MOLECULAR DOCKING, DESIGN, SYNTHESIS, IN VITRO ANTIOXIDANT AND ANTI-INFLAMMATORY EVALUATIONS OF NEW ISOQUINOLINE DERIVATIVES
Keywords:
Antioxidant, N-arylhomophthalimides, Anti-inflammation, (E)-4arylidne-2-(4 chlorophenyl) isoquinoline 1, 3-dione, Molecular DockingAbstract
Objectives: To design and synthesis N-substituted (E)-4-arylidene-isoquinoline-1,3-dione derivatives as anti-inflammatory and antioxidant drug moieties using molecular docking as a tool.
Methods: The structure of compounds (5a-h) was elucidated by means of FT-IR, GC-MS and NMR spectroscopy. Molecular docking was carried out to clarify the molecular aspects of the observed COX-inhibitory activities of the investigated compounds. DPPH radical scavenging analysis method was used to determine antioxidant activity and in-vitro anti-Inflammatory activity was conducted by Human Red Blood Cell (HRBC) membrane stabilization method utilizing Diclofenac sodium as standard.
Results: Isoquinoline (N-substituted (E)-4-arylidene-isoquinoline-1,3-dione) derivatives were achieved using oxalic acid as the catalyst, by aldol condensation of the corresponding aldehydes and the corresponding N-substituted homophthalimides with a maximum yield of 92%. Ligand efficiency (LE) consequences being a clear indication that the action potential of the compounds 5e (-0.72) and 5d (-0.64) is high when compare with the standard (-0.63) for COX-1. While for COX-2, compounds 5e (-0.81) 5d (-0.79) and 5h (-0.98) were shown a remarkable ligand efficiency than the standard (-0.65). Anti-inflammatory and antioxidant studies on the compounds 5h<5d<5g was found best activity results.
Conclusion: From our overall studies, it was understood that the activities of both in silico and in vitro anti-inflammatory results are coincide together. The p-values were significant for all the compounds 5(a-h) in both COX-1 and COX-2 activities which indicate that all the compounds have ‘competency' towards druggability for both anti-inflammatory and antioxidant, especially the compounds 5h<5d<5g<5e can be suggested for in vivo.
Â
Downloads
References
Wong CW, Seow WK, O’callaghan JW, Thong YH. Interrelation of chemical structure and pharmacological activity. Farmatsiya (Moscow) 1992;25:33-8.
Yasukawa K, Takido M, Ikekawa T, Shimada F, Takeuchi M, Nakagawa S. The relative inhibitory activity of berberine-type alkaloids against 12-o-tetradecanoylphorbol-13-acetate-induced inflammation in mice. Chem Pharm Bull 1991;39:1462-5.
Werbel LM, Angelo M, Frei DW, Worth DF. Basically substituted ellipticine analogs as potential antitumor agents. J Med Chem 1986;29:1321-2.
Ames BN, Shigenega MK, Hagen TM. Oxidants and the degenerative diseases of ageing. Proc Natl Acad Sci 1993;90:7915–22.
Shenoy R, Shirwaikar A. Anti-inflammatory and free radical scavenging studies of Hyptis suaveolens (Labiatae). Indian Drugs 2002;39:574–7.
Huang dJ, Ou BX, Prior rL. The chemistry behind antioxidant capacity assays: J Agric Food Chem 2005;53:1841-56.
Denko CW. A role of neuropeptides in inflammation. Whicher JT, Evans SW. Biochemistry of inflammation. Kluwer Pub. London; 1992.
Cotran RS, Kumar V, Collins T. Robbins pathological basis of disease. 6th ed. WB Saunder’s company; 2001.
Picot D, Loll PJ, Garavito RM. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 1994;367:243-9.
Xie WL, 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;88:2692-6.
Kujubu DA, Fletcher BS, Vamum BC, Lim RW, Herschman HR. TIS10:A phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991;266:12866-72.
Dannhardt G, Kiefer W. Cyclooxygenase inhibitors: current status and future prospects. Eur J Med Chem 2001;36:109-26.
Scott W. Rowlinson, James R Kiefer, Jeffery J Prusakiewicz, Jennifer L Pawlitz, Kevin R Kozak, et al. A novel mechanism of cyclooxygenase-2 inhibition involving interactions with ser-530 and tyr-385. J Biol Chem 2003;278:45763–9.
Morris GM, Goodsell DS, Huey R, Olson AJ. Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4. J Comput Aided Mol Des 1996;10:293–304.
Goodsell DS, Morris GM, Olson AJ. Automated docking of flexible ligands: applications of AutoDock. J Mol Recognit 1996;9:1–5.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. 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 W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785-91.
Ejebe DE, Siminialayi IM, Emudainowho JOT, Ofesi U, Morka L. Analgesic and anti-inflammatory activities of the ethanol extract of the leaves of Helianthus annus in wistar rats. Asian Pac J Trop Med 2010;3:341-7.
Gardeli C, Papageorgiou V, Mallouchos A, Kibouris T, Komaitis M. Essential oil composition of Pistacialentiscus L. and Myrtuscommunis L. Evaluation of antioxidant capacity of methanolic extracts. Food Chem 2008;107:1120–30.
Mensor LI, Menezes FS, Leitao GG, Reis AS, Dos Santos T, Coube CS, Leitao SG. Screening of brazilian plants extracts for antioxidant activity by the use of DPPH free radical method. Phytother Res 2001;15:127-30.
Volkamer A, Kuhn D, Rippmann F, Rarey M. DoG site scorer: a web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics 2012;28:2074–5.
N Jegham, Najeh Tka, Yakdhane Kacem, Be chir Ben Hassine. New N-substituted (E)-4-arylidene isoquinoline-1,3-dione derivatives: NMR spectroscopic investigation and antibacterial activity. Synth Commun 2012;42:3328–36.
Ida Musfiroh, Mursamsiar, Ahmad muhtadi, Rahmana E Kartasasmita, Daryono H Tjahjono, Slamet Ibrahim S. In silico study of asiatic acid interaction with inducible nitric oxide synthase (inos) and cyclooxygenase-2 (cox-2). Int J Pharm Pharm Sci 2013;5:204-7.
Tricarico C, Pinzani P, Bianchi S, Paglieriani M, Distante V, Pazzagli M, et al. Quantitative real-time reverse transcription polymerase chain reaction: normalization to rRNA or single housekeeping genes is inappropriate for human tissue biopsies. Anal Biochem 2002;309:293-300.
Hawkey C. COX-2 inhibitors. Lancet 1999;353:307-14.
Vane JR, Mitchell JA, Appleton I, Tomlinson A, Baiely DB, Croxtall J, et al. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A 1994:91:2046-50.
Soares JR, Dins TCP, Cunha AP, Almeida LM. Antioxidant activity of some extracts of Thymus zygis. Free Radical Res 1997;26:469-78.
Guha G, Rajkumar V, Ashok Kumar R, Mathew L. Aqueous extract of Phyllanthus amarus inhibits chromium (VI)-induced toxicity in MDA-MB-435S cells. Food Chem Toxicol 2010;48:396–401.
Ujwala W, Vijender S, Mohammad A. In-vitro antioxidant activity of isolated tannins of alcoholic extract of dried leaves of Phyllanthus amarus schonn and Thonn. Int J Drug Dev Res 2012;4:274-85.