Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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

Synthesis, Molecular Docking and ADME Prediction of 1H-indole/5- substituted Indole Derivatives as Potential Antioxidant and Anti- Inflammatory Agents

Author(s): Archana Kumari and Rajesh Kumar Singh*

Volume 19, Issue 2, 2023

Published on: 27 September, 2022

Page: [163 - 173] Pages: 11

DOI: 10.2174/1573406418666220812152950

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Inflammation is a protective biological process, but under extreme conditions, it can become highly dreadful to the body. Antioxidant and anti-inflammatory agents treat similar disease conditions as inflammation and oxidative stress commonly follow similar causative pathways.

Objective: The goal of this study was to synthesize N-substituted indole derivatives with different heterocyclic moieties through propyl linker with the aim of getting highly potent anti-inflammatory and antioxidant agents.

Methods: Synthesized compounds were analyzed by analytical techniques such as IR, 1H NMR, 13C NMR spectra, and mass spectrometry. Molecular docking and ADME calculation were employed on synthesized compounds to estimate their COX-2 enzyme inhibition and drug like properties, respectively. Antioxidant activity was evaluated by the DPPH assay and the reducing power assay. Selected derivatives were evaluated for anti-inflammatory activity at an acute (carrageenan-induced paw edema method) and chronic level (formalin-induced inflammation method) using indomethacin as a standard drug.

Results: Herein, twelve indole derivatives (11a-c, 12a-c, 13a-c, and 14a-c) were synthesized. Among all, compound 12c was found to be the best inhibitor of the COX-2 enzyme as it displayed good interaction energy. Zero violations of Lipinski's rule were found in the ADME investigation, confirming the drug-like qualities of synthesized compounds. The compounds 11a and 12c were found to be the most potent as compared with standard ascorbic acid in antioxidant evaluation. From the collected results, compounds 12c and 13b were the most potent against acute and chronic inflammation.

Conclusion: The novel synthetic indole derivatives could act as potent leads for the development of novel antioxidant and anti-inflammatory agents.

Keywords: Indole, COX-2, anti-inflammation, antioxidant, molecular docking, ADME, inflammation.

