In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment
Abstract
:1. Introduction
2. Results
2.1. Niclosamide Has a Poor Selectivity Index
2.2. Niclosamide Potency Is SARS-CoV-2 Variant Dependent
2.3. High-Content Analysis Suggests Inhibition of Entry and Syncytia Formation
2.4. Structure-Activity Relationship of Niclosamide Analogs versus SARS-CoV-2 Infection
3. Discussion
4. Methods
4.1. Compounds
4.2. Cells and Virus
4.3. Anti-SARS-CoV-2 High Content Bioassays
4.4. High Content Imaging
4.5. Image Processing
4.6. Concentration Response Analysis and IC50/CC50 Determination
4.7. High Content Imaging Analysis of B.1.1.7 Infection Versus Niclosamide
4.8. Statistical Analysis and Hypothesis Testing
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Hu, B.; Guo, H.; Zhou, P.; Shi, Z.L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 2021, 19, 141–154. [Google Scholar] [CrossRef] [PubMed]
- Aslan, A.; Aslan, C.; Zolbanin, N.M.; Jafari, R. Acute respiratory distress syndrome in COVID-19: Possible mechanisms and therapeutic management. Pneumonia 2021, 13, 1–15. [Google Scholar]
- Mizrahi, B.; Shilo, S.; Rossman, H.; Kalkstein, N.; Marcus, K.; Barer, Y.; Keshet, A.; Shamir-Stein, N.; Shalev, V.; Zohar, A.E.; et al. Longitudinal symptom dynamics of COVID-19 infection. Nat. Commun. 2020, 11, 1–10. [Google Scholar] [CrossRef]
- Dong, E.; Du, H.; Gardner, L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. 2020, 20, 533–534. [Google Scholar] [CrossRef]
- Harvey, W.T.; Carabelli, A.M.; Jackson, B.; Gupta, R.K.; Thomson, E.C.; Harrison, E.M.; Ludden, C.; Reeve, R.; Rambaut, A.; Peacock, S.J.; et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 2021, 19, 409–424. [Google Scholar] [CrossRef] [PubMed]
- Kyriakidis, N.C.; López-Cortés, A.; González, E.V.; Grimaldos, A.B.; Prado, E.O. SARS-CoV-2 vaccines strategies: A comprehensive review of phase 3 candidates. Nat. Rev. Microbiol. 2021, 6, 1–17. [Google Scholar] [CrossRef]
- Cully, M. A tale of two antiviral targets-and the COVID-19 drugs that bind them. Nat. Rev. Drug Discov. 2022, 21, 3–5. [Google Scholar] [CrossRef]
- Whitley, R. Molnupiravir—A Step toward Orally Bioavailable Therapies for COVID-19. N. Engl. J. Med. 2022, 386, 592–593. [Google Scholar] [CrossRef]
- Hammond, J.; Leister-Tebbe, H.; Gardner, A.; Abreu, P.; Bao, W.; Wisemandle, W.; Baniecki, M.; Hendrick, V.M.; Damle, B.; Simón-Campos, A.; et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19. N. Engl. J. Med. 2022, 386, 1397–1408. [Google Scholar] [CrossRef]
- Feinmann, J. COVID-19: Global vaccine production is a mess and shortages are down to more than just hoarding. BMJ 2021, 375, n2375. [Google Scholar] [CrossRef]
- Qomara, W.F.; Primanissa, D.N.; Amalia, S.H.; Purwadi, F.V.; Zakiyah, N. Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19 Treatment: A Systematic Review. Int. J. Gen. Med. 2021, 14, 8557–8571. [Google Scholar] [CrossRef] [PubMed]
- Gottlieb, R.L.; Vaca, C.E.; Paredes, R.; Mera, J.; Webb, B.J.; Perez, G.; Oguchi, G.; Ryan, P.; Nielsen, B.U.; Brown, M.; et al. Early Remdesivir to Prevent Progression to Severe COVID-19 in Outpatients. N. Engl. J. Med. 2022, 386, 305–315. [Google Scholar] [CrossRef] [PubMed]
