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molecules Article 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 Solida Long 1,2,† , Izadora L. Furlani 3,† , Juliana M. de Oliveira 3, Diana I. S. P. Resende 1,4 , Artur M. S. Silva 5 , Luís Gales 6,7, José A. Pereira 6 , Anake Kijjoa 4,6 , Quezia B. Cass 3 , Regina V. Oliveira 3,*, Emília Sousa 1,4,* and Madalena M. M. Pinto 1,4 1 LQOF-Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; [email protected] (S.L.); [email protected] (D.I.S.P.R.); [email protected] (M.M.M.P.) 2 Department of Bioegineering, Faculty of Engineering, Royal University of Phnom Penh, Russian Federation Blevd, Phnom Penh 12156, Cambodia 3 SEPARARE–Núcleo de Pesquisa em Cromatografia, Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luiz, km 235, São Carlos 13565-905, Brazil; [email protected] (I.L.F.); [email protected] (J.M.d.O.); [email protected] (Q.B.C.) 4 CIIMAR-Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos S/N, Matosinhos, 4450-208 Porto, Portugal; [email protected] 5 LAQV-REQUIMTE-Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal; Citation: Long, S.; Furlani, I.L.; [email protected] 6 ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal; Oliveira, J.M.d.; Resende, D.I.S.P.; [email protected] (L.G.); [email protected] (J.A.P.) Silva, A.M.S.; Gales, L.; Pereira, J.A.; 7 i3S-IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4050-313 Porto, Portugal Kijjoa, A.; Cass, Q.B.; Oliveira, R.V.; * Correspondence: [email protected] (R.V.O.); [email protected] (E.S.); Tel.: +55-16-3306-6837 (R.V.O.); et al. Determination of the Absolute +351-220-428-689 (E.S.) Configuration of Bioactive † These authors contributed equally to this work. Indole-Containing Pyrazino[2,1-b] quinazoline-3,6-diones and Study of Abstract: In recent decades, fungi-derived naturally occurring quinazolines have emerged as poten- Their In Vitro Metabolic Profile. tial drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is Molecules 2021, 26, 5070. https:// known about their absorption, distribution, metabolism, and elimination (ADME) properties. To doi.org/10.3390/molecules26165070 perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and Academic Editor: Marcelo its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1- Daniel Preite 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 Received: 29 July 2021 structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography Accepted: 18 August 2021 as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed Published: 21 August 2021 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 Publisher’s Note: MDPI stays neutral time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass with regard to jurisdictional claims in spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated published maps and institutional affil- hydration and hydroxylation mass changes introduced to the parent drugs. iations. Keywords: gram-scale synthesis; enantioselectivity; ECD; X-ray crystallography; in vitro metabolism Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article In the marine world, amino acids are important building blocks associated with distributed under the terms and diverse structures with medley complexity, particularly alkaloids from marine-derived conditions of the Creative Commons fungi. Studies on the isolation, biosynthesis, synthesis, and biological activities of the Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ pyrazino[2,1-b]quinazoline-3,6-dione core linked to an indole moiety have been increasing 4.0/). significantly in the last 20 years [1–4]. Structurally, these quinazolinone alkaloids have Molecules 2021, 26, 5070. https://doi.org/10.3390/molecules26165070 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 12 fungi. Studies on the isolation, biosynthesis, synthesis, and biological activities of the py- razino[2,1-b]quinazoline-3,6-dione core linked to an indole moiety have been increasing significantly in the last 20 years [1–4]. Structurally, these quinazolinone alkaloids have been classified from simple to complex structures and consist of three different building blocks—anthranilic acid, α-amino acids, and tryptophan moieties that merge into a simple ring system [5]. The simplest structures are glyantrypine, fumiquinazolines F and G, and fiscalin B (1, Figure 1), which were reported in several synthetic studies [6–9]. (1S,4R)- Fiscalin B (1) was first isolated in 1992 from a strain of Aspergillus fumigatus found in