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
[1]
Arora, P.; Arora, V.; Lamba, H.S.; Wadhwa, D. Importance of heterocyclic chemistry: A review. Int. J. Pharma Sci., 2012, 3(9), 2947-2955.
[2]
Ravichandiran, V.; Sankaradoss, N. A systematic review on antidiabetic medicinal plants. Research. J. Pharmacogn. Phytochem., 2013, 5(3), 155-168.
[3]
Alam, M.; Zaman, M.S.; Alam, M.M.; Husain, A. Studies on 3,5-Disubstituted-phenyl-3,3a,4,7-tetrahydro-2H-pyrazolo[3,4-c]pyridazine derivatives. J. Pharm. Res., 2014, 8(11), 1586-1591.
[4]
Imran, M.; Asif, M. Biologically active pyridazines and pyridazinone derivatives: A scaffold for the highly functionalized compounds. Russ. J. Bioorganic Chem., 2020, 46(5), 726-744.
[http://dx.doi.org/10.1134/S1068162020050155]
[http://dx.doi.org/10.1134/S1068162020050155]
[5]
Kang, S.; Moon, H.K.; Yoon, Y.J.; Yoon, H.J. Recent progress in the chemistry of pyridazinones for functional group transformations. J. Org. Chem., 2018, 83(1), 1-11.
[http://dx.doi.org/10.1021/acs.joc.7b02481] [PMID: 29207874]
[http://dx.doi.org/10.1021/acs.joc.7b02481] [PMID: 29207874]
[6]
Elagamey, A.G.; Sattar, S.A.; El-Taweel, F.; Said, S. An Efficient synthesis and antibacterial activity of pyrido[2,3-d]pyrimidine, chromeno[3,4-c]pyridine, pyridine, pyrimido[2,3-c]pyridazine, enediamines, and pyridazine derivatives. J. Heterocycl. Chem., 2015, 53(6), 1801-1806.
[http://dx.doi.org/10.1002/jhet.2487]
[http://dx.doi.org/10.1002/jhet.2487]
[7]
Devika, N.; Ruso, J.S.; Mariyappan, M.; Sivakumar, N. Tandem synthesis and antibacterial studies of novel 3-substituted tetrahydrobenzo [4,5] thieno[1,2,4] triazolo [4,3-b] pyridazine and 2- (5-(substituted) -4h-1,2,4-triazole-3-yl) -tetrahydrobenzo [b] thiophene-3-carbonitirile derivatives. Int J Sci Technol Res, 2019, 8(8), 1808-1817.
[8]
Butnariu, R.M.; Mangalagiu, I.I. New pyridazine derivatives: Synthesis, chemistry and biological activity. Bioorg. Med. Chem., 2009, 17(7), 2823-2829.
[http://dx.doi.org/10.1016/j.bmc.2009.02.028] [PMID: 19272782]
[http://dx.doi.org/10.1016/j.bmc.2009.02.028] [PMID: 19272782]
[9]
Popovici, L.; Amarandi, R.M.; Mangalagiu, I.I.; Mangalagiu, V.; Danac, R. Synthesis, molecular modelling and anticancer evaluation of new pyrrolo[1,2-b]pyridazine and pyrrolo[2,1-a]phthalazine derivatives. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 230-243.
[http://dx.doi.org/10.1080/14756366.2018.1550085] [PMID: 30734610]
[http://dx.doi.org/10.1080/14756366.2018.1550085] [PMID: 30734610]
[10]
Islam, M.; Siddiqui, A.A.; Rajesh, R. Synthesis, antitubercular, antifungal and antibacterial activities of 6-substituted phenyl-2-(3′-substituted phenyl pyridazin-6′-yl)-2,3,4,5-tetrahydropyridazin-3-one. Acta Pol. Pharm., 2008, 65(3), 353-362.
[PMID: 18646555]
[PMID: 18646555]
[11]
Bindu, B.; Vijayalakshmi, S.; Manikandan, A. Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities. Eur. J. Med. Chem., 2020, 187, 111912.
[http://dx.doi.org/10.1016/j.ejmech.2019.111912] [PMID: 31812034]
[http://dx.doi.org/10.1016/j.ejmech.2019.111912] [PMID: 31812034]
[12]
Allam, H.A.; Kamel, A.A.; El-Daly, M.; George, R.F. Synthesis and vasodilator activity of some pyridazin-3(2H)-one based compounds. Future Med. Chem., 2020, 12(1), 37-50.
[13]
Mishra, R.; Siddiqui, A.A.; Husain, A.; Rashid, M.; Prakash, A.; Tailang, M.; Kumar, M.; Srivastava, N. Synthesis, characterization and antihypertensive activity of some new substituted pyridazine derivatives. J. Chil. Chem. Soc., 2011, 56(4), 856-859.
[14]
Guan, L.P.; Sui, X.; Deng, X.Q.; Quan, Y.C.; Quan, Z.S. Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine. Eur. J. Med. Chem., 2010, 45(5), 1746-1752.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.077] [PMID: 20116141]
[http://dx.doi.org/10.1016/j.ejmech.2009.12.077] [PMID: 20116141]
[15]
Saeed, M.M.; Khalil, N.A.; Ahmed, E.M.; Eissa, K.I. Synthesis and anti-inflammatory activity of novel pyridazine and pyridazinone derivatives as non-ulcerogenic agents. Arch. Pharm. Res., 2012, 35(12), 2077-2092.
