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
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 words2-Pyrazoline Anxiolytic Antidepressant Locomotor and neuromuscular coordination studies Glide docking FST and TST
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.
- 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
- 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
- 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
- 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
- OECDGuidelines (2001) For testing of chemicals 423: acute oral toxicity—acute toxic class method 2001. Organization For Economic Corporation And Development, Paris, FranceGoogle 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
- 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