The RNA-dependent RNA polymerase (RdRp) represents a prominent target in the discovery and development of new antivirotics against RNA viruses, inhibiting the replication process. One of the most targeted RNA viruses of the last years is, without doubt, SARS-CoV-2, the cause of the recent COVID-19 pandemic. HeE1-2Tyr, a known inhibitor of flaviviral RdRp, has been discovered to also have antiviral potency against this coronavirus. In this study, we report three distinct modifications of HeE1-2Tyr: conversion of the core from a benzothiazole to a benzoxazole moiety and two different scaffold simplifications, respectively. We provide a novel synthetic approach and, in addition, evaluate the final molecules in an in vitro polymerase assay for biological activity.

Department of Organic Chemistry Faculty of Science Charles University Hlavova 2030 8 128 43 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542 2 166 10 Prague Czech Republic

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Bekheit M S, Panda S S, Girgis A S. Eur J Med Chem. 2023;252:115292. doi: 10.1016/j.ejmech.2023.115292. PubMed DOI PMC

Shiraki K, Sato N, Sakai K, Matsumoto S, Kaszynski R H, Takemoto M. Pharmacol Ther. 2022;235:108121. doi: 10.1016/j.pharmthera.2022.108121. PubMed DOI PMC

Sorouri F, Emamgholipour Z, Keykhaee M, Najafi A, Firoozpour L, Sabzevari O, Sharifzadeh M, Foroumadi A, Khoobi M. Mini-Rev Med Chem. 2022;22:273–311. doi: 10.2174/1389557521666210308144302. PubMed DOI

Shiraki K, Daikoku T. Pharmacol Ther. 2020;209:107512. doi: 10.1016/j.pharmthera.2020.107512. PubMed DOI PMC

Keating G M. Drugs. 2014;74:1127–1146. doi: 10.1007/s40265-014-0247-z. PubMed DOI

Izquierdo L, Helle F, Francois C, Castelain S, Duverlie G, Brochot E. Pharmacogenomics Res Pers Med. 2014;7:241–249. doi: 10.2147/pgpm.s52715. PubMed DOI PMC

Hessel M H M, Cohen A F, Rissmann R. Br J Clin Pharmacol. 2016;82(3):878–879. doi: 10.1111/bcp.13011. PubMed DOI PMC

Hillen H S, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Nature. 2020;584:154–156. doi: 10.1038/s41586-020-2368-8. PubMed DOI

Astasio-Picado Á, Zabala-Baños M d C, Jurado-Palomo J. Appl Sci. 2023;13:4471. doi: 10.3390/app13074471. DOI

Kokic G, Hillen H S, Tegunov D, Dienemann C, Seitz F, Schmitzova J, Farnung L, Siewert A, Höbartner C, Cramer P. Nat Commun. 2021;12(1):279. doi: 10.1038/s41467-020-20542-0. PubMed DOI PMC

Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen H S, Höbartner C, Cramer P. Nat Struct Mol Biol. 2021;28(9):740–746. doi: 10.1038/s41594-021-00651-0. PubMed DOI PMC

Jamal Q M S. Int J Mol Sci. 2022;23(21):13564. doi: 10.3390/ijms232113564. PubMed DOI PMC

Gao S, Song L, Xu H, Fikatas A, Oeyen M, De Jonghe S, Zhao F, Jing L, Jochmans D, Vangeel L, et al. Molecules. 2022;28(1):160. doi: 10.3390/molecules28010160. PubMed DOI PMC

Brindani N, Munafò F, Menichetti A, Donati E, Nigro M, Ottonello G, Armirotti A, De Vivo M. Bioorg Med Chem. 2023;80:117179. doi: 10.1016/j.bmc.2023.117179. PubMed DOI PMC

Miropolskaya N, Kozlov M, Petushkov I, Prostova M, Pupov D, Esyunina D, Kochetkov S, Kulbachinskiy A. Biochimie. 2023;206:81–88. doi: 10.1016/j.biochi.2022.10.007. PubMed DOI PMC

