Table Info

Table 7.

List of results of CTs of potential drugs for the treatment of COVID-19 using natural compounds from medicinal plants

Name of chemical compound	Study design; sample size (control group/investigate group)	References on protocol studies	Results	References on results
Artemisinin	An open-label, non-randomized, controlled trial; 41 (23/18)	[87]	Positive effects	[111]
Artesunate	Not fully described; 43 (25/18)	-	Positive effects	[112]
Berberine	Not fully described; 35 (17/18)	-	No significant difference	[113]
Cannabidiol	A single-center, randomized, parallel, double-blind, placebo-controlled CT; 104 (52/52)	[88]	No significant difference	[114]
Colchicine	A randomized controlled CT; 90 (45/45)	[89]	Positive effects	[115]
Colchicine	A randomized, open-labeled, CT; 80 (40/40)	[90]	Positive effects	[116]
Colchicine	A randomized, double-blinded, placebo-controlled CT; 72 (36/36)	[91]	Positive effects	[117]
Colchicine	A multicenter, randomized CT; 152 (89/63)	[92]	Positive effects	[118]
Colchicine	A randomized controlled CT; 112 (34/78)	-	Positive effects	[119]
Colchicine	A randomized controlled CT; 336 (165/171)	-	Positive effects	[120]
Curcumin	A randomized double-blind placebo-controlled trial; 48 (24/24)	[93]	Positive effects	[121]
Curcumin	A randomized controlled, double-blind, placebo-controlled CT; 60 (30/30)	[94]	Positive effects	[122]
Curcumin	A non-randomized open-label, parallel-group CT; 41 (21/20)	[95]	Positive effects	[123]
Curcumin	Randomized double-blind CT; 40 (20/20)	[96]	Positive effects	[124]
Curcumin	A non-randomized open-label, parallel-group CT; 60 (30/30)	[97]	Positive effects	[125]
Curcumin	A randomized, double-blind, placebo-controlled trial; 50 (25/25)	[98]	Positive effects	[126]
Curcumin	A randomized, parallel-group trial; 140 (70/70)	[99]	Positive effects	[127]
Glycyrrhizin	A single-center, randomized, double-blind, placebo-controlled CT; 50 (25/25)	[100]	Positive effects	[128]
Glycyrrhizin	A randomized triple-blind placebo-controlled CT; 125 (62/63)	[101]	Positive effects	[129]
Glycyrrhizin	Retrospective study [in study compares two groups of people: those with the disease under study (cases) and a similar group of people who do not have the disease (controls)]; 147 (66/81)	-	Positive effects	[130]
Hesperidin	Control group, with parallel, double-blind, and randomized groups; 40 (20/20)	[102]	No significant difference	[131]
Hesperidin	Randomized, double-blind, placebo-controlled study; 216 (109/107)	[103]	Positive effects	[132]
Luteolin	Randomized-controlled pilot study; 12 (7/5)	-	Positive effects	[133]
Luteolin	Randomized-controlled study; 69 (59/10)	-	Positive effects	[134]
Plitidepsin	Randomized, parallel, open-label; 30 (15/15)	[104]	Positive effects	[135]
Plitidepsin	Case study (research of one case); 1	-	Positive effects	[136]
Quercetin	Single center, randomized, controlled trial; 429 (380/49)	[105]	No significant differences	[137]
Quercetin	Randomized, parallel assignment, placebo-controlled CT; 60 (30/30)	[106]	Positive effects	[138]
Quercetin	Single-center, prospective, randomized, controlled cohort study; 120 (60/60)	[107]	Positive effects	[139]
Quercetin	Pilot, randomized, controlled and open-label CT; 42 (21/21)	-	Positive effects	[140]
Resveratrol	Randomized, placebo-controlled trial; 30 (14/16)	[108]	No significant differences	[141]
Resveratrol	Not fully described; 230 (200/30)	[109]	Positive effects	[142]
Resveratrol	Double-blind, randomized, placebo-controlled trial; 100 (50/50)	[110]	Positive effects	[143]

-: not applicable

Supplementary materials

The supplementary material for this article is available at: https://www.explorationpub.com/uploads/Article/file/100817_sup_1.pdf.

Declarations

Author contributions

AK: Data curation, Visualization, Writing—original draft. NI: Data curation, Writing—original draft. IG and VP: Conceptualization, Supervision.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The study is performed in the framework of the Program for Basic Research in the Russian Federation for a long-term period (2021–2030) project No. [121102900156-6]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

WHO coronavirus (COVID-19) dashboard [Internet]. World Health Organization; [cited 2023 Feb 9]. Available from: https://covid19.who.int/

François Lamontagne, Arnav Agarwal, Bram Rochwerg, Reed AC Siemieniuk, Thomas Agoritsas, Lisa Askie, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. Erratum in: BMJ. 2022;377:o1045. [DOI] [PubMed]

Rishton GM. Natural products as a robust source of new drugs and drug leads: past successes and present day issues. Am J Cardiol. 2008;101:S43–9. [DOI] [PubMed]

Musarra-Pizzo M, Pennisi R, Ben-Amor I, Mandalari G, Sciortino MT. Antiviral activity exerted by natural products against human viruses. Viruses. 2021;13:828. [DOI] [PubMed] [PMC]

Omrani M, Keshavarz M, Nejad Ebrahimi S, Mehrabi M, McGaw LJ, Ali Abdalla M, et al. Potential natural products against respiratory viruses: a perspective to develop anti-COVID-19 medicines. Front Pharmacol. 2021;11:586993. [DOI] [PubMed] [PMC]

Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS, et al. SARS-CoV-2, SARS-CoV, and MERS-COV: a comparative overview. Infez Med. 2020;28:174–84. [PubMed]

Balkrishna A, Pokhrel S, Singh H, Joshi M, Mulay VP, Haldar S, et al. Withanone from Withania somnifera attenuates SARS-CoV-2 RBD and host ACE2 interactions to rescue spike protein induced pathologies in humanized zebrafish model. Drug Des Devel Ther. 2021;15:1111–33. [DOI] [PubMed] [PMC]

Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, et al. Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain. Front Chem. 2020;8:572885. [DOI] [PubMed] [PMC]

Kim YS, Kwon EB, Kim B, Chung HS, Choi G, Kim YH, et al. Mulberry component kuwanon C exerts potent therapeutic efficacy in vitro against COVID-19 by blocking the SARS-CoV-2 spike S1 RBD:ACE2 receptor interaction. Int J Mol Sci. 2022;23:12516. [DOI] [PubMed] [PMC]

10.

Vaishnavi K, Saxena N, Shah N, Singh R, Manjunath K, Uthayakumar M, et al. Differential activities of the two closely related withanolides, Withaferin A and Withanone: bioinformatics and experimental evidences. PLoS One. 2012;7:e44419. [DOI] [PubMed] [PMC]

11.

Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582:289–93. [DOI] [PubMed]

12.

Tahir Ul Qamar M, Alqahtani SM, Alamri MA, Chen LL. Structural basis of SARS-CoV-2 3CL^pro and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal. 2020;10:313–9. [DOI] [PubMed] [PMC]

13.

Kuzikov M, Costanzi E, Reinshagen J, Esposito F, Vangeel L, Wolf M, et al. Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in vitro repurposing screen. ACS Pharmacol Transl Sci. 2021;4:1096–110. [DOI] [PubMed] [PMC]

14.

Chen Z, Cui Q, Cooper L, Zhang P, Lee H, Chen Z, et al. Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases. Cell Biosci. 2021;11:45. [DOI] [PubMed] [PMC]

15.

Yi Y, Zhang M, Xue H, Yu R, Bao YO, Kuang Y, et al. Schaftoside inhibits 3CL^pro and PL^pro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19. Acta Pharm Sin B. 2022;12:4154–64. [DOI] [PubMed] [PMC]

16.

Chiou WC, Chen JC, Chen YT, Yang JM, Hwang LH, Lyu YS, et al. The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease. Biochem Biophys Res Commun. 2022;591:130–6. [DOI] [PubMed] [PMC]

17.

Park JY, Kim JH, Kwon JM, Kwon HJ, Jeong HJ, Kim YM, et al. Dieckol, a SARS-CoV 3CL^pro inhibitor, isolated from the edible brown algae Ecklonia cava. Bioorg Med Chem. 2013;21:3730–7. [DOI] [PubMed] [PMC]

18.

Nguyen TTH, Jung JH, Kim MK, Lim S, Choi JM, Chung B, et al. The inhibitory effects of plant derivate polyphenols on the main protease of SARS coronavirus 2 and their structure–activity relationship. Molecules. 2021;26:1924. [DOI] [PubMed] [PMC]

19.

Shahhamzehei N, Abdelfatah S, Efferth T. In silico and in vitro identification of pan-coronaviral main protease inhibitors from a large natural product library. Pharmaceuticals. 2022;15:308. [DOI] [PubMed] [PMC]

20.

He CL, Huang LY, Wang K, Gu CJ, Hu J, Zhang GJ, et al. Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products. Signal Transduct Target Ther. 2021;6:131. [DOI] [PubMed] [PMC]

21.

Li Z, Xie H, Tang C, Feng L, Ke C, Xu Y, et al. Flavonoids from the roots and rhizomes of Sophora tonkinensis and their in vitro anti-SARS-CoV-2 activity. Chin J Nat Med. 2022;21:65–80. [DOI] [PubMed] [PMC]

22.

Ghosh R, Chakraborty A, Biswas A, Chowdhuri S. Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors – an in silico docking and molecular dynamics simulation study. J Biomol Struct Dyn. 2021;39:4362–74. [DOI] [PubMed] [PMC]

23.

Azam F, Eid EEM, Almutairi A. Targeting SARS-CoV-2 main protease by teicoplanin: a mechanistic insight by docking, MM/GBSA and molecular dynamics simulation. J Mol Struct. 2021;1246:131124. [DOI] [PubMed] [PMC]

24.

Satyanarayana S, Dileep K, Shiva P, Kameshpandian P, Gayathri P, Swathi B. A computational approach on the activity of hesperidin as antagonist for proteins of SARS-CoV-2. BioNanoScience. 2021;10:2571–7. [DOI]

25.

Chen J, Zhou X, Fu L, Xu H. Natural product-based screening for lead compounds targeting SARS CoV-2 M^pro. Pharmaceuticals (Basel). 2023;16:767. [DOI] [PubMed] [PMC]

26.

Maddah M, Bahramsoltani R, Yekta NH, Rahimi R, Aliabadi R, Pourfath M. Proposing high-affinity inhibitors from Glycyrrhiza glabra L. against SARS-CoV-2 infection: virtual screening and computational analysis. New J Chem. 2021;45:15977–95. [DOI]

27.

Khamto N, Utama K, Tateing S, Sangthong P, Rithchumpon P, Cheechana N, et al. Discovery of natural bisbenzylisoquinoline analogs from the library of Thai traditional plants as SARS-CoV-2 3CL^Pro inhibitors: in silico molecular docking, molecular dynamics, and in vitro enzymatic activity. J Chem Inf Model. 2023;63:2104–21. [DOI] [PubMed]

28.

Liu T, Peng F, Cao X, Liu F, Wang Q, Liu L, et al. Design, synthesis, antibacterial activity, antiviral activity, and mechanism of myricetin derivatives containing a quinazolinone moiety. ACS Omega. 2021;6:30826–33. [DOI] [PubMed] [PMC]

29.

Titford M. The long history of hematoxylin. Biotech Histochem. 2005;80:73–8. [DOI] [PubMed]

30.

Ali FR, Orchard GE, Mallipeddi R. Hematoxylin in history—the heritage of histology. JAMA Dermatol. 2017;153:328. [DOI] [PubMed]

31.

Chacko SM, Thambi PT, Kuttan R, Nishigaki I. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13. [DOI] [PubMed] [PMC]

32.

Tan H, Hu Y, Jadhav P, Tan B, Wang J. Progress and challenges in targeting the SARS-CoV-2 papain-like protease. J Med Chem. 2022;65:7561–80. [DOI] [PubMed] [PMC]

33.

Srinivasan V, Brognaro H, Prabhu PR, de Souza EE, Günther S, Reinke PYA, et al. Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease. Commun Biol. 2022;5:805. [DOI] [PubMed] [PMC]

34.

Li L, Ma L, Hu Y, Li X, Yu M, Shang H, et al. Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease. Phytochemistry. 2022;193:112984. [DOI] [PubMed] [PMC]

35.

Lewis DSM, Ho J, Wills S, Kawall A, Sharma A, Chavada K, et al. Aloin isoforms (A and B) selectively inhibits proteolytic and deubiquitinating activity of papain like protease (PLpro) of SARS-CoV-2 in vitro. Sci Rep. 2022;12:2145. [DOI] [PubMed] [PMC]

36.

Pendyala B, Patras A, Dash C. Phycobilins as potent food bioactive broad-spectrum inhibitors against proteases of SARS-CoV-2 and other coronaviruses: a preliminary study. Front Microbiol. 2021;12:645713. [DOI] [PubMed] [PMC]

37.

Liu R, Meng C, Zhang Z, Ma H, Lv T, Xie S, et al. Comparative metabolism of schaftoside in healthy and calcium oxalate kidney stone rats by UHPLC-Q-TOF-MS/MS method. Anal Biochem. 2020;597:113673. [DOI] [PubMed]

38.

De Melo GO, Muzitano MF, Legora-Machado A, Almeida TA, De Oliveira DB, Kaiser CR, et al. C-Glycosylflavones from the aerial parts of Eleusine indica inhibit LPS-induced mouse lung inflammation. Planta Med. 2005;71:362–3. [DOI] [PubMed]

39.

Dwivedy A, Mariadasse R, Ahmad M, Chakraborty S, Kar D, Tiwari S, et al. Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2. PLoS Comput Biol. 2021;17:e1009384. [DOI] [PubMed] [PMC]

40.

Masyeni S, Iqhrammullah M, Frediansyah A, Nainu F, Tallei T, Emran TB, et al. Molnupiravir: a lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2—a narrative review. J Med Virol. 2022;94:3006–16. [DOI] [PubMed] [PMC]

41.

Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, et al. Baicalein and baicalin inhibit SARS-CoV-2 RNA-dependent-RNA polymerase. Microorganisms. 2021;9:893. [DOI] [PubMed] [PMC]

42.

Huang S, Liu Y, Zhang Y, Zhang R, Zhu C, Fan L, et al. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduct Target Ther. 2020;5:266. [DOI] [PubMed] [PMC]

43.

Malone B, Urakova N, Snijder EJ, Campbell EA. Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design. Nat Rev Mol Cell Biol. 2022;23:21–39. [DOI] [PubMed] [PMC]

44.

Corona A, Wycisk K, Talarico C, Manelfi C, Milia J, Cannalire R, et al. Natural compounds inhibit SARS-CoV-2 nsp13 unwinding and ATPase enzyme activities. ACS Pharmacol Transl Sci. 2022;5:226–39. [DOI] [PubMed] [PMC]

45.

Lu L, Peng Y, Yao H, Wang Y, Li J, Yang Y, et al. Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro. Antiviral Res. 2022;206:105389. [DOI] [PubMed] [PMC]

46.

Akhter S, Batool AI, Selamoglu Z, Sevindik M, Eman R, Mustaqeem M, et al. Effectiveness of natural antioxidants against SARS-CoV-2? Insights from the in-silico world. Antibiotics. 2021;10:1011. [DOI] [PubMed] [PMC]

47.

