Design, synthesis, molecular docking, and some metabolic enzyme inhibition properties of novel quinazolinone derivatives

Abstract

3-Amino-2-ethylquinazolin-4(3H)-one (3) was synthesized in two steps from the reaction of amide (2), which was obtained from the treatment of methyl anthranilate (1) with propionyl chloride, with hydrazine. From the reaction of 3-amino-2ethylquinazolin-4(3H)-one (3) with various aromatic aldehydes, novel benzylidenaminoquinazolin-4(3H)-one (3a-n) derivatives were synthesized. The structures of the novel molecules were characterized using infrared spectroscopy, nuclear magnetic resonance spectroscopy ( 1 H-NMR and 13 C-NMR), and highresolution mass spectroscopy. The novel compounds were tested against some metabolic enzymes, including α-glucosidase (α-Glu), acetylcholinesterase (AChE), and human carbonic anhydrases I and II (hCA I and II). The novel compounds showed K i values in the range of 244-988 nM for hCA I, 194-900 nM for hCA II, 30-156 nM for AChE, and 215-625 nM for α-Glu. The binding affinities of the most active compounds were calculated as −7.636, −6.972, −10.080, and −8.486 kcal/mol for hCA I, hCA II, AChE, and α-Glu enzymes, respectively. The aromatic ring of the quinazoline moiety plays a critical role in the inhibition of the enzymes. K E Y W O R D S3-aminoquinazolin-4(3H)-one, enzyme inhibition, metabolic enzymes, molecular docking, Schiff bases | INTRODUCTIONQuinazolines and quinazolinone derivatives are molecules that represent an important class of heterocyclic compounds. This class of compounds that are known to be natural and synthetic derivatives has attracted the attention of many scientists due to their biological activities and many molecules belonging to this class of compounds have been synthesized in the past 30 years. Many studies concerning anticancer, [1][2][3][4] antitumor, [5,6] antimicrobial, [7][8][9] anti-inflammatory, [10] antifungal, [11] anticonvulsant, [12,13] and anti-HIV [14] properties of quinazoline and quinazolinone derivatives have been reported.Carbonic anhydrases (CAs) are metalloenzymes widespread in nature, being encoded by at least eight genetic classes, which have been identified in organisms. [15,16] By catalyzing a crucial physiologic reaction, by which carbon dioxide is hydrated with the formation of a weak base (bicarbonate) and a strong acid (hydronium ions), these enzymes are involved in plenty of physiologic mechanisms, starting with pH regulation and ending with metabolism. [17,18] Thus, CAs and their inhibitors are drugs having pharmacological applications in many fields. For example, CA II isoenzyme is the most physiologically relevant isoform and is implicated in diseases like glaucoma (such as CA XII), cerebral edema, and epilepsy. [19][20][21]

Synthesis, biological evaluation, and in silico study of novel library sulfonates containing quinazolin‐4(3H)‐one derivatives as potential aldose reductase inhibitors

“…For compounds 7 , 14 , and 21 , bands of the NO 2 groups observed at 1529 and 1354, 1531 and 1350, 1532 and 1352 cm −1 , respectively. These are the characteristic bands and the values are fully compatible with the structures and literature (Tokalı et al, 2021).…”

“…Finally, for compounds 15–21 , peaks of C2 substituted isopropyl carbons were observed at δ 31.9 ppm for CH and δ 20.4 ppm for two CH 3 . Chemical shifts, and number of the peaks are fully compatible with the structures and literature (Tokalı et al, 2021). The data obtained from the spectra have identified the structures of the compounds.…”

“…Finally, for compounds 3 , 10 , and 17 , peaks of the C2 substituted methoxy protons (PhOCH 3 ) were seen as a singlet at δ 3.78, 3.89, and 3.89 ppm, respectively. Chemical shifts, integrations, and splits are fully compatible with the structures and literature (Tokalı et al, 2021).…”

“…This class of compounds, which has many natural and synthetic derivatives, has attracted the attention of many scientists due to its biological activities, and many molecules belonging to this class of compounds have been synthesized in the last 30 years. For many studies concerning anticancer (Ma et al, 2004; Malecki et al, 2004; Park et al, 2004; Sharma et al, 2002), antitumor (Abdel‐Jalil et al, 2005; El‐Azab & ElTahir, 2012), antimicrobial (Chevalier et al, 2010; Gangjee et al, 2008; Mahamoud et al, 2011), anti‐inflammatory (Manivannan & Chaturvedi, 2011; Tokalı et al, 2021), antifungal (Pedrood et al, 2021; Shivananda & Holla, 2011), anticonvulsant (Amir et al, 2013; Bajaj et al, 2003), anti‐HIV (Gürsoy & Karalı, 2003; Sepehri et al, 2020), anticholinesterase (Decker, 2005), anti‐diabetic (Malamas & Millen, 1991), dihydrofolate reductase inhibition (Gangjee et al, 2000), and kinase inhibition (Li et al, 2011) properties of quinazoline and quinazolinone derivatives have been reported.…”

Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as Anti-colorectal Agents

“…Moreover, the enhanced anti-α-glucosidase activity of Schiff base derivative II has been rationalized using molecular docking analysis, which highlighted the role of quinazoline ring in the inhibition of the enzyme. 29 …”