bioorg Med Chem 18:6238–6248

    Article  CAS  PubMed  Google Scholar 

  • Dawane BS, Konda SG, Mandawad GG, Shaikh BM (2010) Poly(ethylene glycol) (PEG-400) as an alternative reaction solvent for the synthesis of some new 1-(4-(4′-chlorophenyl)-2-thiazolyl)-3-aryl-5-(2-butyl-4-chloro-1H-imidazol-5yl)-2-pyrazolines and their in vitro antimicrobial evaluation. Eur J Med Chem 45:387–392

    Article  CAS  PubMed  Google Scholar 

  • Diamond MS (2009) Progress on the development of therapeutics against West Nile virus. Antiviral Res 83:214–227

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fioravanti R, Bolasco A, Manna F, Rossi F, Orallo F, Ortuso F, Alcaro S, Cirilli R (2010) Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors. Eur J Med Chem 45:6135–6138

    Article  CAS  PubMed  Google Scholar 

  • Foley P, Gerlach M, Youdim MB, Riederer P (2000) MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders? Parkinsonism Relat Disord 6:25–47

    Article  CAS  PubMed  Google Scholar 

  • Gareri P, Falconi U, De Fazio P, De Sarro G (2000) Conventional and new antidepressant drugs in the elderly. Prog Neurobiol 61:353–396

    Article  CAS  PubMed  Google Scholar 

  • Girisha KS, Kalluraya B, Narayana V (2010) Synthesis and pharmacological study of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazoline. Eur J Med Chem 45:4640–4644

    Article  CAS  PubMed  Google 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 (Weinheim) 336:362–371

    Article  Google Scholar 

  • Gokhan-Kelekci N, Yabanoglu S, Kupeli E, Salgin U, Ozgen O, Ucar G, Yesilada E, Kendi E, Yesilada A, Bilgin AA (2007) A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics. Bioorg Med Chem 15:5775–5786

    Article  PubMed  Google 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 17:675–689

    Article  PubMed  Google Scholar 

  • Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R (2009) Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem 44:1396–1404

    Article  CAS  PubMed  Google Scholar 

  • Husain K, Abid M, Azam A (2008) Novel Pd(II) complexes of 1-N-substituted 3-phenyl-2-pyrazoline derivatives and evaluation of antiamoebic activity. Eur J Med Chem 43:393–403

    Article  CAS  PubMed  Google Scholar 

  • Insuasty B, Garcia A, Quiroga J, Abonia R, Ortiz A, Nogueras M, Cobo J (2011) Efficient microwave-assisted synthesis and antitumor activity of novel 4,4′-methylenebis[2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols]. Eur J Med Chem 46:2436–2440

    Article  CAS  PubMed  Google 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 21:4296–4300

    Article  CAS  PubMed  Google Scholar 

  • Jayaprakash V, Sinha BN, Ucar G, Ercan A (2008) Pyrazoline-based mycobactin analogues as MAO-inhibitors. Bioorg Med Chem Lett 18:6362–6368

    Article  CAS  PubMed  Google Scholar 

  • Jayashree BS, Arora S, Venugopala KN (2008) Microwave assisted synthesis of substituted coumarinyl chalcones as reaction intermediates for biologically important coumarinyl heterocycles. Asian J Chem 20:1–7

    CAS  Google Scholar 

  • Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Altintop MD, Can OD (2010) New pyrazoline derivatives and their antidepressant activity. Eur J Med Chem 45:4383–4387

    Article  CAS  PubMed  Google 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 18:1875–1881

    Article  CAS  PubMed  Google Scholar 

  • Khode S, Maddi V, Aragade P, Palkar M, Ronad PK, Mamledesai S, Thippeswamy AH, Satyanarayana D (2009) Synthesis and pharmacological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents. Eur J Med Chem 44:1682–1688

    Article  CAS  PubMed  Google Scholar 

  • Lidstrom P, Tierney J, Wathey B, Westman J (2001) Microwave assisted organic synthesis—a review. Tetrahedron 57:9225–9283

    Article  CAS  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google 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 45:4490–4498

    Article  CAS  PubMed  Google Scholar 

  • Manna F, Chimenti F, Bolasco A, Bizzarri B, Befani O, Pietrangeli P, Mondovi B, Turini P (1998) Inhibitory effect of 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives on activity of amine oxidases. J Enzyme Inhib 13:207–216

    Article  CAS  PubMed  Google 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 12:3629–3633

    Article  CAS  PubMed  Google 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 63:1209–1216

    Article  CAS  PubMed  Google 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 21:1969–1973

    Article  CAS  PubMed  Google Scholar 

  • Mitoma J, Ito A (1992) Mitochondrial targeting signal of rat liver monoamine oxidase B is located at its carboxy terminus. J Biochem 111:20–24

    CAS  PubMed  Google Scholar 

  • Ozdemir A, Turan-Zitouni G, Kaplancikli ZA, Revial G, Guven K (2007) Synthesis and antimicrobial activity of 1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives. Eur J Med Chem 42:403–409