Jade D, Alzahrani A, Critchley W, Ponnambalam S, Harrison M A. Struct Chem. 2023;34:1005–1019. doi: 10.1007/s11224-022-02072-1. PubMed DOI PMC

Shahabadi N, Zendehcheshm S, Mahdavi M, Khademi F. Inform Med Unlocked. 2023;36:101147. doi: 10.1016/j.imu.2022.101147. PubMed DOI PMC

Wang J, Reiss K, Shi Y, Lolis E, Lisi G P, Batista V S. Biochemistry. 2021;60:1869–1875. doi: 10.1021/acs.biochem.1c00292. PubMed DOI PMC

Warren T K, Jordan R, Lo M K, Ray A S, Mackman R L, Soloveva V, Siegel D, Perron M, Bannister R, Hui H C, et al. Nature. 2016;531(7594):381–385. doi: 10.1038/nature17180. PubMed DOI PMC

Tarantino D, Cannalire R, Mastrangelo E, Croci R, Querat G, Barreca M L, Bolognesi M, Manfroni G, Cecchetti V, Milani M. Antiviral Res. 2016;134:226–235. doi: 10.1016/j.antiviral.2016.09.007. PubMed DOI

Cannalire R, Tarantino D, Piorkowski G, Carletti T, Massari S, Felicetti T, Barreca M L, Sabatini S, Tabarrini O, Marcello A, et al. Antiviral Res. 2019;167:6–12. doi: 10.1016/j.antiviral.2019.03.004. PubMed DOI

Cannalire R, Ki Chan K W, Burali M S, Gwee C P, Wang S, Astolfi A, Massari S, Sabatini S, Tabarrini O, Mastrangelo E, et al. ACS Med Chem Lett. 2020;11:773–782. doi: 10.1021/acsmedchemlett.9b00619. PubMed DOI PMC

Felicetti T, Burali M S, Gwee C P, Ki Chan K W, Alonso S, Massari S, Sabatini S, Tabarrini O, Barreca M L, Cecchetti V, et al. Eur J Med Chem. 2021;210:112992. doi: 10.1016/j.ejmech.2020.112992. PubMed DOI

Dejmek M, Konkoľová E, Eyer L, Straková P, Svoboda P, Šála M, Krejčová K, Růžek D, Boura E, Nencka R. Viruses. 2021;13(8):1585. doi: 10.3390/v13081585. PubMed DOI PMC

Wardakhan W W, El-Sayed N N E. Phosphorus, Sulfur Silicon Relat Elem. 2009;184:790–804. doi: 10.1080/10426500802274534. DOI

Targowska‐Duda K M, Maj M, Drączkowski P, Budzyńska B, Boguszewska‐Czubara A, Wróbel T M, Laitinen T, Kaczmar P, Poso A, Kaczor A A. ChemMedChem. 2022;17(8):e202100721. doi: 10.1002/cmdc.202100721. PubMed DOI

Nimnual P, Tummatorn J, Thongsornkleeb C, Ruchirawat S. J Org Chem. 2015;80:8657–8667. doi: 10.1021/acs.joc.5b01305. PubMed DOI

Goldberg J A, Nguyen H, Kumar V, Spencer E J, Hoyer D, Marshall E K, Cmolik A, O’Shea M, Marshall S H, Hujer A M, et al. J Med Chem. 2020;63(11):5990–6002. doi: 10.1021/acs.jmedchem.0c00255. PubMed DOI PMC

Potts K T, Kanemasa S. J Org Chem. 1979;44:3808–3811. doi: 10.1021/jo01336a014. DOI

Walkinshaw A J, Xu W, Suero M G, Gaunt M J. J Am Chem Soc. 2013;135:12532–12535. doi: 10.1021/ja405972h. PubMed DOI

Dvorak K A, Swanson D M, Wong V D, inventors. Piperazinyl Derivatives Useful as Modulators of the Neuropeptide Y2 Receptor. US8338426B2. U.S. Patent. 2008 Jun 26;

Schultes S, de Graaf C, Haaksma E E J, de Esch I J P, Leurs R, Krämer O. Drug Discovery Today: Technol. 2010;7:e157–e162. doi: 10.1016/j.ddtec.2010.11.003. DOI