Abstract
Background: The lack of anti-COVID-19 treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that target the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Main Protease (Mpro).
Objective: The binding of the halogenated compounds to Mpro may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the viral life cycle. In times of dire need for anti- COVID-19 treatment, this study lays the groundwork for further experimental research to investigate these compounds' efficacy and potential medical uses to treat COVID-19.
Methods: New heterocyclic compounds were synthesized through the first reaction of cyclohexane- 1, 3-dione (1a) or dimedone (1b) with trichloroacetonitrile (2) to give the 2,2,2-trichloroethylidene) cyclohexane-1,3-dione derivatives 3a and 3b, respectively. The latter compounds underwent a series of heterocyclization reactions to produce biologically active compounds.
Results: Novel compounds, including fused thiophene, pyrimidine and pyran derivatives, were synthesized and tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti-COVID-19 target molecules.
Conclusion: The results showed that compounds 10a, 10b, 10c, 10e, 10f, 10g and 10h showed high % inhibitions against SARs-Covnsp 14. Whereas compounds 5a, 7a, 8b, 10a, 10b, 10c and 10i showed high inhibitions against hRNMT. This study explored the binding affinity of twenty-two halogenated compounds to the SARS-CoV-2 MPro and discovered fifteen compounds with higher binding affinity than Nelfinavir, of which three showed remarkable results. c-Met kinase inhibitions of 10a, 10f, 10g and 10h showed that all compounds exhibited higher inhibitions than the reference Foretinib.
Keywords: Trichloroethylidene, SARS-CoV-2, Corona virus, Main protease, Mpro, Molecular Docking
Graphical Abstract
[http://dx.doi.org/10.1016/j.molstruc.2020.128490]
[http://dx.doi.org/10.1016/j.reprotox.2008.11.065]
[http://dx.doi.org/10.1016/S0014-827X(00)00031-8] [PMID: 10966157]
[http://dx.doi.org/10.1016/j.bbadis.2020.165910]
[http://dx.doi.org/10.1016/j.xphs.2019.10.057] [PMID: 31697947]
[http://dx.doi.org/10.1016/j.biopha.2020.110590] [PMID: 32768885]
[http://dx.doi.org/10.1016/j.dib.2020.105902] [PMID: 32637503]
[http://dx.doi.org/10.1016/j.envres.2019.108825] [PMID: 31683121]
[http://dx.doi.org/10.1016/j.bioorg.2020.103696] [PMID: 32135360]
[http://dx.doi.org/10.1016/j.indcrop.2020.112608]
[http://dx.doi.org/10.1016/j.chemosphere.2020.126156] [PMID: 32062216]
[http://dx.doi.org/10.1016/j.talanta.2020.121515] [PMID: 33303131]
[http://dx.doi.org/10.1016/j.cej.2019.122708]
[http://dx.doi.org/10.1016/j.carbpol.2020.116847] [PMID: 32933686]
[http://dx.doi.org/10.1016/j.ica.2020.119495]
[http://dx.doi.org/10.1016/j.bmcl.2019.126661] [PMID: 31515187]
[http://dx.doi.org/10.1016/j.bmc.2018.08.025] [PMID: 30173929]
[http://dx.doi.org/10.1016/j.fitote.2018.07.013] [PMID: 30056185]
[http://dx.doi.org/10.1016/j.pdpdt.2020.101701] [PMID: 32184175]
[http://dx.doi.org/10.1016/j.molstruc.2019.127470]