[http://dx.doi.org/10.1007/s12272-012-1205-5] [PMID: 23263802]
[http://dx.doi.org/10.1007/s12272-012-1205-5] [PMID: 23263802]
[16]
Koneenk, V. Synthesis and insecticidal properties of some 2-substituted-3-oxo-4-halo-5(2H)-pyridazinyl phosphorus esters. Pestic. Sci., 1973, 4(6), 775-783.
[http://dx.doi.org/10.1002/ps.2780040603]
[http://dx.doi.org/10.1002/ps.2780040603]
[17]
Abubshait, S.A. An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity. Molecules, 2007, 12(1), 25-42.
[http://dx.doi.org/10.3390/12010025] [PMID: 17693951]
[http://dx.doi.org/10.3390/12010025] [PMID: 17693951]
[18]
Dilesh Indorkar, N.; Gautam, O.P.; Chourasia, S.N. Limaye. synthesis and characterization of cinnoline (Benzopyridazine) and cinnoline based pyrazoline derivatives and biological activity. AJRC, 2013, 6(9), 832-838.
[19]
Flefel, E.M.; Waled, A.; Tantawy, W.I.; Sofany, El.; Mahmoud, E.S.; Ahmed, A.; El-Sayed, D.N. Elshafy, Abd. Synthesis of some new pyridazine derivatives for anti-HAV evaluation. Molecules, 2017, 1(22), 1-15.
[20]
Abdelrazek, F.M.; Ahmed, A.F.; Akram, N.E. Novel synthesis of some new pyridazine and pyridazino[4,5-d]pyridazine derivatives. Syn. Comm, 2011, 41(8), 1119-1126.
[21]
Asif, M. Some recent approaches of biologically active substituted pyridazine and phthalazine drugs. Curr. Med. Chem., 2012, 19(18), 2984-2991.
[http://dx.doi.org/10.2174/092986712800672139] [PMID: 22519394]
[http://dx.doi.org/10.2174/092986712800672139] [PMID: 22519394]
[22]
Mirzoeva, S.; Sawkar, A.; Zasadzki, M.; Guo, L.; Velentza, A.V.; Dunlap, V.; Bourguignon, J.J.; Ramstrom, H.; Haiech, J.; Van Eldik, L.J.; Watterson, D.M.; Martin, W. Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J. Med. Chem., 2002, 45(3), 563-566.
[http://dx.doi.org/10.1021/jm015573g] [PMID: 11806708]
[http://dx.doi.org/10.1021/jm015573g] [PMID: 11806708]
[23]
Ike dela, Pena.; Cheong, Jae Hoon. On benzofuroindole analogues as smooth muscle relaxants. J. Biomed. Biotechnol., 2011, 6, 1-7.
[24]
Heinisch, G.; Frank, H. Pharmacologically active pyridazine derivatives. Part 1. Prog. Med. Chem., 1990, 27, 1-49.
[http://dx.doi.org/10.1016/S0079-6468(08)70288-1] [PMID: 2217822]
[http://dx.doi.org/10.1016/S0079-6468(08)70288-1] [PMID: 2217822]
[25]
Broadley, K.J.; Kelly, D.R. Muscarinic receptor agonists and antagonists. Molecules, 2001, 6(3), 142-193.
[http://dx.doi.org/10.3390/60300142]
[http://dx.doi.org/10.3390/60300142]
[26]
Sliwoski, G.; Kumar Kothiwale, S.; Meiler, J.; Edward, W. Lowe. Computational methods in drug discover. Pharmacol. Rev., 2013, 66(1), 334-395.
[http://dx.doi.org/10.1124/pr.112.007336] [PMID: 24381236]
[http://dx.doi.org/10.1124/pr.112.007336] [PMID: 24381236]
[27]
Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Computeraided Drug Des., 2011, 7(2), 146-157.
[http://dx.doi.org/10.2174/157340911795677602] [PMID: 21534921]
[http://dx.doi.org/10.2174/157340911795677602] [PMID: 21534921]
[28]
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with autodock: Theory and practice. Expert Opin. Drug Discov., 2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[29]
Vieira, L.M.C.; Fonseca, A.M.; Raposo, M.M.M.; Kirsch, G. Electrochemical and spectroscopic studies of pyridazine derivatives. Port. Electrochem. Acta, 2004, 22(1), 11-18.
[http://dx.doi.org/10.4152/pea.200401011]
[http://dx.doi.org/10.4152/pea.200401011]
[30]
Fan, M.; Yuqiang, S.; Yusen, Z.; Xianglin, Y.; Miao, L.; Liang, X.; Jiapei, W.; Yang, L.; Li, J. Pyridazine-Containing diazatwistanthracene and tetraazatwisttetracene: Synthesis, crystal structures and third order non-linear optical properties. ChemistrySelect, 2019, 4(9), 2810-2814.
