Towards development of selective and reversible pyrazoline based MAO-inhibitors: Synthesis, biological evaluation and docking studies Anasuya Sahoo a , Samiye Yabanoglu b , Barij N. Sinha a , Gulberk Ucar b , Arijit Basu a , Venkatesan Jayaprakash a, * a Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835 215, India b Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhıye, Ankara, Turkey article info Article history: Received 2 September 2009 Revised 3 November 2009 Accepted 6 November 2009 Available online 12 November 2009 Keywords: Pyrazolines MAO-inhibitors Docking abstract Ten novel 3,5-diaryl pyrazolines were synthesized and investigated for their monoamine oxidase (MAO) inhibitory property. All the molecules were found to be reversible and selective inhibitor for either one of the isoform (MAO-A or MAO-B). Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidases (MAO-A or MAO-B) have been developed through docking studies. The theoretical values are in congruence with their experimental values. Ó 2009 Elsevier Ltd. All rights reserved. Monoamine oxidase inhibitors (MAOIs) have shown therapeutic value in variety diseases especially neurodegenerative diseases. 1 Earlier, MAO-inhibitors introduced into clinical practice were abandoned due to adverse side-effects, such as hepatotoxicity, orthostatic hypertension and the so called ‘cheese effect’ character- ized by hypertensive crises. 2 These side-effects were hypothesized to be related to nonselective and irreversible monoamine oxidase inhibition. Ability of new generations of inhibitors to selectively in- hibit two isoforms (MAO-A and MAO-B) led to a renewed interest in the therapeutic potential of these compounds. These two forms of MAO are characterized by their different sensitivities to inhibi- tors and their different specificities to substrates. 3 MAO-A prefera- bly metabolizes serotonin, adrenaline, and noradrenaline, 4 whereas b-phenylethylamine and benzylamine are predominantly metabolized by MAO-B. 5 Tyramine, dopamine, and some other important amines are common substrates for both the isoen- zymes. 6 Nowadays, the therapeutic interest of MAOIs falls into two major categories. MAO-A inhibitors have been used mostly in the treatment of mental disorders, in particular depression and anxiety, 7–9 while MAO-B inhibitors could be used in the treat- ment of Parkinson’s disease and Alzheimer’s disease. 10,11 Efforts have been oriented toward the discovery of reversible and selec- tive inhibitors of MAO-A/MAO-B leading to a new generation of compounds. The classical period of the MAO-inhibitors started with hydra- zine derivatives. Originally proposed as a tuberculostatic agent, their prototype, iproniazid, was the first modern anti-depressant. 2-Pyrazolines can be considered as a cyclic hydrazine moiety. Pyr- azolines were reported to have MAO inhibitory and anti-depres- sant activity. 12–30 Our group has earlier reported thirty two new 3,5-diaryl carbothioamide pyrazolines with MAO inhibitory activ- ity. 31,32 In an effort to develop selective inhibitors of MAO, ten no- vel analogues were synthesized and screened MAO inhibitory activity. Structure based docking was performed in order to gain more insight towards their binding mode. The compounds were synthesized as reported earlier. 31,32 The synthetic route has been outlined in Scheme 1. Hydroxy chalcones 1 and 2 were prepared through Claisen–Schmidt condensation of 2-hydroxy acetophenone with either 2-hydroxy benzaldehyde or 4-hydroxy benzaldehyde. Compounds 3 and 4 were synthesized by the reaction of hydrazine hydrate with 1 and 2, respectively in ethanol. Reaction of benzoyl chloride with compounds 3 and 4 in pyridine provided compounds 5 and 6, respectively. Reaction of benzene sulfonyl chloride and p-toluene sulphonyl chloride with compound 3 and 4 in tetrahydrofuran provided compounds 7–10. Reaction of thiosemicarbazide with 1 and 2 in ethanol and 2 M equivalent of sodium hydroxide provided compounds 11 and 12, respectively. Compounds 11 and 12 upon treatment with methyl iodide and then with hydroxylamine in methanol provided com- pounds 13 and 14, respectively. Structures, physico-chemical and spectral characterization of the synthesized compounds are given in Supplementary data. 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.11.015 * Corresponding author. Tel.: +91 6512276247. E-mail address: venkatesanj@bitmesra.ac.in (V. Jayaprakash). Bioorganic & Medicinal Chemistry Letters 20 (2010) 132–136 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl