242 © 2025The Author(s). Published by College of Education for Pure Science (Ibn Al-Haitham), University of Baghdad. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License Design, Synthesis of Some New Quinazolinone Derivatives and Evaluation of their Antibacterial Activity Aseel Jassim Mohammed 1* and Oday H.R. Al-Jeilawi 2 1,2 Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq. *Corresponding Author. Received: 24 June 2023 Accepted: 22 November 2023 Published: 20 July 2025 doi.org/10.30526/38.3.3620 Abstract The novel quinazolinone derivatives were synthesized in excellent yields, manufactured, characterized, and investigated for their biological activity. This study aims to produce new quinazolinone derivatives and study their antibacterial activity. Quinazolinone derivatives were synthesized in three steps: the first step included the reaction of methyl anthranilate with isothiocyanatobenzene to produce a thiourea derivative (A1). In the second step (A1) was reacted with hydrazine hydrate to synthesized 3-Amino-2-(phenylamino) quinazolin- 4(3H)-one (A2). The third step consisted of the reaction of (A2) with various organic compounds (phenylisotiocyanate, phenylisocyanate, acid halide, benzyl halide, and alkyl halide derivatives) to produce new derivatives. FT-IR, 1 HNMR, and 13 C NMR spectroscopy were used to identify the chemical structure of these compounds. The agar well diffusion technique was used to determine the antibacterial activity levels exhibited by the samples. Staphylococcus aureus and Escherichia coli were used as test organisms in this study. When compared to the antibiotic used as a standard, amikacin, these compounds demonstrated superior antibacterial activity. Keywords: Antibacterial activity, Methyl anthranilate, Thiourea derivative, Quinazolinone derivatives. 1. Introduction Heterocyclic compounds are a significant area of organic chemistry, which are recognized by the presence of a hetero atom in their cyclic structure in addition to basic carbon atoms like (O, N, S, P, Si and As) (1). Quinazolinones, also referred to as quinazolines, are a class of organic compounds that belong to the category of heterocyclic aromatic chemical substances (2). The molecule in question has a two-ringed structure, with one ring being benzene and the other being pyrimidine (3, 4). They were initially discovered in the late 19th century by Griess (5) Quinazolinones and their derivatives are highly effective compounds in many fields (6). such as medical, pharmaceutical, agricultural and industrial fields (insecticide, anticorrosion, and anti-oxidant) (7-11). There are many applications in pharmacology and physiology for the chemical synthesis known as quinazolinones. Many quinazolinone compounds have been employed clinically https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq https://orcid.org/0009-0000-7295-5269 mailto:aseel.jasim1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-4092-2072 mailto:Oday.h@sc.uobaghdad.edu.iq IHJPAS. 2025, 38(3) 243 due to their low toxicity and high efficiency (12). Recently, there has been a surge of interest in the synthesis of high-nitrogen-containing heterocyclic systems due to their vast range of potential applications. In medicinal chemistry, molecules based on the quinazolinone core play a significant role. That's because they're part of a big genus of products that prevent cancer and boost the immune system (13). A carbonyl group and two nitrogen atoms in (2, 4) positions form one ring of the heterocyclic chemical compounds known as quinazolinones, which also contain a benzene ring (14). Many scientists have experimented with different approaches to synthesizing quinazolinone nuclei over the years (15-17). Researchers in medicinal chemistry have demonstrated a significant interest in the biological assay of quinazoline and quinazolinone derivatives due to the importance of these fused heterocyclic compounds (18). The pharmacological properties of nitrogenated scaffolds, such as quinazolinones, have sparked significant interest in their anticancer effects (19). Infectious diseases are developing resistance to current therapies worldwide. Numerous investigations have yielded novel quinazolinone compounds with substantial antibacterial and antifungal activity, targeting DNA and cell walls (20-24). In the current study, quinazolinone derivatives synthesized from reaction of methyl anthranilate with isothiocyanatobenzene to produced thiourea derivative (A1) and (A1) was reacted with hydrazine hydrate to synthesized 3- Amino-2-(phenylamino) quinazolin-4(3H)-one (A2), the final step included reaction of (A2) with various organic compounds to produce new derivatives and study their antibacterial activity. This study aims to create new quinazolinone derivatives and study their antibacterial activity. 2. Materials and Methods All successful products had their melting points determined in open glass capillaries using the Gallenkamp device, and the results were uncorrected. The TLC method was used to monitor the progression of the reactions (silica gel on aluminum sheet). Many types of eluents were used According to the type of reactants, such as ethyl acetate: petroleum ether (2:1), hexane:ethyl acetate (3:2), chloroform:methanol (1:1), hexane: ethanol (3:2). In the chemistry department of the college of education of pure science at the university of Basrah, some of the produced compounds were characterized using 1 HNMR and 13 C NMR spectra on a Bruker Avance Neo 400 spectrometer, DMSO-d6 as a solvent, and tetramethyl silane as an internal standard. 2.1. Synthesis of Methyl-2-(3-phenylthioureido) benzoate (A1) (25) About (1.3 mL, 0.01 mol) of methyl anthranilate was dissolved in 5 mL ethanol and then added (1.2 mL, 0.01 mol) of phenyl isothiocyanate, the reaction completion after refluxed for 15 hrs, TLC, a solvent system hexane, monitors the reaction: ethyl acetate (3:2). The solution was added to crush ice then filtered the precipitate, washed in ethanol and water and left to dry. The physical properties are listed in Table (1). 2.2. Synthesis of 3-amino-2-(phenyl amino) quinazolin -4(3H)-one (A2) (26) About (0.5 g, 0.001 moles) methyl-2-(3-phenylthioureido) benzoate (A1) was dissolved in 6 mL of dimethylformamide and heated until (A1) completely dissolved. Then, an excess of hydrazine hydrate (4 mL) was added, resulting in a change in color to a turquoise hue. The reaction was completed after being refluxed for 8 hrs. The reaction was monitored by TLC using a solvent system of hexane:ethyl acetate (3:2). The mixture was then cooled with crushed ice. The precipitate was then filtered, washed with water, and left to dry; it was subsequently recrystallized with ethanol. The physical properties are listed in Table (1). IHJPAS. 2025, 38(3) 244 Table 1. Physical properties of synthesized compounds Comp IUPAC names Chemical formula M.wt (g/mol) M.P( (℃ Color Yield % A1 Methyl-2-(3-phenylthioureido) benzoate C15H14O2N2S 286.35 314-316 White 54 A2 3-Amino-2-(phenyl amino) quinazolin -4(3H)-one C14H12ON4 252.28 162-164 Brown 86 B1 1-(4-oxo-2-(phenylamino) quinazolin- 3(4H)-yl)-3-phenyl thiourea C21H17ON5S 387.46 224-227 White 82 B2 1-(4-oxo-2-(phenylamino) quinazolin- 3(4H)-yl)-3-phenyl urea C21H17O2N5 371.40 200-202 White 91 C1 N-(4-oxo-2-(phenylamino)quinazolin- 3(4H)-yl)furan-2-carboxamide C19H14O3N4 346.35 266-270 Yellow 21 C2 4-methoxy-N-(4-oxo-2- (phenylamino)quinazolin-3(4H)- yl)benzamide C22H18O3N4 386.41 253-255 Very light brown 50 D1 3-((4-nitrobenzyl)amino)-2- (phenylamino)quinazolin-4(3H)-one C21H17O3N5 387.40 gummy D2 3-(benzylamino)-2- (phenylamino)quinazolin-4(3H)-one C21H18ON4 342.40 135-138 Brown 60 F1 2-(phenylamino)-3-(prop-2-yn-1- ylamino)quinazolin-4(3H)-one C17H14ON4 290.33 318-320 Nutty 72 F2 3-(allylamino)-2- (phenylamino)quinazolin-4(3H)-one C17H16ON4 292.34 318-320 Nutty 87 2.3. Synthesis of 1-(4-oxo-2-(phenylamino) quinazolin-3(4H)-yl)-3-phenyl thiourea and 1-(4-oxo-2-(phenylamino) quinazolin-3(4H)-yl)-3-phenyl urea (B1,B2) (27) A 0.001 mol of phenyl isothiocyanate, phenyl isocyanate, respectively, were added to the solution (0.5 g, 0.001 mol) A2 in 10 mL of DMF. The produced solution was refluxed for 12- 18 hrs, and the reaction was monitored by using TLC with an eluent solution (2:1) of ethyl acetate and petroleum ether. When the reaction was finished, the mixture was added to ice water, where it became a white precipitate. The precipitate was then filtered, washed with water, and dried. The physical properties are listed in Table (1). 2.4. Synthesis of N-(4-oxo-2-(phenylamino)-quinazolin-3(4H)-yl)substituted amide and (C1,C2) (28) About (0.5 g, 0.001 mol) from A2 was dissolved in 10 mL of DMF, then a few drops of trimethylamine. After that, 0.001 mol of acid chlorides (4-methoxybenzoyl chloride and 2- furyl chloride) were added. The solution of the reaction was refluxed for 8 hrs. The reaction was monitored by TLC using a solvent system of ethyl acetate and petroleum ether (2:1). After the reaction was complete, the mixture was added to ice water. The precipitate of the final products was filtered, washed with water, and dried. The physical properties are listed in Table (1). 2.5. Synthesis of 3-(substituted) amino)-2-(phenylamino) quinazolin-4(3H)-one (D1, D2) (29) About (0.5 g, 0.001 mol) from A2 was dissolved in (10 mL) of DMF with stirring and heating, then a few drops of triethylamine were added, then (0.001 mol) from benzyl halides (benzyl chloride and 4-nitrobenzyl bromide) were added, and the solution was refluxed for 8 hrs. The reaction was monitored by using TLC with a solvent system (3:2) of hexane and ethanol. After the reaction finished, the mixture was added to ice water. The precipitate of the final products was filtered and washed with water, then left to dry. The physical properties are listed in Table (1). IHJPAS. 2025, 38(3) 245 2.6. Synthesis of 3-(alkylamino)-2-(phenylamino) quinazolin-4(3H)-one (F1,F2) (24) A (0.5 g) from A2 was dissolved in 10 mL DMF with heating, followed by adding drops of Et3N (0.001 mol ) from different alkyl halides(propargyl chloride and allyl bromide), and the reaction mixtures were still refluxed for 7 hrs. The reaction was monitored by using TLC, with a solvent system of hexane and ethanol (3:2). After the reaction was complete, the mixture was transferred to a Petri dish until the solvent had evaporated, and the precipitate of the product was washed with ethanol. The physical properties are listed in Table 1. 