2. Academic Validation
  3. 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

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

  • Molecules. 2021 Aug 21;26(16):5070. doi: 10.3390/molecules26165070.
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,  Madalena M M Pinto 1 4
Affiliations

Affiliations

  • 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.
  • 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.
  • 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.
  • 5 LAQV-REQUIMTE-Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal.
  • 6 ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
  • 7 i3S-IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4050-313 Porto, Portugal.
PMID: 34443658 DOI: 10.3390/molecules26165070
Abstract

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.

Keywords

ECD; X-ray crystallography; enantioselectivity; gram-scale synthesis; in vitro metabolism.

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