Derivatives of 4,5-dihydro (1H) pyrazoles as possible MAO-A inhibitors in depression and anxiety disorders: synthesis, biological evaluation and molecular modeling studies
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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.
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Conflict of interest
The authors declare that they have no conflict of interest.
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