Activity of Some Novel Chalcone Substituted 9-anilinoacridines against Coronavirus (COVID-19): A Computational Approach

Author(s): Rajagopal Kalirajan*

Journal Name: Coronaviruses
The World's First International Journal Dedicated to Coronaviruses

Volume 1 , Issue 1 , 2020

Become EABM
Become Reviewer

Abstract:

Background: In the year earlier part of 2020, many scientists urged to discover novel drugs against for the treatments of COVID-19. Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease, was discovered first in China and quickly spread throughout the world. Objective: In the present article, some novel chalcone substituted 9-anilinoacridines (1a-z) were developed by in silico studies for their COVID19 inhibitory activity. Molecular docking studies of the ligands 1a-z were performed against COVID19 (PDB id - 5R82) targeting the coronavirus using Schrodinger suite 2019-4.

Methods: The molecular docking studies were performed by the Glide module and the binding energy of ligands was calculated using the PRIME MM-GB/SA module of Schrodinger suite 2019-4.

Results: From the results, many compounds are significantly active against COVID19 with a Glide score of more than -5.6 when compared to the currently used drug for the treatment of COVID19, Hydroxychloroquine (-5.47). The docking results of the compounds exhibited similar mode of interactions with COVID19 and the residues, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, VAL186, HIE164, ASN142, and GLY143 play a crucial role in binding with ligands. MMGBSA binding calculations of the most potent inhibitors are more stably favourable.

Conclusion: From the results of in-silico studies, it provides strong evidence for the consideration of valuable ligands in chalcone substituted 9-anilinoacridines as potential COVID19 inhibitors and the compounds, 1x,a,r,s with significant Glide scores may produce significant COVID19 activity for further development, which may prove their therapeutic potential.

Keywords: Coronavirus (COVID19), Acridine, Chalcone, docking studies, MM-GBSA, SARS-CoV-2.