[http://dx.doi.org/10.1016/j.ejmech.2012.03.043] [PMID: 22516424]
[http://dx.doi.org/10.1016/j.bmcl.2007.10.083] [PMID: 17997304]
[http://dx.doi.org/10.1016/j.nerep.2022.100072]
[http://dx.doi.org/10.1016/j.saa.2021.120702] [PMID: 34922287]
[http://dx.doi.org/10.1016/S2665-9913(22)00034-0] [PMID: 35317410]
[http://dx.doi.org/10.1016/j.micpath.2021.105133] [PMID: 34390768]
[http://dx.doi.org/10.1016/j.biopha.2020.110668] [PMID: 32861965]
[http://dx.doi.org/10.1016/j.ejmech.2020.112419] [PMID: 32502862]
[http://dx.doi.org/10.1016/j.diagmicrobio.2022.115640] [PMID: 35193798]
[http://dx.doi.org/10.1016/j.jneuroim.2019.02.010] [PMID: 30825859]
[http://dx.doi.org/10.1016/j.apradiso.2019.03.034] [PMID: 30959352]
[http://dx.doi.org/10.1016/j.bbrc.2020.05.127] [PMID: 32736668]
[http://dx.doi.org/10.1016/0166-0934(88)90134-6] [PMID: 2460479]
[http://dx.doi.org/10.1093/nar/gkl1119] [PMID: 17259217]
[http://dx.doi.org/10.1074/jbc.RA118.005953] [PMID: 30962283]
[http://dx.doi.org/10.1016/j.ejca.2021.10.013] [PMID: 34798454]
[http://dx.doi.org/10.1016/j.bioorg.2021.104862] [PMID: 33862474]
[http://dx.doi.org/10.1186/1758-2946-1-15] [PMID: 20150996]
[http://dx.doi.org/10.1021/ja00205a003]
[http://dx.doi.org/10.1016/j.bbrc.2012.07.141] [PMID: 22877750]
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[PMID: 19499576]
[http://dx.doi.org/10.1002/jcc.20289] [PMID: 16222654]
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[http://dx.doi.org/10.1093/nar/gkv315] [PMID: 25873628]
[http://dx.doi.org/10.1016/j.ijsu.2020.02.034] [PMID: 32112977]
[http://dx.doi.org/10.1002/jmv.25681] [PMID: 31967327]
[http://dx.doi.org/10.1016/j.jsb.2009.10.006] [PMID: 19835958]
[http://dx.doi.org/10.1039/C4CE01514B] [PMID: 25663816]
[http://dx.doi.org/10.1002/anie.201006781] [PMID: 21184410]
[http://dx.doi.org/10.1021/jm061242y] [PMID: 17300163]
[http://dx.doi.org/10.1016/0006-2952(95)00029-Y] [PMID: 7763293]
[http://dx.doi.org/10.1016/j.bmcl.2003.09.045] [PMID: 14643315]
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[http://dx.doi.org/10.1002/prot.20015] [PMID: 15146478]
[http://dx.doi.org/10.1002/cmdc.201100353] [PMID: 21898833]
[http://dx.doi.org/10.1016/j.ijcard.2003.12.023] [PMID: 15721505]
[http://dx.doi.org/10.1021/jm200644r] [PMID: 21714539]
[http://dx.doi.org/10.1038/nature01914] [PMID: 12955149]
[http://dx.doi.org/10.1016/j.drudis.2007.07.006] [PMID: 17826685]
[http://dx.doi.org/10.3390/molecules22091397] [PMID: 28837116]
[http://dx.doi.org/10.1016/B978-012374473-9.00772-4]
[http://dx.doi.org/10.1021/acsomega.9b02900] [PMID: 31815237]
[http://dx.doi.org/10.1007/s00044-013-0664-7]
[http://dx.doi.org/10.1007/s00044-014-1273-9]
[http://dx.doi.org/10.1016/j.steroids.2015.03.001] [PMID: 25759119]
[http://dx.doi.org/10.1021/cr0505728] [PMID: 16402771]
[http://dx.doi.org/10.1002/chem.201201591] [PMID: 23512744]
[http://dx.doi.org/10.3390/80100053]
[http://dx.doi.org/10.1002/ejoc.201200030]
[http://dx.doi.org/10.1055/s-1982-29806]
[http://dx.doi.org/10.1021/jm049640t] [PMID: 15566300]