Yosri N, Abd El-Wahed AA, Ghonaim R, Khattab OM, Sabry A, Ibrahim MAA, et al. Anti-viral and immunomodulatory properties of propolis: chemical diversity, pharmacological properties, preclinical and clinical applications, and in silico potential against SARS-CoV-2. Foods. 2021;10:1776. [DOI] [PubMed] [PMC]

48.

Okamoto I, Iwaki K, Koya-Miyata S, Tanimoto T, Kohno K, Ikeda M, et al. The flavonoid kaempferol suppresses the graft-versus-host reaction by inhibiting type 1 cytokine production and CD8⁺ T cell engraftment. Clin Immunol. 2002;103:132–44. [DOI] [PubMed]

49.

Khazdair RM, Anaeigoudari A, Agbor GA. Anti-viral and anti-inflammatory effects of kaempferol and quercetin and COVID-2019: a scoping review. Asian Pac J Trop Biomed. 2021;11:327–34. [DOI]

50.

Tatsimo SJ, Tamokou Jde D, Havyarimana L, Csupor D, Forgo P, Hohmann J, et al. Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum. BMC Res Notes. 2012;5:158. [DOI] [PubMed] [PMC]

51.

Liu DY, Gao L, Zhang J, Huo XW, Ni H, Cao L. Anti-inflammatory and anti-oxidant effects of licorice flavonoids on ulcerative colitis in mouse model. Chinese Herb Med. 2017;9:358–68. [DOI]

52.

Larue RC, Xing E, Kenney AD, Zhang Y, Tuazon JA, Li J, et al. Rationally designed ACE2-derived peptides inhibit SARS-CoV-2. Bioconjugate Chem. 2020;32:215–23. [DOI] [PubMed] [PMC]

53.

Chaves OA, Lima CR, Fintelman-Rodrigues N, Sacramento CQ, de Freitas CS, Vazquez L, et al. Agathisflavone, a natural biflavonoid that inhibits SARS-CoV-2 replication by targeting its proteases. Int J Biol Macromol. 2022;222:1015–26. [DOI] [PubMed] [PMC]

54.

Power H, Wu J, Turville S, Aggarwal A, Valtchev P, Schindeler A, et al. Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein. Bioorg Chem. 2022;119:105574. [DOI] [PubMed] [PMC]

55.

Gao J, Ding Y, Wang Y, Liang P, Zhang L, Liu R. Oroxylin A is a severe acute respiratory syndrome coronavirus 2-spiked pseudotyped virus blocker obtained from Radix Scutellariae using angiotensin-converting enzyme II/cell membrane chromatography. Phytother Res. 2021;35:3194–204. [DOI] [PubMed] [PMC]

56.

Yang C, Pan X, Xu X, Cheng C, Huang Y, Li L, et al. Salvianolic acid C potently inhibits SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein. Signal Transduct Target Ther. 2020;5:220. [DOI] [PubMed] [PMC]

57.

Chen GY, Pan YC, Wu TY, Yao TY, Wang WJ, Shen WJ, et al. Potential natural products that target the SARS-CoV-2 spike protein identified by structure-based virtual screening, isothermal titration calorimetry and lentivirus particles pseudotyped (Vpp) infection assay. J Tradit Complement Med. 2022;12:73–89. [DOI] [PubMed] [PMC]

58.

Zhou H, Li J, Sun F, Wang F, Li M, Dong Y, et al. A review on recent advances in aloperine research: pharmacological activities and underlying biological mechanisms. Front Pharmacol. 2020;11:538137. [DOI] [PubMed] [PMC]

59.

Bailly C. Cepharanthine: an update of its mode of action, pharmacological properties and medical applications. Phytomedicine. 2019;62:152956. [DOI] [PubMed] [PMC]

60.

Wang X, Li X, Xia Y, Wang D, Li X, Liu L, et al. Hernandezine regulates proliferation and autophagy-induced apoptosis in melanoma cells. J Nat Prod. 2022;85:1351–62. [DOI] [PubMed]

61.

Bai J, Zhang S, Cao J, Sun H, Mang Z, Shen WL, et al. Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models. Phytomedicine. 2022;105:154366. [DOI] [PubMed]

62.

Li P, Li X, Wu Y, Li M, Wang X. A novel AMPK activator hernandezine inhibits LPS-induced TNFα production. Oncotarget. 2017;8:67218–26. [DOI] [PubMed] [PMC]

63.

Farooqi AA, Wen R, Attar R, Taverna S, Butt G, Xu B. Regulation of cell-signaling pathways by berbamine in different cancers. Int J Mol Sci. 2022;23:2758. [DOI] [PubMed] [PMC]

64.

Mokhber-Dezfuli N, Saeidnia S, Gohari AR, Kurepaz-Mahmoodabadi M. Phytochemistry and pharmacology of berberis species. Pharmacogn Rev. 2014;8:8–15. [DOI] [PubMed] [PMC]

65.

Zarei A, Changizi-Ashtiyani S, Taheri S, Ramezani M. A quick overview on some aspects of endocrinological and therapeutic effects of Berberis vulgaris L. Avicenna J Phytomed. 2015;5:485–97. [PubMed] [PMC]

66.

Zupin L, Fontana F, Gratton R, Milani M, Clemente L, Pascolo L, et al. SARS-CoV-2 short-time infection produces relevant cytopathic effects in Vero E6 cell line. Int J Environ Res Public Health. 2021;18:9020. [DOI] [PubMed] [PMC]

67.