[1]
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus-infected pneumonia in Wuhan. China: JAMA 2020.
[http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]
[2]
Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology 2020.
[http://dx.doi.org/10.1053/j.gastro.2020.02.054]
[3]
Holshue ML, DeBolt C, Lindquist S, et al. Washington State 2019-nCoV Case Investigation Team. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382(10): 929-36.
[http://dx.doi.org/10.1056/NEJMoa2001191] [PMID: 32004427]
[4]
To KK, Tsang OT, Chik-Yan Yip C, et al. Consistent detection of 2019 novel coronavirus in saliva Clin Infect Dis 2020 ciaa149.
[http://dx.doi.org/10.1093/cid/ciaa149] [PMID: 32047895]
[5]
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
[6]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[7]
Huang Q, Herrmann A. Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV). bioRxiv 2020. 930537
[http://dx.doi.org/10.1101/2020.02.01.930537]
[8]
Zhang H, Kang ZJ, Gong HY, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. Preprint. Posted online January 30, 2020. bioRxiv 2020. 927806
[http://dx.doi.org/10.1101/2020.01.30.927806]
[9]
Chang L, Yan Y, Wang L. Coronavirus Disease 2019: Coronaviruses and Blood Safety. Transfus Med Rev 2020; 34(2): 75-80.
[http://dx.doi.org/10.1016/j.tmrv.2020.02.003] [PMID: 32107119]
[10]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[11]
Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581(7807): 215-20.
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[12]
Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579(7798): 265-9.
[http://dx.doi.org/10.1038/s41586-020-2008-3] [PMID: 32015508]
[13]
Hoffmann M, et al. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells bioRxiv 2020.2020.2001.2031.929042.
[http://dx.doi.org/10.1101/2020.01.31.929042]
[14]
Sun K, Chen J, Viboud C. Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. Lancet Digit. Heal 2020; p. 7500.
[15]
Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 2020; 20(5): 533-4.
[http://dx.doi.org/10.1016/S1473-3099(20)30120-1] [PMID: 32087114]
[16]
Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562-9.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
[17]
Kapuriya N, Kapuriya K, Zhang X, et al. Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage. Bioorg Med Chem 2008; 16(10): 5413-23.
[http://dx.doi.org/10.1016/j.bmc.2008.04.024] [PMID: 18450456]
[18]
Wakelin LPG, Bu X, Eleftheriou A, Parmar A, Hayek C, Stewart BW. Bisintercalating threading diacridines: relationships between DNA binding, cytotoxicity, and cell cycle arrest. J Med Chem 2003; 46(26): 5790-802.
[http://dx.doi.org/10.1021/jm030253d] [PMID: 14667232]
[19]
Bacherikov VA, Chang JY, Lin YW, et al. Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives. Bioorg Med Chem 2005; 13(23): 6513-20.
[http://dx.doi.org/10.1016/j.bmc.2005.07.018] [PMID: 16140018]
[20]
Sun YW, Chen KY, Kwon CH, Chen KM. CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells. Mol Med Rep 2016; 13(1): 933-8.
[http://dx.doi.org/10.3892/mmr.2015.4604] [PMID: 26648164]
[21]
Tabarrini O, Cecchetti V, Fravolini A, et al. Design and synthesis of modified quinolones as antitumoral acridones. J Med Chem 1999; 42(12): 2136-44.
[http://dx.doi.org/10.1021/jm980324m] [PMID: 10377219]
[22]
Antonini I, Polucci P, Jenkins TC, et al. 1-[(ω-aminoalkyl)amino]-4-[N-(ω-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation. J Med Chem 1997; 40(23): 3749-55.
[http://dx.doi.org/10.1021/jm970114u] [PMID: 9371240]
[23]
Nadaraj V, Selvi ST, Mohan S. Microwave-induced synthesis and anti-microbial activities of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives. Eur J Med Chem 2009; 44(3): 976-80.
[http://dx.doi.org/10.1016/j.ejmech.2008.07.004] [PMID: 18718695]
[24]
Kalirajan R, Muralidharan V. Selvaraj Jubie and Sankar S. Microwave assisted Synthesis, Characterization and Evaluation for their Antimicrobial Activities of Some Novel pyrazole substituted 9-Anilino Acridine Derivatives. Int J Health Allied Sci 2013; 2(2): 81-7.
[http://dx.doi.org/10.4103/2278-344X.115682]
[25]
Kalirajan R, Muralidharan V, Jubie S, et al. Synthesis of some novel pyrazole substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and cytotoxic activities. J Heterocycl Chem 2012; 49: 748-54.
[http://dx.doi.org/10.1002/jhet.848]
[26]
Kalirajan R, Rafick MH, Sankar S, Jubie S. Docking studies, synthesis, characterization and evaluation of their antioxidant and cytotoxic activities of some novel isoxazole-substituted 9-anilinoacridine derivatives. ScientificWorldJournal 2012. 2012165258
[http://dx.doi.org/10.1100/2012/165258] [PMID: 22593663]
[27]
Anderson MO, Sherrill J, Madrid PB, et al. Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum. Bioorg Med Chem 2006; 14(2): 334-43.
[http://dx.doi.org/10.1016/j.bmc.2005.08.017] [PMID: 16216519]
[28]
28Sondhi SM, Johar M, Nirupama S, Sukla R, Raghubir R, Dastidar SG. Synthesis of sulpha drug acridine derivatives and their evaluation for anti-anflammatory, analgesic and anticancer acvity. Indian J Chem 2002; 41B: 2659-66.
[29]
Di Giorgio C, Shimi K, Boyer G, Delmas F, Galy JP. Synthesis and antileishmanial activity of 6-mono-substituted and 3,6-di-substituted acridines obtained by acylation of proflavine. Eur J Med Chem 2007; 42(10): 1277-84.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.010] [PMID: 17418916]
[30]
Llama EF, Campo CD, Capo M, Anadon M. Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine. Eur J Med Chem 1989; 24: 391-6.
[http://dx.doi.org/10.1016/0223-5234(89)90083-4]
[31]
