A series of novel sulfonates containing quinazolin-4(3H)-one ring derivatives was designed to inhibit aldose reductase (ALR2, EC 1.1.1.21). Novel quinazolinone derivatives (1-21) were synthesized from the reaction of sulfonated aldehydes with 3-amino-2-alkylquinazolin-4(3H)-ones in glacial acetic acid with good yields (85%-94%). The structures of the novel molecules were characterized using IR, 1 H-NMR, 13 C-NMR, and HRMS. All the novel quinazolinones (1-21) demonstrated nanomolar levels of inhibitory activity against ALR2 (K I s are in the range of 101.50-2066.00 nM). Besides, 4-[(2-isopropyl-4-oxoquinazolin-3[4H]-ylimino)methyl]phenyl benzenesulfonate (15) showed higher inhibitor activity inhibited ALR2 up to 7.7-fold compared to epalrestat, a standard inhibitor. Binding interactions between ALR2 and quinazolinones have been investigated using Schrödinger Small-Molecule Drug Discovery Suite 2021-1, reported possible inhibitor-ALR2 interactions. Both in vitro and in silico study results suggest that these quinazolin-4(3H)-one ring derivatives (1-21) require further molecular modification to improve their drug nominee potency as an ALR2 inhibitor.

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]

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In this study, new benzoic acid derivatives of the quinazolinone ring, which is one of the biologically active members of nitrogen-containing heterocyclic compounds, were synthesized with excellent yields (98-90 %). The structures of the novel compounds (1-12) were characterized with Fourier-transform Infrared (FTIR), Nuclear Magnetic Resonance ( 1 H NMR-13 C NMR), and High-Resolution Mass Spectroscopy (HRMS). α-Glucosidase and α-Amylase inhibition properties were examined to evaluate the anti-diabetic properties of the synthesized compounds. For α-Glucosidase, molecules showed IC 50 in ranging of > 100-3.468 � 0.270 μM and K i s in ranging of > 100-3.310 � 0.326 μM. For α-Amylase, molecules showed IC 50 in ranging of > 100-1.215 � 0.225 μM. 4-[(2-[(4-phenylpiperazin-1-yl)methyl]-4-oxoquinazolin-3(4H)-ylimino)methyl]benzoicacid (10) has the strongest inhibitory effect for both enzymes. It is 5.4 times more potent inhibitor for α-Glucosidase and 34.9 times more potent for α-Amylase than the standard inhibitor Acarbose. Also, the molecular docking study was carried out for the most active compound for the determination of ligand-enzyme interactions. Binding affinities of the most active compound were calculated as À 5.978 kcal/mol and À 5.548 kcal/mol for α-Glucosidase and α-Amylase, respectively. The aromatic ring and the aminomethyl group of the quinazoline and the carboxyl group moieties have played a critical role in the inhibition.