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Letters in Drug Design & Discovery

Author(s): Aamir Malik, Rakhi Mishra*, Rupa Mazumder, Avijit Mazumder and Ketki Garg

DOI: 10.2174/1570180819666220429154430

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In Silico and In Vitro Screening of Novel Pyridazine Analogs as Muscle Relaxant Agent on Acetylcholine Muscarinic Receptor

Page: [628 - 638] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Among Nitrogen-containing heterocyclic compounds, pyridazine derivatives serve as a necessary scaffold as they possess various pharmacological activities. Thus, in recent times, the design of novel synthetic schemes and the selection of a new target for the action of pyridazine derivatives have attracted the attention of researchers.

Objective: This study has focused on synthesizing and evaluating the muscle relaxant activity of pyridazine analogs by in-silico screening and rotarod test.

Methods: In the present work, pyridazine derivatives were synthesized from substituted pyridine and maleic anhydride yielding intermediates (1a-5a), which on reaction with hydrazine, yielded final pyridazine derivatives (1b-5b). They were then screened for muscle relaxant action by an in-silico docking study against muscarinic acetylcholine receptors with protein data bank ID: 5CXV with the use of Autodock 4.2 and Biovia discovery studio tools. Compounds were further tested for muscle relaxant activity by the rotarod test.

Results: Synthesis of the designed compounds was carried out successfully. Obtained result showed that the final compounds (1b-5b) showed 1-3 interactions with acetylcholine muscarinic receptor with -7.2 to -7.9 Kcal/mole affinities. The findings were compared to the typical drug diazepam, which has one interaction with the target and binding energy of -7.7 Kcal/mole. Moreover, the result of the rotarod test showed that substitution by electron-withdrawing groups causes more muscle relaxant activity when compared with the electron releasing groups.

Conclusion: The results of the experimental study showed that pyridazine derivatives could serve as a promising template for the further design and development of muscle relaxant agents.

Keywords: Pyridazine, acetylcholine, muscarinic receptor, autodock, In silico screening, muscle relaxant action, rotarod apparatus.

Graphical Abstract

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