« Previous Next »
Graphical Abstract

[1]
Bhat, M.A.; Al-Omar, M.A.; Raish, M.; Ansari, M.A.; Abuelizz, H.A.; Bakheit, A.H.; Naglah, A.M. Indole derivatives as cyclooxygenase inhibitors: Synthesis, biological evaluation and docking studies. Molecules, 2018, 23(6), 1250.
[http://dx.doi.org/10.3390/molecules23061250] [PMID: 29882911]
[2]
Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature, 2002, 420(6917), 860-867.
[http://dx.doi.org/10.1038/nature01322] [PMID: 12490959]
[3]
Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 2017, 9(6), 7204-7218.
[http://dx.doi.org/10.18632/oncotarget.23208] [PMID: 29467962]
[4]
Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn. Rev., 2010, 4(8), 118-126.
[http://dx.doi.org/10.4103/0973-7847.70902] [PMID: 22228951]
[5]
Mangge, H.; Becker, K.; Fuchs, D.; Gostner, J.M. Antioxidants, inflammation and cardiovascular disease. World J. Cardiol., 2014, 6(6), 462-477.
[http://dx.doi.org/10.4330/wjc.v6.i6.462] [PMID: 24976919]
[6]
Kumari, A.; Singh, R.K. Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR). Bioorg. Chem., 2020, 96103578
[http://dx.doi.org/10.1016/j.bioorg.2020.103578] [PMID: 31978684]
[7]
Sravanthi, T.V.; Manju, S.L. Indoles - A promising scaffold for drug development. Eur. J. Pharm. Sci., 2016, 91, 1-10.
[http://dx.doi.org/10.1016/j.ejps.2016.05.025] [PMID: 27237590]
[8]
Kumar, D.; Sharma, S.; Kalra, S.; Singh, G.; Monga, V.; Kumar, B. Medicinal perspective of indole derivatives: Recent developments and structure-activity relationship studies. Curr. Drug Targets, 2020, 21(9), 864-891.
[http://dx.doi.org/10.2174/1389450121666200310115327] [PMID: 32156235]
[9]
Van Order, R.B.; Lindwall, H.G. Indole. Chem. Rev., 1942, 30(1), 69-96.
[http://dx.doi.org/10.1021/cr60095a004]
[10]
Kumar, S. Ritika, A brief review of the biological potential of indole derivatives. Futur. J. Pharm. Sci., 2020, 6, 121.
[http://dx.doi.org/10.1186/s43094-020-00141-y]
[11]
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89103021
[http://dx.doi.org/10.1016/j.bioorg.2019.103021] [PMID: 31176854]
[12]
Dhiman, A.; Sharma, R.; Singh, R.K. Target-based anticancer indole derivatives and insight into structure-activity relationship: A mechanistic review update (2018-2021). Acta Pharm. Sin. B, 2022.
[http://dx.doi.org/10.1016/j.apsb.2022.03.021] [PMID: 35865090]
[13]
Pingaew, R.; Mandi, P.; Prachayasittikul, V.; Thongnum, A.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. Investigations on anticancer and antimalarial activities of indole-sulfonamide derivatives and in silico studies. ACS Omega, 2021, 6(47), 31854-31868.
[http://dx.doi.org/10.1021/acsomega.1c04552] [PMID: 34870008]
[14]
Reddy, G.S.; Pal, M. Indole derivatives as anti-tubercular agents: An overview on their synthesis and biological activities. Curr. Med. Chem., 2021, 28(22), 4531-4568.
[http://dx.doi.org/10.2174/0929867327666200918144709] [PMID: 32951569]
[15]
Chen, Q.; Wu, C.; Zhu, J.; Li, E.; Xu, Z. Therapeutic potential of indole derivatives as anti-HIV agents: A mini-review. Curr. Top. Med. Chem., 2022, 22(12), 993-1008.
[http://dx.doi.org/10.2174/1568026621666211012111901] [PMID: 34636313]
[16]
Guerra, A.S.; Malta, D.J.; Laranjeira, L.P.; Maia, M.B.; Colaço, N.C. de Lima, Mdo.C.; Galdino, S.L.; Pitta, Ida.R.; Gonçalves-Silva, T. Anti-inflammatory and antinociceptive activities of indole-imidazolidine derivatives. Int. Immunopharmacol., 2011, 11(11), 1816-1822.