- Chen, R.E.; Zhang, X.; Case, J.B.; Winkler, E.S.; Liu, Y.; VanBlargan, L.A.; Liu, J.; Errico, J.M.; Xie, X.; Suryadevara, N.; et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. 2021, 27, 717–726. [Google Scholar] [CrossRef] [PubMed]
- Takashita, E.; Kinoshita, N.; Yamayoshi, S.; Sakai-Tagawa, Y.; Fujisaki, S.; Ito, M.; Iwatsuki-Horimoto, K.; Halfmann, P.; Watanabe, S.; Maeda, K.; et al. Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2. N. Engl. J. Med. 2022, 386, 1475–1477. [Google Scholar] [CrossRef]
- Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2018, 18, 41–58. [Google Scholar] [CrossRef]
- Drayman, N.; DeMarco, J.K.; Jones, K.A.; Azizi, S.A.; Froggatt, H.M.; Tan, K.; Maltseva, N.I.; Chen, S.; Nicolaescu, V.; Dvorkin, S.; et al. Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2. Science 2021, 373, 931–936. [Google Scholar] [CrossRef]
- Mirabelli, C.; Wotring, J.W.; Zhang, C.J.; McCarty, S.M.; Fursmidt, R.; Pretto, C.D.; Qiao, Y.; Zhang, Y.; Frum, T.; Kadambi, N.S.; et al. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. Proc. Natl. Acad. Sci. USA 2021, 118, e2105815118. [Google Scholar] [CrossRef]
- Touret, F.; Gilles, M.; Barral, K.; Nougairède, A.; van Helden, J.; Decroly, E.; de Lamballerie, X.; Coutard, B. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Sci. Rep. 2020, 10, 13093. [Google Scholar] [CrossRef]
- Xiao, X.; Wang, C.; Chang, D.; Wang, Y.; Dong, X.; Jiao, T.; Zhao, Z.; Ren, L.; dela Cruz, C.S.; Sharma, L.; et al. Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2. Front. Immunol. 2020, 11, 586572. [Google Scholar] [CrossRef]
- Jeon, S.; Ko, M.; Lee, J.; Choi, I.; Byun, S.Y.; Park, S.; Shum, D.; Kim, S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob. Agents Chemother. 2020, 64, e00819-20. [Google Scholar] [CrossRef]
- Chen, W.; Mook, R.A.; Premont, R.T.; Wang, J. Niclosamide: Beyond an antihelminthic drug. Cell. Signal. 2018, 41, 89–96. [Google Scholar] [CrossRef] [PubMed]
- Fonseca, B.D.; Diering, G.H.; Bidinosti, M.A.; Dalal, K.; Alain, T.; Balgi, A.D.; Forestieri, R.; Nodwell, M.; Rajadurai, C.v.; Gunaratnam, C.; et al. Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem. 2012, 287, 17530–17545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumar, R.; Coronel, L.; Somalanka, B.; Raju, A.; Aning, O.A.; An, O.; Ho, Y.S.; Chen, S.; Mak, S.Y.; Hor, P.Y.; et al. Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat. Commun. 2018, 9, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jurgeit, A.; McDowell, R.; Moese, S.; Meldrum, E.; Schwendener, R.; Greber, U.F. Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects. PLoS Pathog. 2012, 8, 1002976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, C.J.; Jan, J.T.; Chen, C.M.; Hsieh, H.P.; Hwang, D.R.; Liu, H.W.; Liu, C.Y.; Huang, H.W.; Chen, S.C.; Hong, C.F.; et al. Inhibition of Severe Acute Respiratory Syndrome Coronavirus Replication by Niclosamide. Antimicrob. Agents Chemother. 2004, 48, 2693. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prabhakara, C.; Godbole, R.; Sil, P.; Jahnavi, S.; Gulzar, S.J.; van Zanten, T.S.; Sheth, D.; Subhash, N.; Chandra, A.; Shivaraj, A.; et al. Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors. PLoS Pathog. 2021, 17, e1009706. [Google Scholar] [CrossRef]