    Article  PubMed  Google 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 (Weinheim) 341:701–707

    Article  CAS  Google 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 36:539–543

    Article  CAS  PubMed  Google Scholar 

  • Parekh S, Bhavsar D, Savant M, Thakrar S, Bavishi A, Parmar M, Vala H, Radadiya A, Pandya N, Serly J, Molnar J, Shah A (2011) Synthesis of some novel benzofuran-2-yl(4,5-dihyro-3,5-substituted diphenylpyrazol-1-yl) methanones and studies on the antiproliferative effects and reversal of multidrug resistance of human MDR1-gene transfected mouse lymphoma cells in vitro. Eur J Med Chem 46:1942–1948

    Article  CAS  PubMed  Google 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 14:149–167

    Article  CAS  PubMed  Google Scholar 

  • Pletscher A (1991) The discovery of antidepressants: a winding path. Experientia 47:4–8

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD (1981) Antidepressants. In: Enna SJ, Malick JB, Richelson E (eds) Neurochemical, behavioural and clinical perspectives. Raven Press, New York, pp 129–139

    Google Scholar 

  • Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    CAS  PubMed  Google Scholar 

  • Rajendra Prasad Y, Lakshmana Rao A, Prasoona L, Murali K, Ravi Kumar P (2005) Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2″-hydroxy naphthalen-1″-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 15:5030–5034

    Article  CAS  PubMed  Google Scholar 

  • Ramajayam R, Tan KP, Liu HG, Liang PH (2010) Synthesis and evaluation of pyrazolone compounds as SARS-coronavirus 3C-like protease inhibitors. Bioorg Med Chem 18:7849–7854

    Article  CAS  PubMed  Google 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 55:431–436

    CAS  PubMed  Google 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 20:132–136

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui ZN, Musthafa TN, Ahmad A, Khan AU (2011) Thermal solvent-free synthesis of novel pyrazolyl chalcones and pyrazolines as potential antimicrobial agents. Bioorg Med Chem Lett 21:2860–2865

    Article  CAS  PubMed  Google Scholar 

  • Sivakumar PM, Prabhu Seenivasan S, Kumar V, Doble M (2010) Novel 1,3,5-triphenyl-2-pyrazolines as anti-infective agents. Bioorg Med Chem Lett 20:3169–3172

    Article  CAS  PubMed  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  CAS  PubMed  Google Scholar 

  • Stirrett KL, Ferreras JA, Jayaprakash V, Sinha BN, Ren T, Quadri LE (2008) Small molecules with structural similarities to siderophores as novel antimicrobials against Mycobacterium tuberculosis and Yersinia pestis. Bioorg Med Chem Lett 18:2662–2668

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thase ME (2012) The role of monoamine oxidase inhibitors in depression treatment guidelines. J Clin Psychiatry 73(Suppl 1):10–16

    Article  CAS  PubMed  Google Scholar 

  • Vogel HG (ed) (2002) Drug discovery and evaluation: pharmacological assays, 2nd edn. Springer, Berlin

    Google Scholar 

  • Volz HP, Gleiter CH (1998) Monoamine oxidase inhibitors. A perspective on their use in the elderly. Drugs Aging 13:341–355

    Article  CAS  PubMed  Google Scholar 

  • Wanare G, Aher R, Kawathekar N, Ranjan R, Kaushik NK, Sahal D (2010) Synthesis of novel alpha-pyranochalcones and pyrazoline derivatives as Plasmodium falciparum growth inhibitors. Bioorg Med Chem Lett 20:4675–4678

    Article  CAS  PubMed  Google Scholar 

  • Willner P, Mitchell PJ (2002) The validity of animal models of predisposition to depression. Behav Pharmacol 13:169–188

    Article  CAS  PubMed  Google Scholar 

  • Youdim MB, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309

    Article  CAS  PubMed  Google Scholar 

  • Zeller EA, Barsky J (1952) In vivo inhibition of liver and brain monoamine oxidase by 1-isonicotinyl-2-isopropyl hydrazine. Proc Soc Exp Biol Med 81:459–461

    Article  CAS  PubMed  Google Scholar 

  • Zhuang ZP, Marks B, McCauley RB (1992) The insertion of monoamine oxidase A into the outer membrane of rat liver mitochondria. J Biol Chem 267:591–596

    CAS  PubMed  Google Scholar 

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Acknowledgments

We express our sincere gratitude to Central Drugs Research Institute (CDRI), Lucknow, 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 (RPS), 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.

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  1. Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Babu Banarasi Das Northern India Institute of Technology, BBD City, Faizabad Road, Chinhat, Lucknow, UP, 226028, India

    Avinash C. Tripathi, Savita Upadhyay & Shailendra K. Saraf

  2. Department of Pharmacy, Banasthali Vidyapith, Banasthali, Tonk, Rajasthan, 304022, India

    Sarvesh Paliwal

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Tripathi, A.C., Upadhyay, S., Paliwal, S. et al. 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, 390–406 (2016). https://doi.org/10.1007/s00044-015-1489-3

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