Pyrazoline carboxylates as selective MAO-B inhibitors: Synthesis and Biological screening

Vishnu Nayak Badavath, Alok Kumar Singh, Surender Singh Jadav, Nibha Mishra, Abhimanyu Dev, Barij Nayan Sinha, Venkatesan Jayaprakash


A series of carboxylates of pyrazolines (3a-3h) were synthesized from ethyl 2-benzylidene-3-oxobutanoate esters using hydrazine hydrate and ethanol as solvent. All the compounds (3a-3h) screened for their MAO inhibitory activity using rat brain MAO. All the compounds were found to be selective, reversible and competitive inhibitors of MAO-B except compound 3d and 3h which was found to be non-selective. These compounds were found to be active against MAO-B at concentration close to 1 ?M (3e = 0.99 ?M, 3a = 0.92 ?M and 3b = 1.11?M). Compound 3a was potent amongst these while 3b was more selective towards MAO-B with selectivity index 2.88.


Pyrazoline; Rat liver enzyme; MAO isoform; Selectivity; Inhibitors; Rat liver enzyme; MAO isoform; Selectivity; Inhibitors

Full Text:



Tipton, K. F.; Boyce, S.; O'Sullivan, J.; Davey, G. P.; Healy, J., Monoamine oxidases: certainties and uncertainties. Curr Med Chem 2004, 11, 1965-1982.

Slotkin, T. A., Mary Bernheim and the discovery of monoamine oxidase. Brain Res bull 1999, 50, 373.

Hare, M. L. C., Tyramine oxidase: A new enzyme system in liver. Biochem J 1928, 22, 968.

Bach, A.; Lan, N. C.; Johnson, D. L.; Abell, C. W.; Bembenek, M. E.; Kwan, S.-W.; Seeburg, P. H.; Shih, J. C., cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci 1988, 85, 4934-4938.

Collins, G.; Sandler, M.; Williams, E.; Youdim, M., Multiple forms of human brain mitochondrial monoamine oxidase. Nature 1970, 225, 817-820.

Youdim, M.; Collins, G.; Sandler, M.; Jones, A. B.; Pare, C.; Nicholson, W., Biological Sciences: Human brain monoamine oxidase: Multiple forms and selective inhibitors. Nature 1972, 236, 225-228.

Johnston, J., Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 1968, 17, 1285-1297.

Knoll, J.; Magyar, K., Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 1971, 5, 393-408.

Kalgutkar, A. S.; Castagnoli, N.; Testa, B., Selective inhibitors of monoamine oxidase (MAO?A and MAO?B) as probes of its catalytic site and mechanism. Med Res Rev 1995, 15, 325-388.

Pacher, P.; Kohegyi, E.; Kecskemeti, V.; Furst, S., Current trends in the development of new antidepressants. Curr Med Chem 2001, 8, 89-100.

Pacher, P.; Kecskemeti, V., Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem 2004, 11, 925.

Carreiras, M.; Marco, J., Recent approaches to novel anti-Alzheimer therapy. Curr Pharm Design 2004, 10, 3167-3176.

Chimenti, F.; Bolasco, A.; Manna, F.; Secci, D.; Chimenti, P.; Befani, O.; Turini, P.; Giovannini, V.; Mondov, B.; Cirilli, R., Synthesis and selective inhibitory activity of 1-acetyl-3, 5-diphenyl-4, 5-dihydro-(1 H)-pyrazole derivatives against monoamine oxidase. J Med Chem 2004, 47, 2071-2074.

Chimenti, F.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; Befani, O.; Turini, P.; Alcaro, S.; Ortuso, F., Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3, 5-diaryl-4, 5-dihydro-(1 H)-pyrazole derivatives. J Med Chem 2005, 48, 7113-7122.

Secci, D.; Bolasco, A.; Chimenti, P.; Carradori, S., The state of the art of pyrazole derivatives as monoamine oxidase inhibitors and antidepressant/anticonvulsant agents. Curr Med Chem 2011, 18, 5114-5144.

Khalil, N. A.; Ahmed, E. M.; El-Nassan, H. B.; Ahmed, O. K.; Al-Abd, A. M., Synthesis and biological evaluation of novel pyrazoline derivatives as anti-inflammatory and antioxidant agents. Arch Pharm Res 2012, 35, 995-1002.

Azarifar, D.; Shaebanzadeh, M., Synthesis and characterization of new 3, 5-dinaphthyl substituted 2-pyrazolines and study of their antimicrobial activity. Molecules 2002, 7, 885-895.

Ali, M. A.; Yar, M. S.; Kumar, M.; Pandian, G. S., Synthesis and antitubercular activity of substituted novel pyrazoline derivatives. Nat Prod Res 2007, 21, 575-579.

Puig-Basagoiti, F.; Tilgner, M.; Forshey, B. M.; Philpott, S. M.; Espina, N. G.; Wentworth, D. E.; Goebel, S. J.; Masters, P. S.; Falgout, B.; Ren, P., Triaryl pyrazoline compound inhibits flavivirus RNA replication. Antimicrob Agents Chemother 2006, 50, 1320-1329.

