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

Author(s):Show less -

Long, Solida ^{[1, 2]} ; Furlani, Izadora L. ^[3] ; de Oliveira, Juliana M. ^[3] ; Resende, Diana I. S. P. ^{[1, 4]} ; Silva, Artur M. S. ^[5] ; Gales, Luis ^{[6, 7]} ; Pereira, Jose A. ^[6] ; Kijjoa, Anake ^[6] ; Cass, Quezia B. ^[3] ; Oliveira, Regina V. ^[3] ; Sousa, Emilia ^{[1, 4]} ; Pinto, Madalena M. M. ^{[1, 4]}

Affiliation

^[1] Univ Porto, LQOF Lab Quim Organ & Farmaceut, Dept Ciencias Quim, Fac Farm, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto - Portugal

^[2] Royal Univ Phnom Penh, Dept Bioegn, Fac Engn, Russian Federat Blevd, Phnom Penh 12156 - Cambodia

^[3] Univ Fed Sao Carlos, Dept Quim, SEPARARE Nucleo Pesquisa Cromatog, Rodovia Washington Luiz, Km 235, BR-13565905 Sao Carlos - Brazil

^[4] CIIMAR Ctr Interdisciplinar Invest Marinh & Ambie, Terminal Cruzeiros Porto Leixoes, Av Gen Norton Matos S-N, P-4450208 Porto - Portugal

^[5] Univ Aveiro, LAQV REQUIMTE, Dept Quim, P-3810193 Aveiro - Portugal

^[6] Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4050313 Porto - Portugal

^[7] Univ Porto, i3S, Inst Biol Mol & Celular, IBMC, P-4050313 Porto - Portugal

• Document type: Journal article
• Source: Molecules; v. 26, n. 16 AUG 2021.
• Web of Science Citations: 0

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-pyrazi no{[}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. (AU)

• FAPESP's process: 18/03035-3 - Development of bioreactors for online studies of drug metabolism
• Grantee: Izadora Liranço Furlani
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 20/05965-8 - Metabolomic strategies based on LC-HRMS for investigation of potential biomarkers for clinical diagnosis - Phase I
• Grantee: Regina Vincenzi Oliveira
• Support type: Regular Research Grants
• FAPESP's process: 19/15040-4 - Omic-based strategies for the investigation of biomarkers for early diagnosis of patients with progressive biliary diseases
• Grantee: Juliana Magalhães de Oliveira
• Support type: Scholarships in Brazil - Doctorate