Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Computational Study of Some New 1-(1H-indol-1- yl)ethanone Derivatives on COX-2 Enzyme and Evaluation of In-Vivo Analgesic and Anti-inflammatory Activity

Author(s): Arvind Kumar*, Deepika Kumar, Mayur Porwal and Arun Kumar Mishra

Volume 20, Issue 10, 2023

Published on: 30 September, 2022

Page: [1569 - 1584] Pages: 16

DOI: 10.2174/1570180819666220822111826

Price: $65

Abstract

Background: Indole and its derivatives play an important role in the synthesis of commercially relevant intermediate molecules required for the synthesis of a wide range of bioactive molecules.

Aim: Exploration of the synthesis of novel nonsteroidal anti-inflammatory drugs, as well as their computational studies and pharmacological effects, was aimed as an important component of the present research.

Objective: The objective of the present work was to synthesize some novel 1-(1H-indol-1-yl)ethanone compounds, analyze their computational effects on the COX-2 enzyme and test their in vivo analgesic and anti-inflammatory activity.

Methods: The condensation of 4-(2-(1H-indol-1-yl)-2-oxoethoxy) benzaldehyde with substituted aniline in ethanol in the presence of a catalytic quantity of glacial acetic acid was performed, which yielded the new Indole derivatives. IR, NMR, mass spectroscopy and elemental analysis techniques were used to characterize the structures of new indole derivatives.

To estimate the drug-like candidate’s nature, a number of molecular attributes of these derivatives were computed. The synthesized derivatives were docked with a specific reference cyclooxygenase-2 (COX-2) enzyme. The physical similarity of the newly synthesized derivatives (D1-D8) and indomethacin (the reference drug) was determined by evaluating seven physicochemical features by a software.

Results: Although the bioavailability/drug likeness was found to be in the standard range, the synthesized compounds exhibited close similarity with those of the reference drug, and subsequent optimization was necessary.

Conclusion: The newly synthesized indole derivatives as COX-2 inhibitors were evaluated for their biological properties, which included anti-inflammatory and analgesic efficacy.

Other: D-7 (1-(1H-indol-1-yl)-2-(4-((4-nitrophenyl)imino)methyl)phenoxy)ethanone) was found to have the strongest anti-inflammatory and analgesic activity amongst the eight target compounds.

Keywords: Indole, molecular docking, analgesic activity, anti-inflammatory activity, COX-2 inhibitors, celecoxib.