Leal CM, Leitão SG, Sausset R, Mendonça SC, Nascimento PHA, de Araujo R Cheohen CF, et al. Flavonoids from Siparuna cristata as potential inhibitors of SARS-CoV-2 replication. Rev Bras Farmacogn. 2021;31:658–66. [DOI] [PubMed] [PMC]

68.

ElNaggar MH, Abdelwahab GM, Kutkat O, GabAllah M, Ali MA, El-Metwally MEA, et al. Aurasperone A inhibits SARS CoV-2 in vitro: an integrated in vitro and in silico study. Mar Drugs. 2022;20:179. [DOI] [PubMed] [PMC]

69.

Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, et al. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett. 2021;12:1793–802. [DOI] [PubMed] [PMC]

70.

Gowda P, Patrick S, Joshi SD, Kumawat RK, Sen E. Glycyrrhizin prevents SARS-CoV-2 S1 and Orf3a induced high mobility group box 1 (HMGB1) release and inhibits viral replication. Cytokine. 2021;142:155496. [DOI] [PubMed] [PMC]

71.

Fan H, He ST, Han P, Hong B, Liu K, Li M, et al. Cepharanthine: a promising old drug against SARS-CoV-2. Adv Biol (Weinh). 2022;6:e2200148. [DOI] [PubMed] [PMC]

72.

Alhadrami HA, Sayed AM, Hassan HM, Rateb ME. Aloin A inhibits SARS CoV-2 replication by targeting its binding with ACE2 - evidence from modeling-supported molecular dynamics simulation. J Biomol Struct Dyn. 2023:1–10. [DOI] [PubMed]

73.

Venusova E, Kolesarova A, Horky P, Slama P. Physiological and immune functions of punicalagin. Nutrients. 2021;13:2150. [DOI] [PubMed] [PMC]

74.

Xiao J, Chen S, Chen Y, Su J. The potential health benefits of aloin from genus Aloe. Phytother Res. 2022;36:873–90. [DOI] [PubMed]

75.

Baczenas JJ, Andersen H, Rashid S, Yarmosh D, Puthuveetil N, Parker M, et al. Propagation of SARS-CoV-2 in Calu-3 cells to eliminate mutations in the furin cleavage site of spike. Viruses. 2021;13:2434. [DOI] [PubMed] [PMC]

76.

Chaves OA, Fintelman-Rodrigues N, Wang X, Sacramento CQ, Temerozo JR, Ferreira AC, et al. Commercially available flavonols are better SARS-CoV-2 inhibitors than isoflavone and flavones. Viruses. 2022;14:1458. [DOI] [PubMed] [PMC]

77.

Chhetri BK, Tedbury PR, Sweeney-Jones AM, Mani L, Soapi K, Manfredi C, et al. Marine natural products as leads against SARS-CoV-2 infection. J Nat Prod. 2022;85:657–65. [DOI] [PubMed] [PMC]

78.

Park HH, Lee S, Oh JM, Lee MS, Yoon KH, Park BH, et al. Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacol Res. 2007;55:31–7. [DOI] [PubMed]

79.

Grynkiewicz G, Demchuk OM. New perspectives for fisetin. Front Chem. 2019;7:697. [DOI] [PubMed] [PMC]

80.

Lu TM, Ko HH, Ng LT, Hsieh YP. Free‐radical‐scavenging, antityrosinase, and cellular melanogenesis inhibitory activities of synthetic isoflavones. Chem Biodivers. 2015;12:963–79. [DOI] [PubMed]

81.

Lee AV, Oesterreich S, Davidson NE. MCF-7 cells—changing the course of breast cancer research and care for 45 years. J Natl Cancer Inst. 2015;107:djv073. [DOI] [PubMed]

82.

Bartolomeo CS, Lemes RMR, Morais RL, Pereria GC, Nunes TA, Costa AJ, et al. SARS-CoV-2 infection and replication kinetics in different human cell types: the role of autophagy, cellular metabolism and ACE2 expression. Life Sci. 20221;308:120930. [DOI] [PubMed] [PMC]

83.

Kumar V, Dhanjal JK, Bhargava P, Kaul A, Wang J, Zhang H, et al. Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. J Biomol Struct Dyn. 2022;40:1–13. [DOI] [PubMed] [PMC]

84.

Tolba MF, Omar HA, Azab SS, Khalifa AE, Abdel-Naim AB, Abdel-Rahman SZ. Caffeic acid phenethyl ester: a review of its antioxidant activity, protective effects against ischemia-reperfusion injury and drug adverse reactions. Crit Rev Food Sci Nutr. 2016;56:2183–90. [DOI] [PubMed]

85.

Russo A, Longo R, Vanella A. Antioxidant activity of propolis: role of caffeic acid phenethyl ester and galangin. Fitoterapia. 2002;73:S21–9. [DOI] [PubMed]

86.

Lv L, Cui H, Ma Z, Liu X, Yang L. Recent progresses in the pharmacological activities of caffeic acid phenethyl ester. Naunyn Schmiedebergs Arch Pharmacol. 2021;394:1327–39. [DOI] [PubMed]

87.

Chinese Clinical Trial Registry (ChiCTR) [Internet]. Chinese Clinical Trial Register; c2022 [cited 2022 Oct 4]. Available from: https://www.chictr.org.cn/aboutEN.html

88.