- Gassen, N.C.; Niemeyer, D.; Muth, D.; Corman, V.M.; Martinelli, S.; Gassen, A.; Hafner, K.; Papies, J.; Mösbauer, K.; Zellner, A.; et al. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat. Commun. 2021, 12, 1–15. [Google Scholar] [CrossRef]
- Braga, L.; Ali, H.; Secco, I.; Chiavacci, E.; Neves, G.; Goldhill, D.; Penn, R.; Jimenez-Guardeño, J.M.; Ortega-Prieto, A.M.; Bussani, R.; et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 2021, 594, 88–93. [Google Scholar] [CrossRef]
- Lin, C.K.; Bai, M.Y.; Hu, T.M.; Wang, Y.C.; Chao, T.K.; Weng, S.J.; Huang, R.L.; Su, P.H.; Lai, H.C. Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in ovarian cancer. Oncotarget 2016, 7, 8993. [Google Scholar] [CrossRef] [Green Version]
- Fan, X.; Li, H.; Ding, X.; Zhang, Q.Y. Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability. Drug Metab. Dispos. 2019, 47, 756–763. [Google Scholar] [CrossRef]
- Chang, Y.W.; Yeh, T.K.; Lin, K.T.; Chen, W.C.; Yao, H.T.; Lan, S.J.; Wu, Y.S.; Hsieh, H.P.; Chen, C.M.; Chen, C.T. Pharmacokinetics of anti-SARS-CoV agent niclosamide and its analogs in rats. J. Food Drug Anal. 2020, 14, 15. [Google Scholar] [CrossRef]
- Reddy, A.S.; Zhang, S. Polypharmacology: Drug discovery for the future. Expert Rev. Clin. Pharmacol. 2013, 6, 41–47. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wieland, A.; Trageser, D.; Gogolok, S.; Reinartz, R.; Höfer, H.; Keller, M.; Leinhaas, A.; Schelle, R.; Normann, S.; Klaas, L.; et al. Anticancer effects of niclosamide in human glioblastoma. Clin. Cancer Res. 2013, 19, 4124–4136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamdoun, S.; Jung, P.; Efferth, T. Drug repurposing of the anthelmintic niclosamide to treat multidrug-resistant leukemia. Front. Pharmacol. 2017, 8, 110. [Google Scholar] [CrossRef] [Green Version]
- Rajah, M.M.; Hubert, M.; Bishop, E.; Saunders, N.; Robinot, R.; Grzelak, L.; Planas, D.; Dufloo, J.; Gellenoncourt, S.; Bongers, A.; et al. SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced Spike-mediated syncytia formation. EMBO J. 2021, 40, e108944. [Google Scholar] [CrossRef]
- Saito, A.; Irie, T.; Suzuki, R.; Maemura, T.; Nasser, H.; Uriu, K.; Kosugi, Y.; Shirakawa, K.; Sadamasu, K.; Kimura, I.; et al. Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. Nature 2022, 602, 300–306. [Google Scholar] [CrossRef]
- Zhang, Y.; Zhang, T.; Fang, Y.; Liu, J.; Ye, Q.; Ding, L. SARS-CoV-2 spike L452R mutation increases Omicron variant fusogenicity and infectivity as well as host glycolysis. Signal Transduct. Target. Ther. 2022, 7, 1–3. [Google Scholar] [CrossRef]
- Bhagat, H.A.; Compton, S.A.; Musso, D.L.; Laudeman, C.P.; Jackson, K.M.; Yi, N.Y.; Nierobisz, L.S.; Forsberg, L.; Brenman, J.E.; Sexton, J.Z. N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice. PLoS ONE 2018, 13, e0204605. [Google Scholar] [CrossRef]