« Previous Next »
Graphical Abstract

[1]
Gouda, A.; Ali, H.; Almalki, W.; Azim, M.; Abourehab, M.; Abdelazeem, A. Design, synthesis, and biological evaluation of some novel pyrrolizine derivatives as COX inhibitors with anti-inflammatory/analgesic activities and low ulcerogenic liability. Molecules, 2016, 21(2), 201.
[http://dx.doi.org/10.3390/molecules21020201] [PMID: 26867188]
[2]
Yeomans, N.D.; Hawkey, C.J.; Brailsford, W.; Næsdal, J. Gastroduodenal toxicity of low-dose acetylsalicylic acid: A comparison with non-steroidal anti-inflammatory drugs. Curr. Med. Res. Opin., 2009, 25(11), 2785-2793.
[http://dx.doi.org/10.1185/03007990903212682] [PMID: 19788350]
[3]
Abdellatif, K.R.A.; Elsaady, M.T.; Amin, N.H.; Hefny, A.A. Design, synthesis and biological evaluation of some novel indole derivatives as selective COX-2 inhibitors. J. Appl. Pharm. Sci., 2017, 7, 69-77.
[4]
Dogné, J.M.; Supuran, C.T.; Pratico, D. Adverse cardiovascular effects of the coxibs. J. Med. Chem., 2005, 48(7), 2251-2257.
[http://dx.doi.org/10.1021/jm0402059] [PMID: 15801815]
[5]
Redasani, V.K.; Bari, S.B. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur. J. Med. Chem., 2012, 56, 134-138.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.030] [PMID: 22982120]
[6]
Giuliano, F.; Warner, T.D. Ex vivo assay to determine the cyclooxygenase selectivity of non-steroidal anti-inflammatory drugs. Br. J. Pharmacol., 1999, 126(8), 1824-1830.
[http://dx.doi.org/10.1038/sj.bjp.0702518] [PMID: 10372826]
[7]
Warner, T.D.; Giuliano, F.; Vojnovic, I.; Bukasa, A.; Mitchell, J.A.; Vane, J.R. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc. Natl. Acad. Sci. USA, 1999, 96(13), 7563-7568.
[http://dx.doi.org/10.1073/pnas.96.13.7563] [PMID: 10377455]
[8]
Blobaum, A.L.; Uddin, M.J.; Felts, A.S.; Crews, B.C.; Rouzer, C.A.; Marnett, L.J. The 2′-trifluoromethyl analogue of indomethacin is a potent and selective COX-2 inhibitor. ACS Med. Chem. Lett., 2013, 4(5), 486-490.
[http://dx.doi.org/10.1021/ml400066a] [PMID: 23687559]
[9]
El-Sayed, W.A.; Abdel Megeid, R.E.; Abbas, H.A.S. Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs. Arch. Pharm. Res., 2011, 34(7), 1085-1096.
[http://dx.doi.org/10.1007/s12272-011-0706-y] [PMID: 21811915]
[10]
Radwan, M.A.A.; Ragab, E.A.; Sabry, N.M.; El-Shenawy, S.M. Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents. Bioorg. Med. Chem., 2007, 15(11), 3832-3841.
[http://dx.doi.org/10.1016/j.bmc.2007.03.024] [PMID: 17395469]
[11]
Priyanka, B.; Pogula, M.; Suresh, S.; Sammaiah, G. Synthesis and characterization of new indole derivatives for analgesic activity. Int. J. Pharm. Pharm. Sci., 2012, 4, 231-233.
[12]
Sidhu, J.S.; Singla, R. Mayank; Jaitak, V. Indole derivatives as anticancer agents for breast cancer therapy: A review. Anticancer. Agents Med. Chem., 2015, 16(2), 160-173.
[http://dx.doi.org/10.2174/1871520615666150520144217] [PMID: 25991424]
[13]
Velezheva, V.; Brennan, P.; Ivanov, P.; Kornienko, A.; Lyubimov, S.; Kazarian, K.; Nikonenko, B.; Majorov, K.; Apt, A. Synthesis and antituberculosis activity of indole–pyridine derived hydrazides, hydrazide–hydrazones, and thiosemicarbazones. Bioorg. Med. Chem. Lett., 2016, 26(3), 978-985.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.049] [PMID: 26725953]
[14]
Grasso, S.; Molica, C.; Monforte, A.M.; Monforte, P.; Zappalà, M.; Monforte, M.T.; Trovato, A. Synthesis and antihypertensive activity evaluation of indole derivatives N-acetamido substituted. Farmaco, 1995, 50(2), 113-117.