Kawazura, H.; Takahashi, Y.; Shiga, Y.; Shimada, F.; Ohto, N.; Tamura, A., Cerebroprotective effects of a novel pyrazoline derivative, MS-153, on focal ischemia in rats. Jpn J Pharmacol 1997, 73, 317-324.

Amir, M.; Kumar, H.; Khan, S. A., Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents. Bioorg Med Chem Lett 2008, 18, 918-922.

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

Stirrett, K. L.; Ferreras, J. A.; Jayaprakash, V.; Sinha, B. N.; Ren, T.; Quadri, L. E., Small molecules with structural similarities to siderophores as novel antimicrobials against Mycobacterium tuberculosis and Yersinia pestis. Bioorg Med Chem Lett 2008, 18, 2662-2668.

zdemir, Z.; Kandilci, H. B.; Gm?el, B.; al??, .; Bilgin, A. A., Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med Chem 2007, 42, 373-379.

Marella, A.; Ali, R.; Alam, T.; Saha, R.; Tanwar, O.; Akhter, M.; Shaquiquzzaman, M.; Mumtaz Alam, M., Pyrazolines: a biological review. Mini Rev Med Chem 2013, 13, 921-931.

Jayaprakash, V.; Sinha, B. N.; Ucar, G.; Ercan, A., Pyrazoline-based mycobactin analogues as MAO-inhibitors. Bioorg Med Chem Lett 2008, 18, 6362-6368.

Karuppasamy, M.; Mahapatra, M.; Yabanoglu, S.; Ucar, G.; Sinha, B. N.; Basu, A.; Mishra, N.; Sharon, A.; Kulandaivelu, U.; Jayaprakash, V., Development of selective and reversible pyrazoline based MAO-A inhibitors: Synthesis, biological evaluation and docking studies. Bioorg Med Chem 2010, 18, 1875-1881.

Sahoo, A.; Yabanoglu, S.; Sinha, B. N.; Ucar, G.; Basu, A.; Jayaprakash, V., Towards development of selective and reversible pyrazoline based MAO-inhibitors: Synthesis, biological evaluation and docking studies. Bioorg Med Chem Lett 2010, 20, 132-136.

Mishra, N.; Sasmal, D., Development of selective and reversible pyrazoline based MAO-B inhibitors: virtual screening, synthesis and biological evaluation. Bioorg Med Chem Lett 2011, 21, 1969-1973.

Vishnu Nayak, B.; Ciftci-Yabanoglu, S.; Jadav, S. S.; Jagrat, M.; Sinha, B. N.; Ucar, G.; Jayaprakash, V., Monoamine oxidase inhibitory activity of 3, 5-biaryl-4, 5-dihydro-1H-pyrazole-1-carboxylate derivatives. Eur J of Med Chem 2013, 69, 762-767.

Sicker, D.; Rabe, A.; Zakrzewski, A.; Mann, G., Synthesis Of Substituted N-Hydroxylactams, Lactams, Quinoline-N-Oxides, And Quinolines By Catalyzed Reductive Cyclization Of 2-Nitrocinnamoyl Derivatives With Hydrogen Platinum Black. J Prak Chem 1987, 329, 1063-1070.

Matharu, B.; Sharma, J.; Manrao, M., Synthesis and antifungal potential of 2-chlorobenzal derivatives. Pestic Res J 2006, 18, 113-115.

Elkasaby, M., Michael Condensation Of Ethyl Alpha-Acetylcinnamates With Diethyl Malonate, Deoxybenzoin, Ethyl Phenylacetate, Benzyl Cyanide And Malononitrile. Indian J Chem 1976, B14, 739-741.

Zuo, B.; Wang, Q.; Wang, Y.; Ma, Y., Knoevenagel condensation over acidic zeolite. Chinese J Catal 2002, 23, 555-558.

Poindexter, G. S. 1,4-Dihydropyridine-3,5-dicarboxylates incorporating an alkyleneaminoalkylene-heteroatom moiety, procedure for their preparation, pharmaceutical compositions containing them, and their use as cardiovascular agents. EP247345A2, 1987.

Holt, A.; Sharman, D. F.; Baker, G. B.; Palcic, M. M., A continuous spectrophotometric assay for monoamine oxidase and related enzymes in tissue homogenates. Anal Biochem 1997, 244, 384-392.

Stanchev, S.; Momekov, G.; Jensen, F.; Manolov, I., Synthesis, computational study and cytotoxic activity of new 4-hydroxycoumarin derivatives. Eur J Med Chem 2008, 43, 694-706.

El-Kasaby, M. A.; Salim, M. A. I., Some reactions with ethyl ?-acetylcinnamates. Egypt J Chem 1981, 23, 323-36.

De Colibus, L.; Li, M.; Binda, C.; Lustig, A.; Edmondson, D. E.; Mattevi, A., Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc Natl Acad Sci 2005, 102, 12684-12689.




  • There are currently no refbacks.

Copyright (c)

                              VENSEL PUBLICATIONS@2019

 20, Keelavaithianathapuram, 4th Street, Madurai-625 018 (TN), India