- Park, K.S.; Jo, I.; Pak, Y.; Bae, S.W.; Rhim, H.; Suh, S.H.; Park, S.; Zhu, M.; So, I.; Kim, K. FCCP depolarizes plasma membrane potential by activating proton and Na+ currents in bovine aortic endothelial cells. Pflug. Arch. 2002, 443, 344–352. [Google Scholar] [CrossRef]
- Blaikie, F.H.; Brown, S.E.; Samuelsson, L.M.; Brand, M.D.; Smith, R.A.; Murphy, M.P. Targeting dinitrophenol to mitochondria: Limitations to the development of a self-limiting mitochondrial protonophore. Biosci Rep. 2006, 26, 231–243. [Google Scholar] [CrossRef]
- Shrestha, R.; Johnson, E.; Byrne, F.L. Exploring the therapeutic potential of mitochondrial uncouplers in cancer. Mol. Metab. 2021, 51, 101222. [Google Scholar] [CrossRef] [PubMed]
- Kotova, E.A.; Antonenko, Y.N. Fifty Years of Research on Protonophores: Mitochondrial Uncoupling as a Basis for Therapeutic Action. Acta Nat. 2022, 14, 4. [Google Scholar] [CrossRef]
- Blake, S.; Shaabani, N.; Eubanks, L.M.; Maruyama, J.; Manning, J.T.; Beutler, N.; Paessler, S.; Ji, H.; Teijaro, J.R.; Janda, K.D. Salicylanilides Reduce SARS-CoV-2 Replication and Suppress Induction of Inflammatory Cytokines in a Rodent Model. ACS Infect. Dis. 2021, 7, 2229–2237. [Google Scholar] [CrossRef] [PubMed]
- Cairns, D.M.; Dulko, D.; Griffiths, J.K.; Golan, Y.; Cohen, T.; Trinquart, L.; Price, L.L.; Beaulac, K.R.; Selker, H.P. Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients with Mild to Moderate COVID-19: A Phase 2 Randomized Clinical Trial. JAMA Netw. Open 2022, 5, e2144942. [Google Scholar] [CrossRef] [PubMed]
- Parikh, M.; Liu, C.; Wu, C.Y.; Evans, C.P.; Dall’Era, M.; Robles, D.; Lara, P.N.; Agarwal, N.; Gao, A.C.; Pan, C.X. Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer. Sci. Rep. 2021, 11, 1–7. [Google Scholar] [CrossRef]
- Backer, V.; Sjöbring, U.; Sonne, J.; Weiss, A.; Hostrup, M.; Johansen, H.K.; Becker, V.; Sonne, D.P.; Balchen, T.; Jellingsø, M.; et al. A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19. Lancet Reg. Health-Eur. 2021, 4, 100084. [Google Scholar] [CrossRef]
- Liu, H.; Wei, P.; Kappler, J.W.; Marrack, P.; Zhang, G. SARS-CoV-2 Variants of Concern and Variants of Interest Receptor Binding Domain Mutations and Virus Infectivity. Front. Immunol. 2022, 13, 50. [Google Scholar] [CrossRef]
- Weiss, A.; Touret, F.; Baronti, C.; Gilles, M.; Hoen, B.; Nougairède, A.; de Lamballerie, X.; Sommer, M.O. Niclosamide shows strong antiviral activity in a human airway model of SARS-CoV-2 infection and a conserved potency against the Alpha (B.1.1.7), Beta (B.1.351) and Delta variant (B.1.617.2). PLoS ONE 2021, 16, e0260958. [Google Scholar] [CrossRef]
- Bussani, R.; Schneider, E.; Zentilin, L.; Collesi, C.; Ali, H.; Braga, L.; Volpe, M.C.; Colliva, A.; Zanconati, F.; Berlot, G.; et al. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine 2020, 61, 103104. [Google Scholar] [CrossRef]
- Lin, L.; Li, Q.; Wang, Y.; Shi, Y. Syncytia formation during SARS-CoV-2 lung infection: A disastrous unity to eliminate lymphocytes. Cell Death Differ. 2021, 28, 2019–2021. [Google Scholar] [CrossRef]
