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

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.

Fiscalin Derivatives as Potential Neuroprotective Agents

“…Compound 1a was previously synthesized in our laboratory, via Mazurkiewicz–Ganesan approach, consisting of coupling of linear tripeptides follow by isomerization of 4-imino-4 H -3,1-benzoxozines to obtain the corresponding quinazolin-4-ones of 1a , 3 and 4 ( Scheme 1 Method A) by removing a protecting group. Derivatives 1b , 1c , 2a , 2b and 5 – 15 were also previously obtained using a microwave-assisted multicomponent one-step polycondensation of amino acids [ 30 , 32 , 33 , 38 , 39 , 40 ]. The procedure was summarized as a condensation of N -protected α-amino acids with anthranilic acids under mild heating with triphenylphosphite (PhO) 3 P, generating the intermediate benzoxazine-4-one, followed by flash microwave irradiation with tryptophan ester to yield the desired products ( Scheme 1 Method B).…”

“…Indole-coquinazolinone-3,6-(4H)-diones compounds 1a , 1b , 1c , 2a , 2b , 3 – 15 were previously synthesized and used without further purification after purity assessment [ 30 , 32 , 33 , 38 , 39 , 40 ]: (1 S ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b] quinazolin-3,6-(1H, 4H)-dione ( 1a ), (1 R ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 1b ), (1 S ,4 R )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 1c ), (1 R ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isobutyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 2a ), (1 S ,4 R )-4-(1H-Indol-3-ylmethyl)-1-isobutyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 2b ) [ 38 ]. (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-(2-(methylthio)ethyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-diones ( 3 ), (1 S ,4 S )-4-((1H-indol-3-yl)methyl)-1-(4-hydroxybenzyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 4 ), (1 R ,4 S )-4-((1H-indol-3-yl)methyl)-1-(4-hydroxybenzyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 5 ) [ 30 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-hydroxy-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 6 ), (1 S ,4 R )-4-((1H-indol-2-yl)methyl)-1-isobutyl-9-(1-methyl-1H-tetrazol-5-yl)-1,2-dihydro-6H-pyrazino [2,1-b]quinazoline-3,6(4H)-dione ( 7 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-isobutyl-8-methoxy-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 8 ), (7 R ,10 S )-7-((1H-indol-3-yl)methyl)-10-isobutyl-9,10-dihydro-5H-pyrazino[1,2-a]pyrido[2,3-d]pyrimidine-5,8(7H)-dione ( 9 ) [ 33 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-chloro-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 10 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-chloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 11 ) [ 32 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-(4-(benzyloxy)benzyl)-8,10-dichloro-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 12 ) [ 30 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-iodo-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 13 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-bromo-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 14 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8,10-diiodo-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 15 ) […”

“…The procedure was summarized as a condensation of N-protected α-amino acids with anthranilic acids under mild heating with triphenylphosphite (PhO) 3 P, generating the intermediate benzoxazine-4-one, followed by flash microwave irradiation with tryptophan ester to yield the desired products (Scheme 1 Method B). Indole-coquinazolinone-3,6-(4H)-diones compounds 1a, 1b, 1c, 2a, 2b, 3-15 were previously synthesized and used without further purification after purity assessment [30,32,33,[38][39][40]: (15) [32].…”

Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones Active against Plasmodium and Trypanosomatids

“…Indole-containing pyrazino­[2,1- b ]­quinazoline-3,6-diones (Figure ) constitute a subclass of alkaloids mostly isolated from marine and terrestrial sources. , These structurally unique alkaloids contain simultaneously a quinazoline core which can be found in the structure of the natural febrifugine and an indole moiety commonly found in several drug lead candidates such as spiroindolone and TCMDC-134281 (Figure ). This hybrid structure, containing both moieties, led us to hypothesize the antimalarial potential of derivatives with this scaffold and their ability to overcome the observed cross-resistance with CQ and ACTs (Figure ).…”