Abstract
Quinazolinones represent an important scaffold in medicinal chemistry with diverse biological activities. Here, two series of 2-substituted quinazolin-4(3H)-ones were synthesized and evaluated for their antioxidant properties using three different methods, namely DPPH, ABTS and TEACCUPRAC, to obtain key information about the structure–antioxidant activity relationships of a diverse set of substituents at position 2 of the main quinazolinone scaffold. Regarding the antioxidant activity, ABTS and TEACCUPRAC assays were more sensitive and gave more reliable results than the DPPH assay. To obtain antioxidant activity of 2-phenylquinazolin-4(3H)-one, the presence of at least one hydroxyl group in addition to the methoxy substituent or the second hydroxyl on the phenyl ring in the ortho or para positions is required. An additional ethylene linker between quinazolinone ring and phenolic substituent, present in the second series (compounds 25a and 25b), leads to increased antioxidant activity. Furthermore, in addition to antioxidant activity, the derivatives with two hydroxyl groups in the ortho position on the phenyl ring exhibited metal-chelating properties. Our study represents a successful use of three different antioxidant activity evaluation methods to define 2-(2,3-dihydroxyphenyl)quinazolin-4(3H)-one 21e as a potent antioxidant with promising metal-chelating properties.
Highlights
Quinazoline is a nitrogen containing fused heterocycle, and with additional carbonyl linkage it forms two different quinazolinones (either 4(3H)-quinazolinone or 2(1H)quinazolinone) [1]
In an open flask, the corresponding aldehydes 19a–l reacted with antranilamide (20) in DMSO via aerobic oxidative cyclization to the corresponding quinazolinones 21a–l (Scheme 1) [25,26]
The coupling of a carboxylic group with N,O-dimethylhydroxylamine using 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDC) afforded Weinreb amides 23a–b, which were further reduced with diisobutylaluminium hydride (DIBAL) to yield the cinnamaldehyde derivatives 24a and 24b, which reacted with antranilamide (20) in DMSO to form the final products 25a and 25b
Summary
Quinazoline is a nitrogen containing fused heterocycle, and with additional carbonyl linkage it forms two different quinazolinones (either 4(3H)-quinazolinone or 2(1H)quinazolinone) [1]. Quinazolinones represent an important scaffold in medicinal chemistry due to their synthetic accessibility and diverse in vitro and in vivo pharmacological activities [2,3]. The antioxidant properties were described for structurally diverse quinazolines (Figure 1b), such as 2-pentylquinazolin-4(3H)-one derivatives (e.g., 8) [4], heterocyclic quinazoline-4-one derivatives [5,6] (e.g., 9 [6]), N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)3,4-dihydroquinazolin-2-yl)thio]acetamide (10) [7], quinazolinone-1,3,4-oxadiazole conjugates (e.g., 11) [8], and a series of 2,3-disubstituted-2,3-dihydro-quinazolin-4(1H)-onederived [9,10] and quinazolinone-derived Schiff0 s bases (e.g., 12) [11,12]. Antioxidant activity was reported for 2-thioxobenzo[g]quinazoline derivatives (e.g., 13) [13], bis(2,3-dihydroquinazolin-4(1H)-one derivatives [14], 2-(chloromethyl)-3-(4-methyl-6oxo-5-[(E)-phenyldiazenyl]-2-thioxo-5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones (e.g., 14) [15], guanine-based (E)-2-(2-(pyridin-2-ylmethylene)hydrazinyl)quinazolin-4(3H)-
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