{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:28:23Z","timestamp":1766492903516,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilead \u2018ASKLEPIOS Grants Program\u2019","award":["KRIPIS-MIS450598","ACIP 18-2015"],"award-info":[{"award-number":["KRIPIS-MIS450598","ACIP 18-2015"]}]},{"DOI":"10.13039\/501100003448","name":"General Secretariat for Research and Technology","doi-asserted-by":"publisher","award":["KRIPIS-MIS450598","ACIP 18-2015"],"award-info":[{"award-number":["KRIPIS-MIS450598","ACIP 18-2015"]}],"id":[{"id":"10.13039\/501100003448","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Pasteur Network","award":["KRIPIS-MIS450598","ACIP 18-2015"],"award-info":[{"award-number":["KRIPIS-MIS450598","ACIP 18-2015"]}]},{"name":"Hellenic Pasteur Institute","award":["KRIPIS-MIS450598","ACIP 18-2015"],"award-info":[{"award-number":["KRIPIS-MIS450598","ACIP 18-2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 \u03bcM against HCV 1b and 2.57 \u03bc\u039c against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.<\/jats:p>","DOI":"10.3390\/v16081238","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T15:26:53Z","timestamp":1722526013000},"page":"1238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Pyrazino[1,2-a]indole-1,3(2H,4H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2564-6628","authenticated-orcid":false,"given":"Erofili","family":"Giannakopoulou","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ifigeneia","family":"Akrani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Mpekoulis","sequence":"additional","affiliation":[{"name":"Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Efseveia","family":"Frakolaki","sequence":"additional","affiliation":[{"name":"Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5699-2289","authenticated-orcid":false,"given":"Marios","family":"Dimitriou","sequence":"additional","affiliation":[{"name":"Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-9634","authenticated-orcid":false,"given":"Vassilios","family":"Myrianthopoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-3438","authenticated-orcid":false,"given":"Niki","family":"Vassilaki","sequence":"additional","affiliation":[{"name":"Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, GR-11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-5186","authenticated-orcid":false,"given":"Grigoris","family":"Zoidis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"ref_1","unstructured":"(2024, February 20). Hepatitis C. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hepatitis-c."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1099\/jgv.0.000672","article-title":"ICTV Virus Taxonomy Profile: Flaviviridae","volume":"98","author":"Simmonds","year":"2017","journal-title":"J. Gen. 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