Recanatini M, Cavalli A, Belluti F, et al. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J Med Chem 2000; 43(10): 2007-18.
[http://dx.doi.org/10.1021/jm990971t] [PMID: 10821713]
[32]
Goodell JR, Madhok AA, Hiasa H, Ferguson DM. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg Med Chem 2006; 14(16): 5467-80.
[http://dx.doi.org/10.1016/j.bmc.2006.04.044] [PMID: 16713270]
[33]
Rastogi K, Chang JY, Pan WY, et al. Antitumor AHMA linked to DNA minor groove binding agents: synthesis and biological evaluation. J Med Chem 2002; 45(20): 4485-93.
[http://dx.doi.org/10.1021/jm0200714] [PMID: 12238927]
[34]
Harrison RJ, Cuesta J, Chessari G, et al. Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. J Med Chem 2003; 46(21): 4463-76.
[http://dx.doi.org/10.1021/jm0308693] [PMID: 14521409]
[35]
Kalirajan R, Sivakumar SU, Jubie S, Gowramma B, Suresh B. Synthesis and biological evaluation of some heterocyclic derivatives of chalcones. Int J Chem Sci 2009; 1(1): 27-34.
[36]
Kalirajan R. Mohammed rafick MH, Sankar S, Gowramma B. Green synthesis of some novel chalcone and isoxazole substituted 9-anilinoacridine derivatives and evaluation of their antimicrobial and larvicidal activities. Indian J Chem 2018; 57B: 583-90.
[37]
Kalirajan R, Pandiselvi A, Sankar S, Gowramma B. Molecular Docking Studies and Insilico ADMET Screening of Some Novel Chalcone Substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. SF J Pharm Anal Chem 2018; 1(1): 1004-9.
[38]
Kalirajan R, Jubie S, Gowramma B. Microwave Irradated Synthesis, Characterization and Evaluation for their Antibacterial and Larvicidal Activities of some Novel Chalcone and Isoxazole Substituted 9-Anilino Acridines Open J Chem 2015; 1(1): 001-7.
[39]
Kalirajan R. Vivek kulshrestha, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti oxidant and anticancer activities as topo isomerase II inhibitors. Eur J Med Chem 2012; 56: 217-24.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.025] [PMID: 22982526]
[40]
Kalirajan R. Leela Rathore, Jubie S, Gowramma B, Gomathy S, Sankar S, Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities. Indian J Chem 2011; 50B: 1794-801.
[41]
Kalirajan R, Sankar S, Jubie S, Gowramma B. Molecular Docking studies and in-silico ADMET Screening of Some novel Oxazine substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. Indian J Pharm Educ Res 2017; 51(1): 110-5.
[http://dx.doi.org/10.5530/ijper.51.1.15]
[42]
Kalirajan R, Gowramma B, Jubie S, Sankar S. Molecular Docking Studies and In silico ADMET Screening of Some Novel Heterocyclic Substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. JSM Chem 2017; 5(1): 1039-44.
[43]
Kalirajan R, Gaurav K, Pandiselvi A, Gowramma B, Sankar S. Novel Thiazine Substituted 9-Anilinoacridines: Synthesis, Antitumour Activity and Structure Activity Relationships. Anticancer Agents Med Chem 2019; 19(11): 1350-8.
[http://dx.doi.org/10.2174/1871520619666190408134224] [PMID: 30961512]
[44]
Kalirajan R. Vivek kulshrestha, Sankar S. Synthesis, Characterization and Evaluation for Antitumour Activity of Some Novel Oxazine Substituted 9-Anilinoacridines and their 3D-QSAR Studies. Indian J Pharm Sci 2018; 80(5): 921-9.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000439]
[45]
Kalirajan R. Leela Rathore, Jubie S, Gowramma B, Gomathy S, Sankar S, Elango K. Microwave Assisted Synthesis and Biological Evaluation of Pyrazole Derivatives of Benzimidazoles, Indian J Pharm. Educ Res 2010; 44(4): 358-62.
[46]
Kalirajan R. Chitra, Jubie S, Gowramma B. Synthesis and biological evaluation of Mannich bases of 2-substituted Benzimidazoles. Asian J Chem 2009; 21(7): 5207-11.
[47]
Kalirajan R. Leela Rathore, Jubie S. Gowramma B, Gomathy, S. Sankar S. Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities. Indian J Chem 2011; 50B: 1794-801.
[48]
Kalirajan R, Pandiselvi A, Gowramma B. In-silico Drug Design by Docking Studies, ADMET Screening, MM-GBSA Binding Free Energy of Some Chalcone Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer. Int J Comp Theo Chem 2019; 7(1): 6-13.
[http://dx.doi.org/10.11648/j.ijctc.20190701.12]
[49]
Kalirajan R, Pandiselvi A, Gowramma B, Balachandran P. In-silico design, ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted 9-anilinoacridines as HER2 inhibitors targeting breast cancer. Curr Drug Res Rev 2019; 11(2): 118-28.
[http://dx.doi.org/10.2174/2589977511666190912154817] [PMID: 31513003]
[50]
Halperin I, Ma B, Wolfson H, Nussinov R. Principles of docking: An overview of search algorithms and a guide to scoring functions. Proteins 2002; 47(4): 409-43.
[http://dx.doi.org/10.1002/prot.10115] [PMID: 12001221]
[51]
Naga Srinivas Tripuraneni. Mohammed.Afzal Azam. Pharmacophore modelling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. J Theor Biol 2016; 394: 117-26.
[http://dx.doi.org/10.1016/j.jtbi.2016.01.007] [PMID: 26804643]
[52]
Lengaur T, Rarey M. Computational method for bio molecular docking: curr. Opin Strut Biol 1996; 6(3): 402-6.
[http://dx.doi.org/10.1016/S0959-440X(96)80061-3]
[53]
Reetu VK. Computer aided design of selective calcium channel blockers: using pharmacophore - based and docking simulations. Indian J Pharm Sci Res 2012; 3(3): 805-10.
[54]
Li J, Abel R, Zhu K, Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins 2011; 79(10): 2794-812.
[http://dx.doi.org/10.1002/prot.23106] [PMID: 21905107]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 1
ISSUE: 1
Year: 2020
Published on: 08 September, 2020
Page: [13 - 22]
Pages: 10
DOI: 10.2174/2666796701999200625210746
Price: $65

Article Metrics

PDF: 27
HTML: 1