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.
Highlights
In the marine world, amino acids are important building blocks associated with diverse structures with medley complexity, alkaloids from marine-derived fungi
Taking into account that the understanding and description of the metabolism of new chemical entities are an essential part of biological evaluation as an important parameter for both drug safety and efficacy, prediction of drug metabolism studies on human liver microsomes using these target alkaloids, 1 and 2, via cytochromes P450-mediated reactions by ultra-high-performance liquid chromatography (UHPLC)-high-resolution mass spectrometry (HRMS), were performed
The gram-scale synthesis of fiscalin B (1) followed the protocol used in the milligram
Summary
Amino acids are important building blocks associated with diverse structures with medley complexity, alkaloids from marine-derived fungi. Biosynthesis, synthesis, and biological activities of the pyrazino[2,1-b]quinazoline-3,6-dione core linked to an indole moiety have been increasing significantly in the last 20 years [1,2,3,4] These quinazolinone alkaloids have μ g/mL) and 8 μ g/mL for a methicillin-resistant strain (S. aureus 66/1, positive control kan amycin MIC = 32 μ g/mL). We reported the synthesis and biological activities of four different series of indole-containing pyrazino[2,1-b]quinazoline-3,6-diones by using this synthetic methodology as well as by performing different modifications in order to study the structure–activity relationship [14,15,16,18] From these studies, we were able to obtain a significant number of hit compounds, either as neuroprotective, antitumor, and antibacterial agents [14,15,16,18]. Taking into account that the understanding and description of the metabolism of new chemical entities are an essential part of biological evaluation as an important parameter for both drug safety and efficacy, prediction of drug metabolism studies on human liver microsomes using these target alkaloids, 1 and 2, via cytochromes P450 (phase I)-mediated reactions by UHPLC-HRMS, were performed
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