CANnabiDiol for CoviD-19 pATiEnts with mild to moderate symptoms (CANDIDATE) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04467918

89.

Effect of combined use of ivermectin and colchicine in COVID-19 patients [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05246072

90.

Effectiveness of colchicine among patients with COVID-19 infection [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04867226

91.

RBR-8jyhxh clinical trial for the treatment of COVID-19 with chloroquine and colchicine [Internet]. The Brazilian Registry of Clinical Trials; [cited 2022 Oct 4]. Available from: https://ensaiosclinicos.gov.br/rg/RBR-8jyhxh/

92.

Effect of colchicine in treatment of COVID-19 [Internet]. World Health Organization; c2022 [cited 2022 Oct 4]. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190810044500N5

93.

Effect of nanocurcumin supplementation on the severity of symptoms and length of hospital stay in patients with COVID-19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/51310

94.

Effects of nano curcumin supplementation on the reduction of inflammation and mortality in patients with coronavirus 2019 admitted to ICU ward of Imam Reza hospital in Tabriz [Internet]. Iranian Registry of Clinical Trials riz; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/46712

95.

Evaluation of SinaCurcumin as a complementary therapy in mild to moderate COVID-19: an open label non-randomized clinical trial [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/47061

96.

Evaluation of the effect of nano micelles containing curcumin (Sina Ccurcumin) as a therapeutic supplement in patients with COVID-19 and investigating of immune responses balance changes following treatment: a randomized double blind clinical trial [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/48843

97.

Evaluation the anti-inflammatory effects of curcumin in the treatment of patients with COVID-19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/48292

98.

Nutritional supplementation of flavonoids quercetin and curcumin for early mild symptoms of COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05130671

99.

Effect of nutritional supplement made from Haldi and Black Pepper to prevent and treat active corona virus infection [Internet]. CTRI; [cited 2022 Oct 4]. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI%2F2020%2F05%2F025482

100.

Complementary intervention for COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04487964

101.

The effect of Aftogel strips on results of nasopharyngeal secretion PCR test in volunteers with positive test for COVID-19 virus [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/51774

102.

Investigating the effectiveness of the use of hesperidin on the clinical conditions of patients with the new coronavirus (SARS-COV-2) [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://www.irct.ir/trial/49150

103.

Study of hesperidin therapy on COVID-19 symptoms (HESPERIDIN) (Hesperidin) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04715932

104.

Trial to determine the efficacy/safety of plitidepsin vs control in patients with moderate COVID-19 infection (neptuno) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04784559

105.

Effect of quercetin on prophylaxis and treatment of COVID-19 [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04377789

106.

Evaluation of the effect of quercetin on the effectiveness of antiviral drug regimen in patients with COVID19 [Internet]. Iranian Registry of Clinical Trials; c2022 [cited 2022 Oct 4]. Available from: https://en.irct.ir/trial/47396

107.

Quercetin in the prevention of covid-19 infection [Internet]. Clinical Trials Register; c2022 [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT05037240

108.

Can SARS-CoV-2 viral load and COVID-19 disease severity be reduced by resveratrol-assisted zinc therapy (reszinate) [Internet]. Clinical Trials Register; [cited 2022 Oct 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04542993

109.

Resveratrol and copper for the treatment of COVID-19 pnuemonia [Internet]. Clinical Trials Registry-India; c2022 [cited 2022 Oct 4]. Available from: https://ctri.nic.in/Clinicaltrials/showallp.php?mid1=45115&EncHid=&userName=Rosemarie%20desouza

110.

Randomized proof-of-concept trial to evaluate the safety and explore the effectiveness of resveratrol, a plant polyphenol, for COVID-19 [Internet]. Clinical Trials Registry; [cited 2022 Oct 4]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04400890

111.

Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, et al. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: an open-label, non-randomised and controlled trial. Int J Antimicrob Agents. 2021;57:106216. [DOI] [PubMed] [PMC]

112.

Lin Y, Wu F, Xie Z, Song X, Zhu Q, Wei J, et al. Clinical study of artesunate in the treatment of coronavirus disease 2019. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32:417–20. Chinese. [DOI] [PubMed]

113.

Zhang BY, Chen M, Chen XC, Cao K, You Y, Qian YJ, et al. Berberine reduces circulating inflammatory mediators in patients with severe COVID-19. Br J Surg. 2021;108:e9–11. [DOI] [PubMed] [PMC]

114.

Crippa JAS, Pacheco JC, Zuardi AW, Guimarães FS, Campos AC, Osório FL, et al. Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE study): a randomized, double-blind, placebo-controlled clinical trial. Cannabis Cannabinoid Res. 2022;7:658–69. [DOI] [PubMed]

115.

Dorward J, Yu LM, Hayward G, Saville BR, Gbinigie O, Van Hecke O, et al.; PRINCIPLE Trial Collaborative Group PRINCIPLE Trial Collaborative Group. Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. Br J Gen Pract. 2022;72:e446–55. [DOI] [PubMed] [PMC]

116.

El Sayed RG, Hafez AF, Mohammed Haggag AM, Alhadidy MA. Effect of combined use of ivermectin and colchicine in COVID-19 patients. Egy J Anaesth. 2022;38:365–72. [DOI]

117.

