DESIGN, SYNTHESIS AND BIOLOGICAL SCREENING OF AMINOACETYLENIC TETRAHYDROPHTHALIMIDE ANALOGUES AS NOVEL CYCLOOXYGENASE (COX) INHIBITORS
Keywords:Aminoacetylenic, Tetrahydrophthalimide, Molecular modelling, Cyclooxygenase inhibitors, Anti-inflammatory
Objective: To design and synthesise a new amino acetylenic tetrahydro phthalimide derivative and investigate their selective inhibitory activity to COXs.
Methods: Aminoacetylenic tetrahydro phthalimide derivatives were synthesised by alkylation of tetrahydro phthalimide with propargyl bromide afforded 2-(prop-2-yn-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione. The alkylated tetrahydro phthalimide was subjected to Mannich reaction afforded the desired amino acetylenic tetra phthalimide derivatives (AZ 1-6). The elemental analysis was indicated by the EuroEA elemental analyzer and biological characterization was via IR, 1H-NMR, C-NMR, DSC was determined with the aid of Bruker FT-IR and Varian 300 MHz spectrometer and DMSO-d6 as a solvent, molecular docking was done using the Autodock Tool software (version 4.2). ChemBioDraw was used in the drawing of our schemes.
Results: The IR, 1H-NMR, 13C-NMR, DSC and elemental analysis were consistent with the assigned structures. The designers of the compounds as COXs inhibitor activity were based on the nationalisation of the important criteria that provide effective inhibitory binding with COXsâ€“receptor. The results indicated that the synthesised compounds (AZ1-6) showed a close similarity in the binding affinity to both COXs and may be more specific to COX-1. AZ-5 showed the highest % of inhibition for COX-1 even better than aspirin. Which may suggest that the aryl group is required for COX-2 inhibition.
Conclusion: For the first time, we indicate the requirement of aromaticity in COX-2 structural inhibitory activity.Â
Bhati SK, Kumar AS. Synthesis of new substituted azetidinyol and thiazolidinoyl-1,3,4-thiadiazino(6,5-b) indoles as promising anti-inflammatory agents. Eur J Med Chem 2008;43:2323â€“30.
Lombardino G. Non-Steroidal Antiinflammatory drugs. 1st ed. John Wiley and Sons, New York; 1985.
Dannhardi G, Kiefer W. Cyclooxygenase inhibitorsâ€“current status and future prospects. Eur J Med Chem 2001;36:109â€“26.
Carter JS. Inhibition of cyclooxygenase-2. Expert Opin Ther Pat 2000;10:1011â€“20.
Farooqui M, Bora R, Patil CR. Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles. Eur J Med Chem 2009;44:794â€“9.
Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991;88:2692â€“6.
Ranatunge RR, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, et al. Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles. Bioorg Med Chem 2004;12:1357â€“66.
Orjales A, Mosquera R, Lopez B, Olivera R, Labeaga L, Nunez MT. Novel 2-(4-methylsulfonylphenyl) pyrimidine derivatives as highly potent and speciï¬c COX-2 inhibitors. Bioorg Med Chem 2008;16:2183â€“99.
Reddy MV, Billa VK, Pallela VR, Mallireddigar MR, Boominathan R, Gabriel JL, et al. Design, synthesis and biological evaluation of 1-(4-sulfamylphenyl)-3-triï¬‚uoromethyl-5-indolylpyrazolines as cyclo-oxygenase-2 (COX2) and lipoxygenase (LOX) inhibitors. Bioorg Med Chem 2008;16:3907â€“16.
Al-Qaisi JA, Alhussain TM, Qinna NA, Matalka KZ, Al-Kaissi EN, Muhi-eldeen ZA. Synthesis and pharmacological evaluation of amino acetylenic isoindoline-1,3-dione derivatives as anti-inflammatory agents. Arab J Chem 2014;7:1024â€“30.
Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, et al. Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen. J Biol Chem 2010;285:34950-9.
RCSB Protein Data Bank. Available from: http://www.pdb.org/. [Last accessed on 02 Sep 2016]
Sidhu RS, Lee JY, Yuan C, Smith WL. Comparison of cyclooxygenase-1 crystal structures; cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry 2010;49:7069-79.
Devi SK, Velmurugan D. Molecular modelling, Quantitative structure-activity relationship and pharmacophore studies on antiviral, anti-malarial and anti-inflammatory bioactive compounds from marine sources. Asian J Pharm Clin Res 2015;8:36-43.
Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model 1999;17:57-61.
Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G. A new force field for the molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 1984;106:765-84.
Jayaprakash R, Saroj Kumar SHA, Hemalatha S, Easwaramoorthy D. Synthesis, characterization, quantitative structure-activity relationship, docking, antibacterial activity, and brine shrimp lethal, studies on L-phenylalanine Schiff bases. Asian J Pharm Clin Res 2016;9:1-6.
Morris GM, Goodsell DS, Holliday RS, Huey R, Hart WE, Belew RK. Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 1998;19:1639-62.
Morris GM, Huey R, Lindstrom WF, Sanner MF, Belew RK, Goodsell DS. AutoDock4 and AutoDockTool4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785-91.
Maestro, version 9.2, SchrÓ§dinger, LLC, New York, NY; 2011.
Jorgensen WL, Tirado-Rives J. The OPLS (optimised potentials for liquid simulations) potential functions for proteins, energy minimization for crystals of cyclic peptides and crambin. J Am Chem Soc 1988;110:1657-66.
Gasteiger J, Marssili M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charge. Tetrahedron 1980;36:3219-28.
Muthukala B, Sivakumari K, Ashok K, In silico docking of quercetin compound against the Hela cell line protein. Int J Chem Pharm Res 2015;7:13-6.