[http://dx.doi.org/10.1002/slct.201804065]
[http://dx.doi.org/10.1002/slct.201804065]
[31]
Nandu, T.G.; Ananda, B.V.; Shiburaj, S. High-Throughput and In Silico screening in drug discovery. Bioresour. Bioprocess., 2017, 9(11), 246-273.
[32]
Madeswaran, A.; Muthuswamy, U.; Kuppusamy, A.; Thirumalaisamy, S.; Varadharajan, S.; Puliyath, J. Docking studies: In silico phosphodiesterase inhibitory activity of commercially available flavonoids. Bangladesh J. Pharmacol., 2012, 7(1), 70-75.
[http://dx.doi.org/10.3329/bjp.v7i1.10595]
[http://dx.doi.org/10.3329/bjp.v7i1.10595]
[33]
Ammal, P.R.; Prasad, A.R.; Joseph, A. Synthesis, characterization, in silico, and in vitro biological screening of coordination compounds with 1,2,4-triazine based biocompatible ligands and selected 3d-metal ions. Heliyon, 2020, 6(10)e05144
[http://dx.doi.org/10.1016/j.heliyon.2020.e05144] [PMID: 33083609]
[http://dx.doi.org/10.1016/j.heliyon.2020.e05144] [PMID: 33083609]
[34]
Ahmed, E.M.; Hassan, M.S.A.; El-Malah, A.A.; Kassab, A.E. New pyridazine derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents; design, synthesis and biological evaluation. Bioorg. Chem., 2020, 95, 103497.
[http://dx.doi.org/10.1016/j.bioorg.2019.103497] [PMID: 31838289]
[http://dx.doi.org/10.1016/j.bioorg.2019.103497] [PMID: 31838289]
[35]
Webb, R.C. Smooth muscle contraction and relaxation. Adv. Physiol. Educ., 2003, 27(1-4), 201-206.
[http://dx.doi.org/10.1152/advances.2003.27.4.201] [PMID: 14627618]
[http://dx.doi.org/10.1152/advances.2003.27.4.201] [PMID: 14627618]
[36]
Severina, H.I.; Georgiyants, V.A.; Kovalenko, S.M.; Avdeeva, N.V.; Yarcev, A.I.; Prohoda, S.N. Molecular docking studies of N-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives as potential modulators of glutamate receptors. Pharmacol. Res., 2020, 6(1), 69-82.
[37]
Shravani, S.P.; Sachin, H.R. Review on discovery studio: An important tool for molecular docking. Chem. Asian J., 2021, 14(1), 86-88.
[38]
Othman, M.M.I.; Abdel Haleem, M. Synthesis, characterization, and biological studies of some novel pyrazolecarboxamide, pyridazine and thienopyridazine derivatives. Syn. Comm, 2020, 27(4), 201-206.
[39]
Mogilski, S.; Kubacka, M.; Redzicka, A.; Kazek, G.; Dudek, M.; Malinka, W.; Filipek, B. Antinociceptive, anti-inflammatory and smooth muscle relaxant activities of the pyrrolo[3,4-d]pyridazinone derivatives: Possible mechanisms of action. Pharmacol. Biochem. Behav., 2015, 133, 99-110.
[http://dx.doi.org/10.1016/j.pbb.2015.03.019] [PMID: 25847619]
[http://dx.doi.org/10.1016/j.pbb.2015.03.019] [PMID: 25847619]
[40]
Sharma, B.; Verma, A.; Sharma, K.U.; Prajapati, S. Efficient synthesis, anticonvulsant and muscle relaxant activities of new 2-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives. Med. Chem. Res., 2014, 23(1), 1-12.
[http://dx.doi.org/10.1007/s00044-013-0618-0]
[http://dx.doi.org/10.1007/s00044-013-0618-0]
[41]
Hou, V.Y.; Hirshman, C.A.; Emala, C.W. Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors. Anesthesiology, 1998, 88(3), 744-750.
[http://dx.doi.org/10.1097/00000542-199803000-00026] [PMID: 9523819]
[http://dx.doi.org/10.1097/00000542-199803000-00026] [PMID: 9523819]
[42]
Okanlami, O.A.; Fryer, A.D.; Hirshman, C. Interaction of nondepolarizing muscle relaxants with M2 and M3 muscarinic receptors in guinea pig lung and heart. Anesthesiology, 1996, 84(1), 155-161.
[http://dx.doi.org/10.1097/00000542-199601000-00018] [PMID: 8572329]
[http://dx.doi.org/10.1097/00000542-199601000-00018] [PMID: 8572329]
[43]
Bender, A.M.; Weiner, R.L.; Luscombe, V.B.; Ajmera, S.; Cho, H.P.; Chang, S.; Zhan, X.; Rodriguez, A.L.; Niswender, C.M.; Engers, D.W.; Bridges, T.M.; Conn, P.J.; Lindsley, C.W. Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists. Bioorg. Med. Chem. Lett., 2017, 27(15), 3576-3581.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.042] [PMID: 28633897]
[http://dx.doi.org/10.1016/j.bmcl.2017.05.042] [PMID: 28633897]
Article Metrics
1