Jalal AM, Aref SF, Albustany DA. Effectiveness of colchicine among patients with COVID-19 infection: a randomized, open-labeled, clinical trial. Indian J Rheumatol. 2022;17:136–41.

118.

Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7:e001455. [DOI] [PubMed] [PMC]

119.

Pourdowlat G, Saghafi F, Mozafari A, Sahebnasagh A, Abedini A, Nabi Meybodi M, et al. Efficacy and safety of colchicine treatment in patients with COVID-19: a prospective, multicenter, randomized clinical trial. Phytother Res. 2022;36:891–8. [DOI] [PubMed]

120.

Sandhu T, Tieng A, Chilimuri S, Franchin G. a case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020;2020:8865954. [DOI] [PubMed] [PMC]

121.

Honarkar Shafie E, Taheri F, Alijani N, Okhovvat AR, Goudarzi R, Borumandnia N, et al. Effect of nanocurcumin supplementation on the severity of symptoms and length of hospital stay in patients with COVID-19: a randomized double-blind placebo-controlled trial. Phytother Res. 2022;36:1013–22. [DOI] [PubMed]

122.

Abbaspour-Aghdam S, Hazrati A, Abdolmohammadi-Vahid S, Tahmasebi S, Mohseni J, Valizadeh H, et al. Immunomodulatory role of nanocurcumin in COVID-19 patients with dropped natural killer cells frequency and function. Eur J Pharmacol. 2022;933:175267. [DOI] [PubMed] [PMC]

123.

Saber-Moghaddam N, Salari S, Hejazi S, Amini M, Taherzadeh Z, Eslami S, et al. Oral nano-curcumin formulation efficacy in management of mild to moderate hospitalized coronavirus disease-19 patients: an open label nonrandomized clinical trial. Phytother Res. 2021;35:2616–23. [DOI] [PubMed]

124.

Hassaniazad M, Eftekhar E, Inchehsablagh BR, Kamali H, Tousi A, Jaafari MR, et al. A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients. Phytother Res. 2021;35:6417–27. [DOI] [PubMed] [PMC]

125.

Asadirad A, Nashibi R, Khodadadi A, Ghadiri AA, Sadeghi M, Aminian A, et al. Antiinflammatory potential of nano-curcumin as an alternative therapeutic agent for the treatment of mild-to-moderate hospitalized COVID-19 patients in a placebo-controlled clinical trial. Phytother Res. 2022;36:1023–31. [DOI] [PubMed]

126.

Khan A, Iqtadar S, Mumtaz SU, Heinrich M, Pascual-Figal DA, Livingstone S, et al. Oral co-supplementation of curcumin, quercetin, and vitamin d3 as an adjuvant therapy for mild to moderate symptoms of COVID-19—results from a pilot open-label, randomized controlled trial. Front Pharmacol. 2022;13:898062. [DOI] [PubMed] [PMC]

127.

Pawar KS, Mastud RN, Pawar SK, Pawar SS, Bhoite RR, Bhoite RR, et al. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: a randomized clinical trial. Front Pharmacol. 2021;12:669362. [DOI] [PubMed] [PMC]

128.

Gomaa AA, Mohamed HS, Abd-Ellatief RB, Gomaa MA, Hammam DS. Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial. Inflammopharmacology. 2022;30:477–86. [DOI] [PubMed] [PMC]

129.

Pourahmad M, Shahzamani K, Nikokar F, Saniei M, Saniei M, Soltani R. The effects of licorice mucoadhesive patches on the results of nasopharyngeal swab real-time polymerase chain reaction test of SARS-CoV-2; a randomized triple-blind placebo-controlled clinical trial. Immunopathol Persa. 2022;[Epub ahead of print]. [DOI]

130.

Liao FL, Peng DH, Chen W, Hu HN, Tang P, Liu YY, et al. Evaluation of serum hepatic enzyme activities in different COVID-19 phenotypes. J Med Virol. 2021;93:2365–73. [DOI] [PubMed]

131.

Jahangirifard A, Mirtajani SB, Karimzadeh M, Forouzmehr M, Kiani A, Moradi M, et al. The effect of hesperidin on laboratory parameters of patients with COVID 19: a preliminary report of a clinical trial study. J Iran Med Council. 2022;5:89–95. [DOI]

132.

Dupuis J, Laurin P, Tardif JC, Hausermann L, Rosa C, Guertin MC, et al. Fourteen-day evolution of COVID-19 Symptoms during the third wave in nonvaccinated subjects and effects of hesperidin therapy: a randomized, double-blinded, placebo-controlled study. Evid Based Complement Alternat Med. 2022;2022:3125662. [DOI] [PubMed] [PMC]

133.

D’Ascanio L, Vitelli F, Cingolani C, Maranzano M, Brenner MJ, Di Stadio A. Randomized clinical trial “olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with palmitoylethanolamide and luteolin”: preliminary results. Eur Rev Med Pharmacol Sci. 2021;25:4156–62. [DOI] [PubMed]

134.

De Luca P, Camaioni A, Marra P, Salzano G, Carriere G, Ricciardi L, et al. Effect of ultra-micronized palmitoylethanolamide and luteolin on olfaction and memory in patients with long COVID: results of a longitudinal study. Cells. 2022;11:2552. [DOI] [PubMed] [PMC]

135.