2.7. Anti-bacterial activity determination The antibacterial activity of each of the synthesized compounds is described in Table (1). The in vitro antibacterial activity of some samples was analyzed using the agar well-diffusion technique (30). The materials were tested against different strains of bacteria, including E. coli and Staphylococcus aureus. The antibiotic Amikacin served as the benchmark for comparison. In a solution of DMSO at a concentration of 1 mg per mL, test samples and standard references were generated After being sanitized and reduced to a liquid form, the agar was then mixed with a microbe suspension at a ratio of (1 ml/ 100 mL of medium) of medium and put onto a Petri dish to a depth of about 3 millimeters., The test samples and references were placed in wells created in a solidified medium. The resultant plates were then chilled for 1 hour at 5 °C and subsequently incubated for 18 hours at 37 °C. The inhibition zones on the growth of bacteria that were induced by the test samples and the standard references were measured in millimeters, and the findings are presented in Table (4). 3. Results and Discussion Scheme (1) includes synthesized quinazolinone derivatives by reacting methyl anthranilate with isothiocyanateobenzene to make A1, then reacting A1 with hydrazine hydrate to make A2, and finally reacting A2 with with various organic compounds (phenylisotiocyanate, phenylisocyanate), acid halide, benzyl halide and alkyl halide derivatives in DMF as solvent and Et3N as a catalyst to produce new quinazolinone derivatives. The TLC was used to determine where the reaction stopped. The FT-IR spectral data of compound (A1) showed the disappearance absorbance of ʋ (NH2) for methyl anthranilate while appearance a new absorption at (3245) cm -1 , which was attributed to the secondary amine group ʋ (NH), in addition stretching and bending vibrations at (1533, 1288 and 989) cm -1 due to involving interaction between (C=S) group and (C-N) group of the C=S group attached to a nitrogen atom (31,32). These bands were good evidence for the formation of the compound (A1) (Figure 1). The FT-IR spectral data of A2 derivative showed the disappearance of ʋ (C=S), while the appearance of two new stretching vibrations at (3450) and (3305) cm -1 for (NH2) and bands at (1660) cm -1 and (1616) cm -1 due to C=O amide and C=N, respectively. The 1 HNMR spectral data of compound A2 a singlet signal at 5.8 ppm, which belongs to the NH2 proton, and a singlet signal at 9.8 ppm, which belongs to the N-H proton (33). The FT-IR spectrum of compounds (B1, B2) showed the disappearance of (NH2), while the band at (1531, 1232 and 929) cm -1 due to (C=S interaction with –N-C=S) for B1 and band at (1662) cm -1 due to (C=O) for B2 will appear (34), the 1 HNMR spectrum of compound (B1, B2) showed singlet signals at (8.72-9.82) ppm due to one proton for the (H-N), a singlet signal at (9.56-13.07) ppm due to two protons for (NH urea and thiourea) group, While the 13 C NMR spectrum showed signals at signals at (153.29-160.29) ppm for (C=N), 176.52 and 180.06 ppm for (C=O) and (C=S) group respectively. The FT-IR spectrum of compound (C1, C2) showed the disappearance of ʋ (NH2), while the band at ʋ (1662) cm -1 , ʋ (1622) cm -1 due to amide group (C=O) and (C=N). The 1 HNMR spectrum of IHJPAS. 