{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T04:42:53Z","timestamp":1761021773578,"version":"build-2065373602"},"reference-count":74,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["406739-2018-8","303804-2020-3","306900\/2023-8","407779\/2021-3","309744\/2022-9","312538\/2021-9"],"award-info":[{"award-number":["406739-2018-8","303804-2020-3","306900\/2023-8","407779\/2021-3","309744\/2022-9","312538\/2021-9"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Apoio \u00e0 Pesquisa","award":["SEI-260003\/001599\/2022","E-26\/211.357\/2021","E-26\/200.393\/2023"],"award-info":[{"award-number":["SEI-260003\/001599\/2022","E-26\/211.357\/2021","E-26\/200.393\/2023"]}]},{"DOI":"10.13039\/501100004901","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Minas Gerais","doi-asserted-by":"publisher","award":["APQ-CEX00518-17"],"award-info":[{"award-number":["APQ-CEX00518-17"]}],"id":[{"id":"10.13039\/501100004901","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Instituto Nacional de Ci\u00eancia e Tecnologia em F\u00e1rmacos e Medicamentos","award":["465249\/2014-0"],"award-info":[{"award-number":["465249\/2014-0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against SARS-CoV-2 to a antiviral activity and inhibitory effect against angiotensin converting enzyme 2 (ACE2). A possible inhibitory effect affecting the interaction between the receptor-binding domain (RBD) protein and\/or ACE2 was evaluated using LUMMIT kit. A SARS-CoV-2-induced pulmonary pneumonia model was developed to evaluate the effects of the compounds after 3 days of treatment. Results: Compounds PQM-243 and PQM-249 exhibited IC50 values of 0.0648 \u00b1 0.041 \u00b5M and 0.2860 \u00b1 0.057 \u00b5M against SARS-CoV-2 with a selective index of &gt;1543.21 and 349.65, respectively, and IC50 values of 12.1 nM and 13.3 nM, respectively, against ACE2. All concentrations used significantly reduced interactions between ACE2 and RBD. Computational studies suggest that these new compounds are potent direct anti-SARS-CoV-2 agents, capable of reducing both virus viability and its invasive ability in the host cells by reducing the interaction between RBD and ACE2. It was also demonstrated that even when administered by the oral route, both compounds reduced SARS-CoV-2-induced lung inflammation. Our data suggests that both compounds can act as potent direct anti-SARS-CoV-2 agents, reducing both viral viability and host cell entry. In addition, they exhibited a significant multi-target-directed pharmacological profile, also reducing SARS-CoV-2-induced lung inflammation when administered orally. Conclusions: Overall, these findings support further investigation of PQM-243 and PQM-249 as promising antiviral and anti-inflammatory multi-target prototypes for the development of innovative drug candidates targeting SARS-CoV-2 and other virus-related respiratory diseases.<\/jats:p>","DOI":"10.3390\/ph18101565","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:33:22Z","timestamp":1760632402000},"page":"1565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Multifunctional Cannabidiol-Based Analogues with In Silico, In Vitro, and In Vivo Anti-SARS-CoV-2 Effect"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5524-8199","authenticated-orcid":false,"given":"Graziella dos Reis Rosa","family":"Franco","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-818X","authenticated-orcid":false,"given":"Vanessa Silva","family":"Gontijo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-2851","authenticated-orcid":false,"given":"Fl\u00e1via Pereira Dias","family":"Viegas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-2758","authenticated-orcid":false,"given":"Matheus de Freitas","family":"Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9988-8895","authenticated-orcid":false,"given":"Cindy Juliet Cristancho","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9354-0708","authenticated-orcid":false,"given":"Caio Miranda","family":"Dam\u00e1sio","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella Marie Fernandes","family":"Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Th\u00e2mara Gaspar","family":"Campos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5442-6240","authenticated-orcid":false,"given":"Erik