[PMID: 7766275]
[15]
Xu, Q.; Huang, L.; Liu, J.; Ma, L.; Chen, T.; Chen, J.; Peng, F.; Cao, D.; Yang, Z.; Qiu, N.; Qiu, J.; Wang, G.; Liang, X.; Peng, A.; Xiang, M.; Wei, Y.; Chen, L. Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes. Eur. J. Med. Chem., 2012, 52, 70-81.
[http://dx.doi.org/10.1016/j.ejmech.2012.03.006] [PMID: 22483089]
[16]
Stanton, J.L.; Ackerman, M.H. Synthesis and anticonvulsant activity of some tetracyclic indole derivatives. J. Med. Chem., 1983, 26(7), 986-989.
[http://dx.doi.org/10.1021/jm00361a010] [PMID: 6864737]
[17]
Giampieri, M.; Balbi, A.; Mazzei, M.; La Colla, P.; Ibba, C.; Loddo, R. Antiviral activity of indole derivatives. Antiviral Res., 2009, 83(2), 179-185.
[http://dx.doi.org/10.1016/j.antiviral.2009.05.001] [PMID: 19445965]
[18]
Davyt, D.; Entz, W.; Fernandez, R.; Mariezcurrena, R.; Mombrú, A.W.; Saldaña, J.; Domínguez, L.; Coll, J.; Manta, E. A new indole derivative from the red alga Chondria atropurpurea. Isolation, structure determination, and anthelmintic activity. J. Nat. Prod., 1998, 61(12), 1560-1563.
[http://dx.doi.org/10.1021/np980114c] [PMID: 9868166]
[19]
Mutschler, E.; Winkler, W. Synthesis of 1-,2-, and 3-(aminoacetyl) indoles and 1-(aminoacetyl)indolines (author’s transl). Arch. Pharm. (Weinheim), 1978, 311(3), 248-255.
[http://dx.doi.org/10.1002/ardp.19783110311] [PMID: 655792]
[20]
Karlgren, M.; Bergstrom, C.A.S. How physicochemical properties of drug affect their metabolism and clearance. In: ew horizons in predictive drug metabolism and pharmacokinetics;; Wilson, A.G.E.Ed., 2015; 49, pp. 1-26.
[21]
Zhao, Y.H.; Abraham, M.H.; Le, J.; Hersey, A.; Luscombe, C.N.; Beck, G.; Sherborne, B.; Cooper, I. Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res., 2002, 19(10), 1446-1457.
[http://dx.doi.org/10.1023/A:1020444330011] [PMID: 12425461]
[22]
SwissADME. Available from: http://www.swissadme.ch
[23]
Osiris Property Explorer. Available from: http://www.organic-chemistry.org/prog/peo
[24]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[25]
Pascual, M.; Blanco, A.M.; Cauli, O.; Miñarro, J.; Guerri, C. Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur. J. Neurosci., 2007, 25(2), 541-550.
[http://dx.doi.org/10.1111/j.1460-9568.2006.05298.x] [PMID: 17284196]
[26]
Bijev, A.; Yaneva, D.; Bocheva, A.; Stoev, G. Ligand-based design, synthesis and primary in vivo screening of pyrrole derivatives as potential tricyclic anti-inflammatory agents. Arzneimittelforschung, 2006, 56(11), 753-759.
[PMID: 17220053]
[27]
Bali, A.; Sharma, K.; Bhalla, A.; Bala, S.; Reddy, D.; Singh, A.; Kumar, A. Synthesis, evaluation and computational studies on a series of acetophenone based 1-(aryloxypropyl)-4-(chloroaryl) piperazines as potential atypical antipsychotics. Eur. J. Med. Chem., 2010, 45(6), 2656-2662.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.008] [PMID: 20207451]
[28]
Shukla, D.A.K.; Srivastav, D.A.K. Comparative study of tramadol and diclofenac as analgesic for postoperative pain. Int. J. Med. Res. Rev., 2015, 3(11), 1311-1316.
[http://dx.doi.org/10.17511/ijmrr.2015.i11.238]
[29]
OCED/OCDC. OECD guidelines for testing of chemicals. In: In: Revised draft guidelines 423, acute oral toxicity class method,; , 2000.
[30]
Eddy, N.B.; Leimbach, D. Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines. J. Pharmacol. Exp. Ther., 1953, 107(3), 385-393.