[http://dx.doi.org/10.1016/j.intimp.2011.07.010] [PMID: 21855654]
[17]
Zhang, S.S.; Tan, Q.W.; Guan, L.P. Antioxidant, anti-inflammatory, antibacterial, and analgesic activities and mechanisms of quinolines, indoles and related derivatives. Mini Rev. Med. Chem., 2021, 21(16), 2261-2275.
[http://dx.doi.org/10.2174/1389557521666210111145011] [PMID: 33430728]
[18]
Brandão, P.; Marques, C.; Burke, A.J.; Pineiro, M. The application of isatin-based multicomponent-reactions in the quest for new bioactive and druglike molecules. Eur. J. Med. Chem., 2021, 211113102
[http://dx.doi.org/10.1016/j.ejmech.2020.113102] [PMID: 33421712]
[19]
Mésangeau, C.; Amata, E.; Alsharif, W.; Seminerio, M.J.; Robson, M.J.; Matsumoto, R.R.; Poupaert, J.H.; McCurdy, C.R. Synthesis and pharmacological evaluation of indole-based sigma receptor ligands. Eur. J. Med. Chem., 2011, 46(10), 5154-5161.
[http://dx.doi.org/10.1016/j.ejmech.2011.08.031] [PMID: 21899931]
[20]
el-Diwani, H.; Nakkady, S.S.; Hishmat, O.H.; El-Shabrawy, O.A.; Mahmoud, S.S. Synthesis of some N-substituted indole derivatives and their biological activities. Pharmazie, 1992, 47(3), 178-181.
[PMID: 1615022]
[21]
Kiliç, Z.; Sener, F. Işgr, Y.G.; Coban, T.; Olgen, S. N-substituted indole-3-imine derivatives and their amine congeners: Antioxidant and Src kinase inhibitory effects. Z. Naturforsch. C J. Biosci., 2010, 65(5-6), 347-354.
[http://dx.doi.org/10.1515/znc-2010-5-606] [PMID: 20653236]
[22]
Al-Khaldi, A.; Ghoneim, A.A.; El-sherif, M.A.; Elbargisy, R.; Ghanem, H.B.; Zafar, R. Construction, molecular docking, antimicrobial and antioxidant activity of some novel 3-substitued indole derivatives using 3-Acetyl indole. J. Saudi Chem. Soc., 2021, 25101360
[http://dx.doi.org/10.1016/j.jscs.2021.101360]
[23]
Kourounakis, A.P.; Xanthopoulos, D.; Tzara, A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev., 2020, 40(2), 709-752.
[http://dx.doi.org/10.1002/med.21634] [PMID: 31512284]
[24]
Sethi, N.S.; Prasad, D.N.; Singh, R.K. An insight into the synthesis and SAR of 2,4-Thiazolidinediones (2,4-TZD) as multifunctional scaffold: A review. Mini Rev. Med. Chem., 2020, 20(4), 308-330.
[http://dx.doi.org/10.2174/1389557519666191029102838] [PMID: 31660809]
[25]
Hsieh, C.Y.; Ko, P.W.; Chang, Y.J.; Kapoor, M.; Liang, Y.C.; Lin, H.H.; Horng, J.C.; Hsu, M.H. Design and synthesis of benzimidazole-chalcone derivatives as potential anticancer agents. Molecules, 2019, 24(18), 3259.
[http://dx.doi.org/10.3390/molecules24183259] [PMID: 31500191]
[26]
Estevão, M.S.; Carvalho, L.C.; Ribeiro, D.; Couto, D.; Freitas, M.; Gomes, A.; Ferreira, L.M.; Fernandes, E.; Marques, M.M. Antioxidant activity of unexplored indole derivatives: Synthesis and screening. Eur. J. Med. Chem., 2010, 45(11), 4869-4878.
[http://dx.doi.org/10.1016/j.ejmech.2010.07.059] [PMID: 20727623]
[27]
Choppara, P.; Bethu, M.S.; Prasad, Y.V.; Rao, C.V.; Krishna, K.H.; Trimoorthulu, G.; Rao, G.U.M.; Rao, J.V.; Murthy, Y.L.N. Synthesis, characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study. Arab. J. Chem., 2019, 12, 2721-2731.
[http://dx.doi.org/10.1016/j.arabjc.2015.05.015]
[28]
Renton, P.; Speed, J.; Maddaford, S.; Annedi, S.C.; Ramnauth, J.; Rakhit, S.; Andrews, J. 1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(18), 5301-5304.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.022] [PMID: 21813276]
[29]
Sehajpal, S.; Prasad, D.N.; Singh, R.K. Prodrugs of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): A long march towards synthesis of safer NSAIDs. Mini Rev. Med. Chem., 2018, 18(14), 1199-1219.