Varona JF, Landete P, Lopez-Martin JA, Estrada V, Paredes R, Guisado-Vasco P, et al. Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. Life Sci Alliance. 2022;5:e202101200. [DOI] [PubMed] [PMC]

136.

Guisado-Vasco P, González-Cortijo L, D’Errico G, Serrera-Alvarez A, Sotres-Fernandez G, García-Coca M, et al. Plitidepsin for the management of a cancer patient infected with SARS-CoV-2 while receiving chemotherapy. Ann Oncol. 2021;32:1295–7. [DOI] [PubMed] [PMC]

137.

Önal H, Arslan B, Üçüncü Ergun N, Topuz Ş, Yilmaz Semerci S, Kurnaz ME, et al. Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial. Turk J Biol. 2021;45:518–29. [DOI] [PubMed] [PMC]

138.

Shohan M, Nashibi R, Mahmoudian-Sani MR, Abolnezhadian F, Ghafourian M, Alavi SM, et al. The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: a randomized controlled trial. Eur J Pharmacol. 2022;914:174615. [DOI] [PubMed] [PMC]

139.

Rondanelli M, Perna S, Gasparri C, Petrangolini G, Allegrini P, Cavioni A, et al. Promising effects of 3-month period of Quercetin Phytosome^® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study. Life (Basel). 2022;12:66. [DOI] [PubMed] [PMC]

140.

Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, et al. Potential clinical benefits of quercetin in the early stage of COVID-19: results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med. 2021;14:2807–16. [DOI] [PubMed] [PMC]

141.

Kaplan HG, Wang K, Reeves KM, Scanlan JM, Nunn CC, Kieper DA, et al. Reszinate—a phase 1/2 randomized clinical trial of zinc and resveratrol utilizing home patient-obtained nasal and saliva viral sampling. Front Drug Discov. 2022;2:910124. [DOI]

142.

Mittra I, de Souza R, Bhadade R, Madke T, Shankpal PD, Joshi M, et al. Resveratrol and copper for treatment of severe COVID-19: an observational study (RESCU 002). medRxiv [Preprint]. 2020 [cited 2020 Jul 21]. Available from: https://www.medrxiv.org/content/10.1101/2020.07.21.20151423v1

143.

McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep. 2021;12:10978. [DOI] [PubMed] [PMC]

144.

Rattis BAC, Ramos SG, Celes MRN. Curcumin as a potential treatment for COVID-19. Front Pharmacol. 2021;12:675287. [DOI] [PubMed] [PMC]

145.

Ibrahim MAA, Abdelrahman AHM, Hussien TA, Badr EAA, Mohamed TA, El-Seedi HR, et al. In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors. Comput Biol Med. 2020;126:104046. [DOI] [PubMed] [PMC]

146.

Marín-Palma D, Tabares-Guevara JH, Zapata-Cardona MI, Flórez-Álvarez L, Yepes LM, Rugeles MT, et al. Curcumin inhibits in vitro SARS-CoV-2 infection in Vero E6 cells through multiple antiviral mechanisms. Molecules. 2021;26:6900. [DOI] [PubMed] [PMC]

147.

Bahun M, Jukić M, Oblak D, Kranjc L, Bajc G, Butala M, et al. Inhibition of the SARS-CoV-2 3CL^pro main protease by plant polyphenols. Food Chem. 2022;373:131594. [DOI] [PubMed] [PMC]

148.

Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, Inflammation and Immunity. Nutrients. 2016;8:167. [DOI] [PubMed] [PMC]

149.

Schlesinger N, Firestein BL, Brunetti L. Colchicine in COVID-19: an old drug, new use. Curr Pharmacol Rep. 2020;6:137–45. [DOI] [PubMed] [PMC]

150.

Yu Y, Liu G, Piao M, Lang M, Wang Y, Jin M, et al. Chemical constituents of Polygonum aviculare L. and their chemotaxonomic significance. Biochem Syst Ecol. 2022;105:104529. [DOI]

151.

Zannella C, Giugliano R, Chianese A, Buonocore C, Vitale GA, Sanna G, et al. Antiviral activity of Vitis vinifera leaf extract against SARS-CoV-2 and HSV-1. Viruses. 2021;13:1263. [DOI] [PubMed] [PMC]

152.

Liu S, Wang B, Li XZ, Qi LF, Liang YZ. Preparative separation and purification of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera GAERTN using high-speed counter-current chromatography. J Sep Sci. 2009;32:2476–81. [DOI] [PubMed]

153.

Sanna C, Marengo A, Acquadro S, Caredda A, Lai R, Corona A, et al. In vitro anti-HIV-1 reverse transcriptase and integrase properties of Punica granatum L. leaves, bark, and peel extracts and their main compounds. Plants. 2021;10:2124. [DOI] [PubMed] [PMC]

154.

Pasquereau S, Nehme Z, Haidar Ahmad S, Daouad F, Van Assche J, Wallet C, et al. Resveratrol inhibits HCoV-229E and SARS-CoV-2 coronavirus replication in vitro. Viruses. 2021;13:354. [DOI] [PubMed] [PMC]

155.

de Oliveira JR, Antunes BS, do Nascimento GO, Kawall JCS, Oliveira JVB, Silva KGDS, et al. Antiviral activity of medicinal plant-derived products against SARS-CoV-2. Exp Biol Med (Maywood). 2022;247:1797–809. [DOI] [PubMed]