{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:16:04Z","timestamp":1760235364706,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["CIIMAR UIDB\/04423\/2020 , PTDC\/SAU-PUB\/28736\/2017 (reference POCI-01\u20130145-FEDER-028736)"],"award-info":[{"award-number":["CIIMAR UIDB\/04423\/2020 , PTDC\/SAU-PUB\/28736\/2017 (reference POCI-01\u20130145-FEDER-028736)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.<\/jats:p>","DOI":"10.3390\/molecules26165070","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"5070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Determination of the Absolute Configuration of Bioactive Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones and Study of Their In Vitro Metabolic Profile"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-4864","authenticated-orcid":false,"given":"Solida","family":"Long","sequence":"first","affiliation":[{"name":"LQOF-Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Department of Bioegineering, Faculty of Engineering, Royal University of Phnom Penh, Russian Federation Blevd, Phnom Penh 12156, Cambodia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2745-7612","authenticated-orcid":false,"given":"Izadora L.","family":"Furlani","sequence":"additional","affiliation":[{"name":"SEPARARE\u2013N\u00facleo de Pesquisa em Cromatografia, Departamento de Qu\u00edmica, Universidade Federal de S\u00e3o Carlos, Rodovia Washington Luiz, km 235, S\u00e3o Carlos 13565-905, Brazil"}]},{"given":"Juliana M. de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"SEPARARE\u2013N\u00facleo de Pesquisa em Cromatografia, Departamento de Qu\u00edmica, Universidade Federal de S\u00e3o Carlos, Rodovia Washington Luiz, km 235, S\u00e3o Carlos 13565-905, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-6060","authenticated-orcid":false,"given":"Diana I. S. P.","family":"Resende","sequence":"additional","affiliation":[{"name":"LQOF-Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR-Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos S\/N, Matosinhos, 4450-208 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-8286","authenticated-orcid":false,"given":"Artur M. S.","family":"Silva","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE-Departamento de Qu\u00edmica, Universidade de Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Lu\u00eds","family":"Gales","sequence":"additional","affiliation":[{"name":"ICBAS-Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"i3S-IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2604-2375","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Pereira","sequence":"additional","affiliation":[{"name":"ICBAS-Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3321-1061","authenticated-orcid":false,"given":"Anake","family":"Kijjoa","sequence":"additional","affiliation":[{"name":"CIIMAR-Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos S\/N, Matosinhos, 4450-208 Porto, Portugal"},{"name":"ICBAS-Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6550-1194","authenticated-orcid":false,"given":"Quezia B.","family":"Cass","sequence":"additional","affiliation":[{"name":"SEPARARE\u2013N\u00facleo de Pesquisa em Cromatografia, Departamento de Qu\u00edmica, Universidade Federal de S\u00e3o Carlos, Rodovia Washington Luiz, km 235, S\u00e3o Carlos 13565-905, Brazil"}]},{"given":"Regina V.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"SEPARARE\u2013N\u00facleo de Pesquisa em Cromatografia, Departamento de Qu\u00edmica, Universidade Federal de S\u00e3o Carlos, Rodovia Washington Luiz, km 235, S\u00e3o Carlos 13565-905, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"LQOF-Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR-Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos S\/N, Matosinhos, 4450-208 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-1409","authenticated-orcid":false,"given":"Madalena M. M.","family":"Pinto","sequence":"additional","affiliation":[{"name":"LQOF-Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"CIIMAR-Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. 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Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejmech.2014.10.084","article-title":"Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances continue","volume":"90","author":"Khan","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1080\/13543776.2018.1432596","article-title":"Quinazoline and quinazolinone as important medicinal scaffolds: A comparative patent review (2011\u20132016)","volume":"28","author":"Hameed","year":"2018","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9787","DOI":"10.1016\/j.tet.2006.07.098","article-title":"The chemistry of recently isolated naturally occurring quinazolinone alkaloids","volume":"62","author":"Mhaske","year":"2006","journal-title":"Tetrahedron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6339","DOI":"10.1021\/jo0508043","article-title":"Three-Component One-Pot Total Syntheses of Glyantrypine, Fumiquinazoline F, and Fiscalin B Promoted by Microwave Irradiation","volume":"70","author":"Liu","year":"2005","journal-title":"J. Org. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1016\/S0957-4166(01)00515-8","article-title":"1-Alkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as glycine templates. Synthesis of Fiscalin B","volume":"12","author":"Buenadicha","year":"2001","journal-title":"Tetrahedron Asymm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1021\/jo9914364","article-title":"Total Synthesis of the Fumiquinazoline Alkaloids:\u2009 Solution-Phase Studies1","volume":"65","author":"Wang","year":"2000","journal-title":"J. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/jo980360t","article-title":"Total Synthesis of the Quinazoline Alkaloids (\u2212)-Fumiquinazoline G and (\u2212)-Fiscalin B","volume":"63","author":"Wang","year":"1998","journal-title":"J. Org. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1002\/cbdv.201400193","article-title":"Bioprospection of cytotoxic compounds in fungal strains recovered from sediments of the brazilian coast","volume":"12","author":"Rodrigues","year":"2015","journal-title":"Chem. Biodivers."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1248\/cpb.44.1843","article-title":"Isolation of new tremorgenic metabolites from an Ascomycete, Corynascus setosus","volume":"40","author":"Fujimoto","year":"1996","journal-title":"Chem. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"545","DOI":"10.7164\/antibiotics.46.545","article-title":"Fiscalins: New substance P inhibitors produced by the fungus Neosartorya fisheri taxonomy, fermentation, structure, and biological properties","volume":"46","author":"Wong","year":"1993","journal-title":"J. Antibiot."},{"key":"ref_13","first-page":"271","article-title":"Two new alkaloids from a marine-derived fungus Neosartorya fischeri","volume":"9","author":"Wu","year":"2015","journal-title":"Rec. Nat. Prod."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Long, S., Resende, D.I.S.P., Kijjoa, A., Silva, A.M.S., Fernandes, R., Xavier, C.P.R., Vasconcelos, M.H., Sousa, E., and Pinto, M.M.M. (2019). Synthesis of New Proteomimetic Quinazolinone Alkaloids and Evaluation of Their Neuroprotective and Antitumor Effects. Molecules, 24.","DOI":"10.3390\/molecules24030534"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Long, S., Resende, D., Kijjoa, A., Silva, A., Pina, A., Fern\u00e1ndez-Marcelo, T., Vasconcelos, M., Sousa, E., and Pinto, M. (2018). Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products. Mar. Drugs, 16.","DOI":"10.3390\/md16080261"},{"key":"ref_16","unstructured":"Sousa, M.E.L.S., Pinto, M.M.d.M., Resende, D.I.S.P., Kijjoa, A., Martins da Costa, P., Freitas da Silva, J.M.M., and Nogueira, F. (2021). Pyrazino [1,2-b]Quinazoline-3,6-diones Derivatives, Their Production and Uses. (WO\/2021\/033159), Thereof. Patent."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1021\/ar400309b","article-title":"Microwave-Assisted Chemistry: Synthetic Applications for Rapid Assembly of Nanomaterials and Organics","volume":"47","author":"Gawande","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31187","DOI":"10.1039\/D0RA05319H","article-title":"New marine-derived indolymethyl pyrazinoquinazoline alkaloids with promising antimicrobial profiles","volume":"10","author":"Long","year":"2020","journal-title":"RSC Adv."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bessa, L.J., Buttachon, S., Dethoup, T., Martins, R., Vasconcelos, V., Kijjoa, A., and Martins da Costa, P. (2016). Neofiscalin A and fiscalin C are potential novel indole alkaloid alternatives for the treatment of multidrug-resistant Gram-positive bacterial infections. FEMS Microbiol. Lett., 363.","DOI":"10.1093\/femsle\/fnw150"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.apsb.2018.04.003","article-title":"Drug metabolism in drug discovery and development","volume":"8","author":"Zhang","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1056-8719(00)00110-6","article-title":"Present and future in vitro approaches for drug metabolism","volume":"44","author":"Ekins","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S1359-6446(03)03019-8","article-title":"Strategies for using in vitro screens in drug metabolism","volume":"9","author":"Plant","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.trac.2014.06.021","article-title":"Coupling ultra-high-pressure liquid chromatography with mass spectrometry for in-vitro drug-metabolism studies","volume":"63","author":"Spaggiari","year":"2014","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Cryst. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/chir.20733","article-title":"ECD cotton effect approximated by the Gaussian curve and other methods","volume":"22","author":"Stephens","year":"2010","journal-title":"Chirality"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/16\/5070\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:38Z","timestamp":1760165318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/16\/5070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,21]]},"references-count":25,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["molecules26165070"],"URL":"https:\/\/doi.org\/10.3390\/molecules26165070","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,8,21]]}}}