[http://dx.doi.org/10.2174/1389557518666180330112416] [PMID: 29600762]
[30]
Sehajpal, S.; Prasad, D.N.; Singh, R.K. Novel ketoprofen-antioxidants mutual codrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, kinetic and pharmacological evaluation. Arch. Pharm. (Weinheim), 2019, 352(7)e1800339
[http://dx.doi.org/10.1002/ardp.201800339] [PMID: 31231875]
[31]
Narasegowda, R.S.; Yathirajan, H.S.; Nagaraja, P.; Lynch, D.E. 4-(2-Chloroethyl)morpholinium chloride. Acta Crystallogr., 2005, E61, o849-o850.
[32]
Singh, P. Pooja. N-1, C-3 substituted indoles as 5-LOX inhibitors--in vitro enzyme immunoaasay, mass spectral and molecular docking investigations. Bioorg. Med. Chem. Lett., 2013, 23(5), 1433-1437.
[http://dx.doi.org/10.1016/j.bmcl.2012.12.068] [PMID: 23337599]
[33]
In vivo ADME: What you need and why you need it | SEKISUI XenoTech Available from: https://www.xenotech.com/blog/in-vivo-adme-what-you-need-and-why-you-need-it/(Accessed on 18 February 2022)
[34]
Singh, K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and in vitro cytotoxicity study of benzodiazepine-mustard conjugates as potential brain anticancer agents. J. Saudi Chem. Soc., 2017, 21, S86-S93.
[http://dx.doi.org/10.1016/j.jscs.2013.10.004]
[35]
Jasiewicz, B.; Kozanecka-Okupnik, W.; Przygodzki, M. Warżajtis, B.; Rychlewska, U.; Pospieszny, T.; Mrówczyńska, L. Synthesis, antioxidant and cytoprotective activity evaluation of C-3 substituted indole derivatives. Sci. Rep., 2021, 11(1), 15425.
[http://dx.doi.org/10.1038/s41598-021-94904-z] [PMID: 34326403]
[36]
Oyaizu, M. Studies on products of browning reaction-Antioxidative activities of products of browning reaction. Prepared from glucosamine. Japanese J. Nutr., 1986, 44, 307-315.
[http://dx.doi.org/10.5264/eiyogakuzashi.44.307]
[37]
Vogel, H.G. Drug Discovery and Evaluation: Pharmacological Assays, 2nd ed; Springer Science & Business Media: Berlin/Heidelberg, Germany, 2002.
[http://dx.doi.org/10.1007/3-540-29837-1]
[38]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111, 544-547.
[http://dx.doi.org/10.3181/00379727-111-27849] [PMID: 14001233]
[39]
Dixit, A.; Pathak, D.; Sharma, G.K. Synthesis, antibacterial and free radical scavenging activity of some newer N-((10-nitro-1H-indolo[1, 2-c]quinazolin-12-yl)methylene)benzenamines. Eur. Pharm. J., 2019, 67(1), 7-16.
[40]
Narayana, B.; Ashalatha, B.V.; Vijaya Raj, K.K.; Fernandes, J.; Sarojini, B.K. Synthesis of some new biologically active 1,3,4-oxadiazolyl nitroindoles and a modified Fischer indole synthesis of ethyl nitro indole-2-carboxylates. Bioorg. Med. Chem., 2005, 13(15), 4638-4644.
[http://dx.doi.org/10.1016/j.bmc.2005.04.068] [PMID: 15927475]
[41]
Cheng, B.; Lin, Y.; Kuang, M.; Fang, S.; Gu, Q.; Xu, J.; Wang, L. Synthesis and anti-neuroinflammatory activity of lactone benzoyl hydrazine and 2-nitro-1-phenyl-1h-indole derivatives as p38 α MAPK inhibitors. Chem. Biol. Drug Des., 2015, 86(5), 1121-1130.
[http://dx.doi.org/10.1111/cbdd.12581] [PMID: 25960125]
[42]
Prajapati, T.R.; Pandey, D.P.; Gupta, V.; Joshi, B.; Dhingra, G.K. Synthesis and anti-inflammatory activity of some newer potential isoxazoline derivatives of indole. Essence Int. J. Env. Rehab. Conserv, 2018, IX(1), 87-93.
[http://dx.doi.org/10.31786/09756272.18.9.2.213]

Rights & Permissions Print Cite
Article Metrics
57
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy