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
| Autor: | Artur M. S. Silva, Juliana Magalhaes de Oliveira, Solida Long, Luís Gales, Regina V. Oliveira, Izadora L. Furlani, Diana I. S. P. Resende, Madalena Pinto, Quezia B. Cass, José Alberto Pereira, Emília Sousa, Anake Kijjoa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Indole test
Circular dichroism Stereochemistry Absolute configuration Pharmaceutical Science Organic chemistry in vitro metabolism Analytical Chemistry Hydroxylation gram-scale synthesis chemistry.chemical_compound QD241-441 chemistry Chemistry (miscellaneous) Drug Discovery enantioselectivity Quinazoline Molecular Medicine ECD Physical and Theoretical Chemistry Quinazolinone Antibacterial agent ADME X-ray crystallography |
| Zdroj: | Molecules, Vol 26, Iss 5070, p 5070 (2021) Molecules Volume 26 Issue 16 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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