[PMID: 13035677]
[31]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Exp. Biol. Med. (Maywood), 1962, 111(3), 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[32]
Palm, K.; Stenberg, P.; Luthman, K.; Artursson, P.I. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm. Res., 1997, 14(5), 568-571.
[http://dx.doi.org/10.1023/A:1012188625088] [PMID: 9165525]
[33]
Ugwu, D.I.; Okoro, U.C.; Ukoha, P.O.; Gupta, A.; Okafor, S.N. Novel anti-inflammatory and analgesic agents: Synthesis, molecular docking and in vivo studies. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 405-415.
[http://dx.doi.org/10.1080/14756366.2018.1426573] [PMID: 29372659]
[34]
Cashman, J.N. The mechanisms of action of NSAIDs in analgesia. Drugs, 1996, 52(5), S13-S23.
[http://dx.doi.org/10.2165/00003495-199600525-00004] [PMID: 8922554]
[35]
El-Serwy, W.S.A.; Mohamed, N.M.M.; Kassem, E.; Mahmoud, K.; Mounier, M.M. Synthesis, biological evaluation and docking analysis of some novel quinazolin derivatives as antitumor agents. Iran. J. Pharm. Res., 2016, 15(1), 179-196.
[PMID: 27610158]
[36]
Kelder, J.; Grootenhuis, P.D.J.; Bayada, D.M.; Delbressine, L.P.C.; Ploemen, J.P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res., 1999, 16(10), 1514-1519.
[http://dx.doi.org/10.1023/A:1015040217741] [PMID: 10554091]
[37]
AltTox. Toxicity testing overview., Available from: mapp/toxicity-testing-overview/[Accessed on: May 15, 2017]
[38]
Pacifici, G.M. Clinical pharmacology of indomethacin in preterm infants: Implications in patent ductus arteriosus closure. Paediatr. Drugs, 2013, 15(5), 363-376.
[http://dx.doi.org/10.1007/s40272-013-0031-7] [PMID: 23754139]
[39]
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]
[40]
Abdullah, M.I.; Mahmood, A.; Madni, M.; Masood, S.; Kashif, M. Synthesis, characterization, theoretical, anti-bacterial and molecular docking studies of quinoline based chalcones as a DNA gyrase inhibitor. Bioorg. Chem., 2014, 54, 31-37.
[http://dx.doi.org/10.1016/j.bioorg.2014.03.006] [PMID: 24747187]
[41]
Amin, N.H.; El-Saadi, M.T.; Hefny, A.A.; Abdelazeem, A.H.; Elshemy, H.A.H.; Abdellatif, K.R.A. Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. Future Med. Chem., 2018, 10(21), 2521-2535.
[http://dx.doi.org/10.4155/fmc-2018-0224] [PMID: 30518260]
[42]
Abdellatif, K.R.A.; Lamie, P.F.; Omar, H.A. 3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: Design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents. J. Enzyme Inhib. Med. Chem., 2016, 31(2), 318-324.
[http://dx.doi.org/10.3109/14756366.2015.1022174] [PMID: 25798690]
[43]
Perveen, M.; Nazir, S.; Arshad, A.W.; Khan, M.I.; Shamim, M.; Ayub, K.; Khan, M.A.; Iqbal, J. Therapeutic potential of graphitic carbon nitride as a drug delivery system for cisplatin (anticancer drug): A DFT approach. Biophys. Chem., 2020, 267, 106461.
[http://dx.doi.org/10.1016/j.bpc.2020.106461] [PMID: 32919257]
[44]
Tariq, A.; Nazir, S.; Arshad, A.W.; Nawaz, F.; Ayub, K.; Iqbal, J. DFT study of the therapeutic potential of phosphorene as a new drug-delivery system to treat cancer. RSC Advances, 2019, 9(42), 24325-24332.
[http://dx.doi.org/10.1039/C9RA02778E] [PMID: 35527876]
[45]
Mahmood, A.; Saqib, M.; Ali, M.; Abdullah, M.I.; Khalid, B. Theoretical investigation for the designing of novel antioxidants. Can. J. Chem., 2012, 91(2), 1-5.

Rights & Permissions Print Cite
Article Metrics
16
2
© 2024 Bentham Science Publishers | Privacy Policy