the intestine of the marine fish Pseudolabrus japonicas and later in 1993 from the ethyl acetate extract of a cell mass from a fungal culture of Neosartorya fischeri collected from We Fung Chi, Taiwan [10–13]. Naturally occurring and synthetic fiscalin B (1) have been reported for their activities such as substance P inhibition [12], neuroprotective [14], antitumor [15], and antimalarial [16]. However, the ADME profile of pyrazino[2,1-b]quinazoline-3,6-dio- nes, including these bioactive fungi-derived compounds, has not yet been reported [1]. Owing to the increasing interest of fiscalin B (1) in medicinal and organic chemistry, some synthetic procedures enabling its facile production have been developed in recent decades [6,8,9,17]. Recently, we reported the synthesis and biological activities of four dif- ferent series of indole-containing pyrazino[2,1-b]quinazoline-3,6-diones by using this syn- thetic methodology as well as by performing different modifications in order to study the structure–activity relationship [14–16,18]. From these studies, we were able to obtain a significant number of hit compounds, either as neuroprotective, antitumor, and antibac- terial agents [14–16,18]. Herein, we report the concise total synthesis of 1, possessing an- timalarial activity [16], and its derivative 4-[(1H-indol-3-yl)methyl]-8,10-dichloro-1-isobu- tyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione 2, a hit compound with an- tibacterial activity [18], in gram scale via a microwave-assisted methodology. This deriv- ative exhibited potent antibacterial activity against S. aureus strains, with MIC values of 4 µg/mL for a reference strain (S. aureus ATCC 29213, positive control cefotaxime MIC = 8 µg/mL) and 8 µg/mL for a methicillin-resistant strain (S. aureus 66/1, positive control kan- amycin MIC = 32 µg/mL). Compared with the structurally related marine natural product neofiscalin A [19], a two-fold reduction in the MIC values was observed, showing that simpler molecules are quite promising to find new agents to overcome multidrug-re- Molecules 2021, 26, 5070 2 of 12 sistant (MDR) strains [18]. Furthermore, 2 was able to impair S. aureus biofilm production, and no significant cytotoxicity towards differentiated and non-differentiated SH-SY5Y cells was observed [18]. been classified from simple to complex structures and consist of three different building Indole-containing pyrazino[2,1-b]quinazoline-3,6-diones could be promising drug blocks—anthranilic acid, α-amino acids, and tryptophan moieties that merge into a simple ringcandidates system [;5 however,]. The simplest investigations structures are on glyantrypine, their metaboli fumiquinazolinessm parameters F andto predict G, and biologi- fiscalincally active B (1, Figuremetabolites1), which or even were toxicity, reported that in several could synthetic help translat studiese these [ 6–9 ].secondary (1S,4R)- metab- Fiscalinolites to B useful (1) was drug first isolatedcandidates in 1992 and from development a strain of Aspergillusprocesses, fumigatus are still missing.found in theTaking into intestineaccount ofthat the the marine understanding fish Pseudolabrus and japonicasdescriptandion laterof the in metabolism 1993 from the of ethyl new acetate chemical enti- extractties are of an a cellessential mass from part aof fungal biological culture evaluation of Neosartorya as an fischeri importantcollected parameter from We Fungfor both drug Chi,safety Taiwan and [10efficacy,–13]. Naturally prediction occurring of drug and metabolism synthetic fiscalin studies B (1) haveon human been reported liver microsomes for theirusing activities these target such as alkaloids, substance P1 inhibitionand 2, via [12 cytochromes], neuroprotective P450 [14 (phase], antitumor I)-mediated [15], and reactions b antimalarialby UHPLC- [HRMS,16]. However, were performed. the ADME profile of pyrazino[2,1- ]quinazoline-3,6-diones, including these bioactive fungi-derived compounds, has not yet been reported [1]. Figure 1. Structures of target compounds for gram syntheses, (1S,4R)-4-(1H-Indol-3-ylmethyl)-1- isopropyl-2H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (fiscalin B) (1) and (1S,4R)-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). Owing to the increasing interest of fiscalin B (1) in medicinal and organic chem- istry, some synthetic procedures enabling its facile production have been developed in recent decades [6,8,9,17].

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