- Rajah, M.M.; Bernier, A.; Buchrieser, J.; Schwartz, O. The Mechanism and Consequences of SARS-CoV-2 Spike-Mediated Fusion and Syncytia Formation. J. Mol. Biol. 2022, 434, 167280. [Google Scholar] [CrossRef] [PubMed]
- Reed, L.J.; Muench, H. A simple method of estimating fifty per cent endpoints. Am. J. Epidemiol. 1938, 27, 493–497. [Google Scholar] [CrossRef]
- Wotring, J.W.; Fursmidt, R.; Ward, L.; Sexton, J.Z. Evaluating the in vitro efficacy of bovine lactoferrin products against SARS-CoV-2 variants of concern. J. Dairy Sci. 2022, 105, 2791–2802. [Google Scholar] [CrossRef] [PubMed]
- McQuin, C.; Goodman, A.; Chernyshev, V.; Kamentsky, L.; Cimini, B.A.; Karhohs, K.W.; Doan, M.; Ding, L.; Rafelski, S.M.; Thirstrup, D.; et al. CellProfiler 3.0: Next-generation image processing for biology. PLoS Biol. 2018, 16, e2005970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berthold, M.R.; Cebron, N.; Dill, F.; Gabriel, T.R.; Kötter, T.; Meinl, T.; Ohl, P.; Thiel, K.; Wiswedel, B. KNIME: The Konstanz information miner. ACM SIGKDD Explor. Newsl. 2009, 11, 58–61. [Google Scholar] [CrossRef] [Green Version]
Compound | R1 | R2 | R3 | R4 | R5 | R6 | R7 | Vero-E6 (B.1.1.7) | H1437 (WA1) | MW (g/mol) | cLogP | pKa | logS | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
IC50 (nM) | CC50 (nM) | IC50 (nM) | CC50 (nM) | ||||||||||||
1 (niclosamide) | OH | Cl | H | Cl | H | NO2 | H | 564 | 1050 | 16,770 | 17,060 | 327.1 | 4.17 | 7.98 | −5.00 |
2 | OH | H | H | Cl | H | NO2 | H | 296 | 5590 | 4915 | 8403 | 292.7 | 3.47 | 7.52 | −4.32 |
3 | OH | CH3 | H | Cl | H | NO2 | H | 1254 | 6277 | 2595 | 3056 | 306.7 | 3.97 | 7.52 | −4.66 |
4 | OH | OCH3 | H | Cl | H | NO2 | H | 1769 | 10,110 | 10,880 | 8941 | 322.7 | 3.39 | 7.65 | −4.39 |
5 | OH | Cl | H | Cl | H | H | H | 890 | 8435 | >20,000 | 18,570 | 282.1 | 4.17 | 8.01 | −4.54 |
6 | OH | Cl | H | Cl | H | CH3 | H | 760 | 4591 | >20,000 | 6048 | 296.2 | 4.66 | 8.01 | −4.88 |
7 | OH | Cl | H | Cl | H | COOCH3 | H | 334 | 8142 | Inverted | >20,000 | 340.2 | 4.15 | 7.98 | −4.94 |
8 | OH | Cl | H | Cl | H | COOH | H | >20,000 | >20,000 | Inverted | >20,000 | 326.1 | 3.67 | 4.03 | −4.54 |
9 | H | Cl | H | Cl | H | NO2 | H | >20,000 | >20,000 | >20,000 | >20,000 | 311.1 | 4.63 | 14 | −5.27 |
10 | OH | Cl | H | Cl | H | OCH3 | H | 4248 | >20,000 | Inverted | 18,900 | 312.2 | 4.05 | 8.02 | −4.59 |
11 | OH | t-Bu | H | Cl | H | NO2 | H | 423 | 3407 | 3097 | 1921 | 348.8 | 5.50 | 7.51 | −5.68 |
12 | OH | OCH3 | H | Cl | H | NO2 | H | 1498 | 10,290 | 16,880 | 7529 | 322.7 | 3.39 | 7.65 | −4.39 |
13 | OH | t-Bu | H | Cl | H | COOCH3 | H | >20,000 | 14,570 | >20,000 | >20,000 | 361.8 | 5.49 | 7.50 | −5.62 |
14 | OH | t-Bu | H | Cl | H | COOH | H | >20,000 | 14,250 | Inverted | >20,000 | 347.8 | 5.00 | 4.93 | −5.22 |
15 | OH | t-Bu | H | F | H | COOH | H | >20,000 | >20,000 | Inverted | >20,000 | 331.3 | 4.41 | 4.73 | −4.69 |
16 | OH | t-Bu | H | CH3 | H | COOH | H | >20,000 | >20,000 | Inverted | >20,000 | 327.4 | 4.49 | 4.95 | −4.74 |
17 | OH | t-Bu | H | Cl | H | H | COOH | >20,000 | >20,000 | Inverted | >20,000 | 347.8 | 5.00 | 4.93 | −5.22 |
18 | OH | t-Bu | t-Bu | Cl | H | CH3SO2N | H | >20,000 | >20,000 | Inverted | >20,000 | 453.0 | 5.98 | 7.02 | −6.39 |
19 | OH | t-Bu | t-Bu | Cl | H | NH2 | H | >20,000 | 17,590 | Inverted | >20,000 | 374.9 | 6.58 | 7.57 | −6.14 |
20 | OH | t-Bu | t-Bu | H | CH3 | COOH | H | >20,000 | >20,000 | >20,000 | >20,000 | 383.5 | 6.52 | 4.96 | −6.10 |
21 | OH | Cy | H | Cl | H | COOCH3 | H | 9910 | >20,000 | >20,000 | >20,000 | 387.9 | 5.96 | 7.50 | −6.66 |
22 | OH | Cy | H | Cl | H | COOH | H | 4511 | >20,000 | Inverted | >20,000 | 373.8 | 5.48 | 4.93 | −6.26 |
23 | OH | CF3 | H | CH3 | H | COOCH3 | H | >20,000 | >20,000 | >20,000 | >20,000 | 341.4 | 4.97 | 7.49 | −5.15 |
24 | OH | Cl | H | Cl | H | CN | H | 348 | 4720 | 1070 | 880 | 307.1 | 4.27 | 8.00 | −5.03 |
25 | OH | H | t-Bu | Cl | H | COOCH3 | H | >20,000 | >20,000 | Inverted | >20,000 | 361.8 | 5.22 | 7.52 | −5.52 |
26 | OH | t-Bu | t-Bu | Cl | H | COOH | H | >20,000 | >20,000 | >20,000 | >20,000 | 403.9 | 6.77 | 4.93 | −6.48 |
27 | OH | t-Bu | t-Bu | H | CH3 | COOH | H | 16,500 | >20,000 | >20,000 | >20,000 | 383.5 | 6.52 | 4.96 | −6.10 |
28 | OH | OCH3 | H | CH3 | H | COOH | H | >20,000 | >20,000 | Inverted | >20,000 | 301.3 | 2.38 | 4.95 | −3.46 |
29 | OH | H | t-Bu | Cl | H | COOCH3 | H | >20,000 | >20,000 | Inverted | >20,000 | 361.8 | 5.22 | 7.52 | −5.52 |
30 | OH | H | t-Bu | Cl | H | COOH | H | >20,000 | >20,000 | Inverted | >20,000 | 347.8 | 4.74 | 4.93 | −5.12 |
31 | OH | H | t-Bu | Cl | H | NO2 | H | >20,000 | 7214 | >20,000 | 1110 | 348.8 | 5.24 | 7.52 | −5.58 |
32 | OH | H | t-Bu | Cl | H | NH2 | H | >20,000 | >20,000 | >20,000 | >20,000 | 318.8 | 4.55 | 7.58 | −4.78 |
33 | OH | H | t-Bu | Cl | H | NSO2CH3 | H | 2879 | >20,000 | Inverted | >20,000 | 396.9 | 3.95 | 7.03 | −5.03 |
34 | OH | Cl | H | Cl | H | Br | H | 760 | 5473 | 3491 | 3620 | 361.0 | 4.97 | 8.01 | −5.36 |
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Wotring, J.W.; McCarty, S.M.; Shafiq, K.; Zhang, C.J.; Nguyen, T.; Meyer, S.R.; Fursmidt, R.; Mirabelli, C.; Clasby, M.C.; Wobus, C.E.; et al. In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment. Vaccines 2022, 10, 1284. https://doi.org/10.3390/vaccines10081284
Wotring JW, McCarty SM, Shafiq K, Zhang CJ, Nguyen T, Meyer SR, Fursmidt R, Mirabelli C, Clasby MC, Wobus CE, et al. In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment. Vaccines. 2022; 10(8):1284. https://doi.org/10.3390/vaccines10081284
Chicago/Turabian StyleWotring, Jesse W., Sean M. McCarty, Khadija Shafiq, Charles J. Zhang, Theophilus Nguyen, Sophia R. Meyer, Reid Fursmidt, Carmen Mirabelli, Martin C. Clasby, Christiane E. Wobus, and et al. 2022. "In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment" Vaccines 10, no. 8: 1284. https://doi.org/10.3390/vaccines10081284
APA StyleWotring, J. W., McCarty, S. M., Shafiq, K., Zhang, C. J., Nguyen, T., Meyer, S. R., Fursmidt, R., Mirabelli, C., Clasby, M. C., Wobus, C. E., O’Meara, M. J., & Sexton, J. Z. (2022). In Vitro Evaluation and Mitigation of Niclosamide’s Liabilities as a COVID-19 Treatment. Vaccines, 10(8), 1284. https://doi.org/10.3390/vaccines10081284