Vinicius de Sousa","family":"Reis","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Virologia B\u00e1sica e Aplicada, Instituto de Ci\u00eancias Biol\u00f3gicas, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3028-3187","authenticated-orcid":false,"given":"Felipe Alves","family":"Clarindo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Virologia B\u00e1sica e Aplicada, Instituto de Ci\u00eancias Biol\u00f3gicas, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tha\u00eds de F\u00e1tima Silva","family":"Moraes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Virologia B\u00e1sica e Aplicada, Instituto de Ci\u00eancias Biol\u00f3gicas, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0659-6365","authenticated-orcid":false,"given":"Matheus M\u00fcller Pereira da","family":"Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica (LNCC), Petr\u00f3polis 25651-075, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patr\u00edcia Ribeiro de Carvalho","family":"Fran\u00e7a","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia da Dor e da Inflama\u00e7\u00e3o, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella Alvim","family":"Guedes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica (LNCC), Petr\u00f3polis 25651-075, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8518-8062","authenticated-orcid":false,"given":"Laurent Emmanuel","family":"Dardenne","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica (LNCC), Petr\u00f3polis 25651-075, Rio de Janeiro, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordana Grazziela Alves Coelho dos","family":"Reis","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Virologia B\u00e1sica e Aplicada, Instituto de Ci\u00eancias Biol\u00f3gicas, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6870-6745","authenticated-orcid":false,"given":"Patr\u00edcia Dias","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia da Dor e da Inflama\u00e7\u00e3o, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-992X","authenticated-orcid":false,"suffix":"Jr.","given":"Claudio","family":"Viegas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Qu\u00edmica Medicinal (PeQuiM), Instituto de Qu\u00edmica, Universidade Federal de Alfenas, Alfenas 37130-001, Minas Gerais, Brasil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","first-page":"1824","article-title":"Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review","volume":"323","author":"Sanders","year":"2020","journal-title":"JAMA\u2014J. Am. Med. Assoc."},{"key":"ref_2","unstructured":"World Health Organization (2025). WHO COVID-19 Dashboard, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1080\/21645515.2020.1735227","article-title":"COVID-19, an Emerging Coronavirus Infection: Advances and Prospects in Designing and Developing Vaccines, Immunotherapeutics, and Therapeutics","volume":"16","author":"Dhama","year":"2020","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1111\/all.14429","article-title":"Distribution of ACE2, CD147, CD26, and Other SARS-CoV-2 Associated Molecules in Tissues and Immune Cells in Health and in Asthma, COPD, Obesity, Hypertension, and COVID-19 Risk Factors","volume":"75","author":"Radzikowska","year":"2020","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/jmv.25681","article-title":"Emerging Coronaviruses: Genome Structure, Replication, and Pathogenesis","volume":"92","author":"Chen","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_8","unstructured":"(2024, September 15). COVID-19 Deaths Reported (2024 Global). Available online: https:\/\/data.who.int\/dashboards\/covid19\/."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tasneem, A., Sultan, A., Singh, P., Bairagya, H.R., Almasoudi, H.H., Alhazmi, A.Y.M., Binshaya, A.S., Hakami, M.A., Alotaibi, B.S., and Abdulaziz Eisa, A. (2024). Identification of Potential Therapeutic Targets for COVID-19 through a Structural-Based Similarity Approach between SARS-CoV-2 and Its Human Host Proteins. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1292280"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kanimozhi, G., Pradhapsingh, B., Pawar, C.S., Khan, H.A., Alrokayan, S.H., and Prasad, N.R. (2021). SARS-CoV-2: Pathogenesis, Molecular Targets and Experimental Models. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.638334"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.dsx.2020.03.012","article-title":"Contentious Issues and Evolving Concepts in the Clinical Presentation and Management of Patients with COVID-19 Infection with Reference to Use of Therapeutic and Other Drugs Used in Co-Morbid Diseases (Hypertension, Diabetes Etc)","volume":"14","author":"Gupta","year":"2020","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mei, M., and Tan, X. (2021). Current Strategies of Antiviral Drug Discovery for COVID-19. Front. Mol. Biosc., 8.","DOI":"10.3389\/fmolb.2021.671263"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1021\/acs.molpharmaceut.0c00608","article-title":"COVID-19 Transmission, Current Treatment, and Future Therapeutic Strategies","volume":"18","author":"Salian","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12359","DOI":"10.1021\/acs.jmedchem.0c00606","article-title":"COVID-19: Drug Targets and Potential Treatments","volume":"63","author":"Gil","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4014\/jmb.2110.10029","article-title":"COVID-19 Drug Development","volume":"32","author":"Kim","year":"2022","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/jmv.25707","article-title":"Potential Interventions for Novel Coronavirus in China: A Systematic Review","volume":"92","author":"Zhang","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal Structure of SARS-CoV-2 Main Protease Provides a Basis for Design of Improved a-Ketoamide Inhibitors","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-Based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Senger, M.R., Evangelista, T.C.S., Dantas, R.F., Santana, M.V.S., Gon\u00e7alves, L.C.S., Neto, L.R.S., Ferreira, S.B., and Silva-Junior, F.P. (2020). COVID-19: Molecular Targets, Drug Repurposing and New Avenues for Drug Discovery. Mem. Inst. Oswaldo Cruz, 115.","DOI":"10.1590\/0074-02760200254"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Stasi, C., Fallani, S., Voller, F., and Silvestri, C. (2020). Treatment for COVID-19: An Overview. Eur. J. Pharmacol., 889.","DOI":"10.1016\/j.ejphar.2020.173644"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-20542-0","article-title":"Mechanism of SARS-CoV-2 Polymerase Stalling by Remdesivir","volume":"12","author":"Kokic","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mahase, E. (2020). COVID-19: Remdesivir Probably Reduces Recovery Time, but Evidence Is Uncertain, Panel Finds. BMJ, 370.","DOI":"10.1136\/bmj.m3049"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sheahan, T.P., Sims, A.C., Leist, S.R., Sch\u00e4fer, A., Won, J., Brown, A.J., Montgomery, S.A., Hogg, A., Babusis, D., and Clarke, M.O. (2020). Comparative Therapeutic Efficacy of Remdesivir and Combination Lopinavir, Ritonavir, and Interferon Beta against MERS-CoV. Nat. Commun., 11.","DOI":"10.1038\/s41467-019-13940-6"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1126\/science.abc1560","article-title":"Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir","volume":"368","author":"Yin","year":"2020","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rochwerg, B., Agarwal, A., Zeng, L., Leo, Y.S., Appiah, J.A., Agoritsas, T., Bartoszko, J., Brignardello-Petersen, R., Ergan, B., and Ge, L. (2020). Remdesivir for Severe COVID-19: A Clinical Practice Guideline. BMJ, 370.","DOI":"10.1136\/bmj.m2924"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1146\/annurev-med-042220-012417","article-title":"COVID-19: Inflammatory Profile","volume":"73","author":"Wang","year":"2022","journal-title":"Annu. Rev. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, K., Chen, W., Zhang, Z., Deng, Y., Lian, J.Q., Du, P., Wei, D., Zhang, Y., Sun, X.X., and Gong, L. (2020). CD147-Spike Protein Is a Novel Route for SARS-CoV-2 Infection to Host Cells. Signal Transduct. Target. Ther., 5.","DOI":"10.1038\/s41392-020-00426-x"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The Trinity of COVID-19: Immunity, Inflammation and Intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Guo, Z., Li, Q., Han, Y., Liang, Y., Xu, Z., and Ren, T. (2012). Prevention of Lps-Induced Acute Lung Injury in Mice by Progranulin. Mediat. Inflamm., 2012.","DOI":"10.1155\/2012\/540794"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1371\/journal.pmed.0040269","article-title":"Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin","volume":"4","author":"Mei","year":"2007","journal-title":"PLoS Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1164\/ajrccm.151.2.7842182","article-title":"Clinical Risks for Development of the Acute Respiratory Distress Syndrome","volume":"151","author":"Hudson","year":"1995","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/0002-9610(82)90612-2","article-title":"Clinical Predictors of the Adult Respiratory Distress Syndrome","volume":"1","author":"Pepe","year":"1982","journal-title":"Am. J. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1177\/0192623315598399","article-title":"Mouse Models of Acute Respiratory Distress Syndrome","volume":"43","author":"Aeffner","year":"2015","journal-title":"Toxicol. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1165\/rcmb.2009-0210ST","article-title":"An Official American Thoracic Society Workshop Report: Features and Measurements of Experimental Acute Lung Injury in Animals","volume":"44","author":"Downey","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1165\/rcmb.2021-0531ST","article-title":"Update on the Features and Measurements of Experimental Acute Lung Injury in Animals An Official American Thoracic Society Workshop Report","volume":"66","author":"Kulkarni","year":"2022","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical Course and Risk Factors For Mortality Of Adult In Patients with COVID-19 In Wuhan, China: A Retrospective Cohort Study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Heimfarth, L., Serafini, M.R., Martins-Filho, P.R., Quintans, J.S.S., and Quintans-J\u00fanior, L.J. (2020). Drug Repurposing and Cytokine Management in Response to COVID-19: A Review. Int. Immunopharmacol., 88.","DOI":"10.1016\/j.intimp.2020.106947"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Shrestha, R., Johnson, P.M., Ghimire, R., Whitley, C.J., and Channappanavar, R. (2024). Differential TLR-ERK1\/2 Activity Promotes Viral SsRNA and DsRNA Mimic-Induced Dysregulated Immunity in Macrophages. Pathogens, 13.","DOI":"10.1101\/2024.05.24.595760"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Silva, M.J.A., Ribeiro, L.R., Gouveia, M.I.M., Marcelino, B.d.R., dos Santos, C.S., Lima, K.V.B., and Lima, L.N.G.C. (2023). Hyperinflammatory Response in COVID-19: A Systematic Review. Viruses, 15.","DOI":"10.3390\/v15020553"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41593-025-01871-z","article-title":"Microglia Dysfunction, Neurovascular Inflammation and Focal Neuropathologies Are Linked to IL-1- and IL-6-Related Systemic Inflammation in COVID-19","volume":"28","author":"Fekete","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Caohuy, H., Eidelman, O., Chen, T., Mungunsukh, O., Yang, Q., Walton, N.I., Pollard, B.S., Khanal, S., Hentschel, S., and Florez, C. (2024). Inflammation in the COVID-19 Airway Is Due to Inhibition of CFTR Signaling by the SARS-CoV-2 Spike Protein. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-66473-4"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4049\/jimmunol.2000413","article-title":"COVID-19 as an Acute Inflammatory Disease","volume":"205","author":"Manjili","year":"2020","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Souza, M.L., Paiva, J.P.B., Franco, G.R.R., Gontijo, V.S., Alves, M.A., Souza, H.M.R., Lontra, A.C.P., Oliveira, E.A., Giorno, T.B.S., and Guedes, I.A. (2025). Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues. Pharmaceuticals, 18.","DOI":"10.3390\/ph18050755"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"De Freitas Silva, M., Ortiz, C.J.C., Coelho, L.F., Pruccoli, L., Pagliarani, B., Pisani, L., Catto, M., Poli, G., Tuccinardi, T., and Vilela, F.C. (2024). Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson\u2019s disease. Bioorg. Chem., 150.","DOI":"10.1016\/j.bioorg.2024.107587"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/jpp\/rgad077","article-title":"A synthetic resveratrol-curcumin hybrid derivative exhibits chemopreventive effects on colon pre-neoplastic lesions by targeting Wnt\/\u03b2-catenin signaling, anti-inflammatory and antioxidant pathways","volume":"76","author":"Baptistella","year":"2023","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1039\/D1MD00374G","article-title":"Design, synthesis, and biological evaluation of new thalidomide-donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation","volume":"13","author":"Ortiz","year":"2022","journal-title":"RSC Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1007\/s11064-020-03148-2","article-title":"Cinnamoyl-N-Acylhydrazone-Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurodegenerative Diseases","volume":"45","author":"Ortiz","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.3390\/molecules25143165","article-title":"Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer\u2019s Disease","volume":"25","author":"Silva","year":"2020","journal-title":"Molecules"},{"key":"ref_50","first-page":"254","article-title":"Cannabinoids as Immune System Modulators: Cannabidiol Potential Therapeutic Approaches and Limitations","volume":"8","author":"Aziz","year":"2023","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nguyen, L.C., Yang, D., Nicolaescu, V., Best, T.J., Gula, H., Saxena, D., Gabbard, J.D., Chen, S.N., Ohtsuki, T., and Friesen, J.B. (2022). Cannabidiol Inhibits SARS-CoV-2 Replication through Induction of the Host ER Stress and Innate Immune Responses. Sci. Adv., 8.","DOI":"10.1126\/sciadv.abi6110"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"48499","DOI":"10.1021\/acsomega.3c08407","article-title":"Naturally Occurring Isorhamnetin Glycosides as Potential Agents Against Influenza Viruses: Antiviral and Molecular Docking Studies","volume":"50","author":"Bogoyavlenskiy","year":"2023","journal-title":"ACS Omega"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.ijpddr.2018.10.002","article-title":"Chloroquine Analogs as Antimalarial Candidates with Potent in Vitro and in Vivo Activity","volume":"8","author":"Aguiar","year":"2018","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Le\u00f3n, P., Ca\u00f1as-Arranz, R., Bustos, M.J., S\u00e1iz, M., and Sobrino, F. (2023). Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals. Antimicrob. Agents Chemother., 67.","DOI":"10.1128\/aac.01703-22"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Williams, T.L., Colzani, M.T., Macrae, R.G.C., Robinson, E.L., Bloor, S., Greenwood, E.J.D., Zhan, J.R., Strachan, G., Kuc, R.E., and Nyimanu, D. (2021). Human Embryonic Stem Cell-Derived Cardiomyocyte Platform Screens Inhibitors of SARS-CoV-2 Infection. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-02453-y"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41577-020-0331-4","article-title":"Pathological Inflammation in Patients with COVID-19: A Key Role for Monocytes and Macrophages","volume":"20","author":"Merad","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Catanzaro, M., Fagiani, F., Racchi, M., Corsini, E., Govoni, S., and Lanni, C. (2020). Immune Response in COVID-19: Addressing a Pharmacological Challenge by Targeting Pathways Triggered by SARS-CoV-2. Signal Transduct. Target. Ther., 5.","DOI":"10.1038\/s41392-020-0191-1"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Sacchi, A., Giannessi, F., Sabatini, A., Percario, Z.A., and Affabris, E. (2023). SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119353"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ferreira, G.M., Clarindo, F.A., Ribeiro, \u00c1.L., Gomes-de-Pontes, L., Carvalho, L.D., Martins-Filho, O.A., Fonseca, F.G., Teixeira, M.M., Sabino, A.P., and Eapen, M.S. (2023). Taming the SARS-CoV-2-Mediated Proinflammatory Response with BromAc\u00ae. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1308477"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1080\/17568919.2025.2515821","article-title":"New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity","volume":"17","author":"Franco","year":"2025","journal-title":"Future Med. Chem."},{"key":"ref_61","unstructured":"Reis, J.G.A.C., Reis, E.V.S., Moraes, T.F.S., Clarindo, F.A., Moraes, T.F.S., Guedes, I.A., Dardenne, L.E., Fran\u00e7a, P.R.C., Fernandes, P.D., and Viegas, C. (2024). Uso de hidrazonas an\u00e1logas ao canabidiol em medicamentos antivirais. (BR 10 2024 010067 0)."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Coelho dos Reis, J.G.A., Ferreira, G.M., Louren\u00e7o, A.A., Ribeiro, \u00c1.L., Mata, C.P.S.M., Oliveira, P.M., Marques, D.P.A., Ferreira, L.L., Clarindo, F.A., and Silva, M.F. (2022). Ex-Vivo Mucolytic and Anti-Inflammatory Activity of BromAc in Tracheal Aspirates from COVID-19. Biomed. Pharmacother., 148.","DOI":"10.1016\/j.biopha.2022.112753"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Guimar\u00e3es Santana, B.C., Marques, D.P.A., Freitas, A.S., Ferreira, M.M., Lopes, D.S., Bagno, F.F., Fonseca, F.G., Reis, J.G.A.C., Mendes, T.A.O., and Santos, J.L. (2023). Protease Inhibitors from Theobroma cacao Impair SARS-CoV-2 Replication in Vitro. Heliyon, 9.","DOI":"10.1016\/j.heliyon.2023.e15860"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1007\/s00044-023-03134-7","article-title":"Synthesis of Indole-Based Ferulic Acid Derivatives and in Vitro Evaluation of Antiviral Activity against SARS-CoV-2","volume":"32","author":"Verzola","year":"2023","journal-title":"Med. Chem. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Marques, G.V.L., Marques, D.P.A., Clarindo, F.A., Avenda\u00f1o-Villarreal, J.A., Guerra, F.S., Fernandes, P.D., Santos, E.N., Gusevskaya, E.V., Kohlhoff, M., and Moreira, F.A. (2023). Synthesis of Cannabidiol-Based Compounds as ACE2 Inhibitors with Potential Application in the Treatment of COVID-19. Eur. J. Med. Chem., 260.","DOI":"10.1016\/j.ejmech.2023.115760"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Guedes, I.A., Barreto, A.M.S., Marinho, D., Krempser, E., Kuenemann, M.A., Sperandio, O., Dardenne, L.E., and Miteva, M.A. (2021). New Machine Learning and Physics-Based Scoring Functions for Drug Discovery. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-82410-1"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Guedes, I.A., Silva, M.M.P., Galheigo, M., Krempser, E., Magalh\u00e3es, C.S., Barbosa, H.J.C., and Dardenne, L.E. (2024). DockThor-VS: A Free Platform for Receptor-Ligand Virtual Screening. J. Mol. Biol., 436.","DOI":"10.1016\/j.jmb.2024.168548"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1021\/acs.jcim.9b00905","article-title":"Highly Flexible Ligand Docking: Benchmarking of the DockThor Program on the LEADS-PEP Protein-peptide Dataset","volume":"60","author":"Santos","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Guedes, I.A., Costa, L.S.C., Santos, K.B., Karl, A.L.M., Rocha, G.K., Teixeira, I.M., Galheigo, M.M., Medeiros, V., Krempser, E., and Cust\u00f3dio, F.L. (2021). Drug Design and Repurposing with DockThor-VS Web Server Focusing on SARS-CoV-2 Therapeutic Targets and Their Non-Synonym Variants. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-84700-0"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/ct100578z","article-title":"PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K a Predictions","volume":"7","author":"Olsson","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: A Software Program for PK a Prediction and Protonation State Generation for Drug-like Molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1021\/acs.jctc.3c00044","article-title":"Epik: PKa and Protonation State Prediction through Machine Learning","volume":"19","author":"Johnston","year":"2023","journal-title":"J. Chem. Theory Comput."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ins.2014.08.002","article-title":"A dynamic niching genetic algorithm strategy for docking highly flexible ligands","volume":"289","author":"Almeida","year":"2014","journal-title":"Inf. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Silva, M., Vidal, L., Guedes, I., Magalh\u00e3es, C., Cust\u00f3dio, F., and Dardenne, L. (2025). Data-centric training enables meaningful interaction learning in protein\u2013ligand binding affinity prediction. ChemRxiv.","DOI":"10.26434\/chemrxiv-2025-khbrl-v2"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1565\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T04:19:14Z","timestamp":1761020354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/10\/1565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":74,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ph18101565"],"URL":"https:\/\/doi.org\/10.3390\/ph18101565","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2025,10,16]]}}}