2025, 38(3) 246 compound (C1) showed singlet signal at δ= (9.56) ppm was due to one proton for the (H-N) group, and a singlet signal at δ= (13.07) ppm due to one proton for (O=C-NH) group, While the 13 C NMR spectrum compound (C1) showed signals at (140.7) ppm for (C-N), (160.29) ppm, (176.52) ppm for (C=O) group. The FT-IR spectrum of compound (D1,D2) showed the disappearance of ʋ (NH2), while the bands at ʋ (3442- 3431) cm -1 were due to (N-H) will appear (Fingers 2-9). Scheme 1. Synthesis of quinazolinone derivatives The 1 HNMR spectrum of compound (D1,D2) showed singlet signals at (3.42-3.45) ppm due to one proton of (NH-CH2) While the 13 C NMR spectrum of compound (D1) showed signals at (162.03) ppm for (C=N) and signal at (167.2) ppm for carbonyl group. The FT-IR spectrum of compound (F1,F2) showed the disappearance of ʋ (NH2), while the bands at ʋ (3440-3429) cm -1 due to (N-H). FT-IR, 1 HNMR and 13 C NMR spectral data for some derivatives are listed in Tables (2) and (3) respectively. IHJPAS. 2025, 38(3) 247 Table 2. FT-IR spectral data for synthesized derivatives No. Com. Structure Major FT-IR Absorptions cm -1 ʋ (NH) ʋ (C-H) arom. ʋ (C-H) aliph. ʋ(C=O) quinazolin e ʋ (C=C) arom. Other bands A1 3245 3029 2968, 2891 -- 1598, 1558 1665 (C=O) ester, (1533,1288,989) (C=S) interaction with (-N-C=S) A2 3224 3058 --- 1660 1577, 1541 3450(asym) and 3305(sym) (NH2) , 1616 (C=N) B1 3242 3033 -- 1662 1595, 1552 1531, 1232, 929 (C=S) interaction with (N-C=S) B2 3245 3035 -- 1662 1595, 1554 1650(C=O) for urea , 1622 (C=N) C1 3247 3033 -- 1662 overlap with (C=O) of amide 1562, 1531 1620 (C=N) C2 3217 3033 2972, 2846 1662 overlap with (C=O) of amide 1560, 1533 1600 (C=N) D1 3442 3065 2975, 2941 1681 1550 1606 (C=N), (1521, 1348) NO2 D2 3431 3060 2977, 2943 1689 1573, 1552 1600 (C=N) F1 3429 3060 2981, 2937 1681 1571, 1560 3151 (CH) acetylenic , 2100 (C≡C) F2 3440 3045 2997, 2877 1674 1575, 1548 1635 (C=C) , 1600 (C=N) IHJPAS. 2025, 38(3) 248 Table 3. The 1 HNMR and 13 C NMR spectral data of some synthesized compounds No. Comp. Structure 1 H NMR 13 C NMR A2 5.8(s,2H, NH2) 7.03- 8.91(m,13H, Ar-H), 9.8 (s,1H, NH) 120.95-147.6(C5-C10 and C13-C18), 159.55(C2), 167(C4). B1 7.1-7.97(m,14H, Ar- H), 9.82 (s,1H, -N-H), 13.07(s, 2H, NH-C=S) 116.17-139.91 (C9-C14 and C16-C21 and C23-C28), 160.29 (C6), 176.52 (C8), 180.06 (C2) B2 6.95-7.97 (m,14H, Ar- H) 8.72(s, 1H, NH), 9,56(s,1H, O=C-NH), 10.20(s,1H, O=C-NH- N) 114.30-140.20 (C9-C14 and C16-C21 and C23-C28), 153.01(C6) , 160.3 (C2), 176.52 (C8) C1 7.2-8.3(m,12H, Ar-H) 9.56 (s,1H, NH) 13.07 (s,1H, O=C-NH) 116.16-139.78(C1, C9-C14 , C16-C21, C23, C24 and C26 ), 140.07 (C6) ,160.29 (C2) 176.52 (C8) D1 3.45(d,2H, NH-CH2) 4.7(t,1H, CH2-NH), 7.3-8.4(m,13H, Ar-H), 9.62 (s,1H, NH) 52.93(C2), 116.51-161.17(C1, C8-C13, C15-C20 and C22- C26), 162.03 (C5), 167.26 (C7) D2 3.42(d,2H, N-CH2) 4.47(s,1H, CH2-NH) 7.2-8.3(m,14H, Ar-H) 9.56(s,1H, NH) 52.4 (C2), 120.05-157.39 (C1, C8-C13, C15-C20 and C22- C26), 159.05 (C5) 161.21 (C7) F1 2.89(s,1H, ≡CH) 3.34(t,2H, NH- CH2),4.06-4.36(t,1H, NH-CH2) 7.52-8.32 (m, 9H, Ar-H), 9.63 (s,1H, NH) 53.40(C1), 72.68(C22), 82.85 (C21), 116.51-136.41(C7- C12 and C14-C19), 148.98 (C4) 159.05 (C6) F2 3.3 (t,1H, N-NH), 3.8(t,2H, -CH2- CH=CH2) 5.1,5.3(d,2H, -CH2- CH=CH2) 5.97(m,1H, -CH2- CH=CH2), 7.4- 8.2(m,9H, Ar-H), 9.5 (s,1H, NH) 56.06(C1),116.40(C22),133.33(C21), 119.36-130.33 and 135.38-147.71(C7-C12 and C14-C19), 157.16 (C4), 161.22 (C6) IHJPAS. 2025, 38(3) 249 Figure 1. FT-IR spectrum for compound A2 Figure 2. FT-IR spectrum for compound B1 Figure 3. FT-IR spectrum for compound B2 IHJPAS. 2025, 38(3) 250 Figure 4. FT-IR spectrum for compound F1. Figure 5. 1 HNMR spectrum for compound (A2). Figure 6. 13 C NMR spectrum for compound (A2). IHJPAS. 2025, 38(3) 251 Figure 7. 1 HNMR spectrum for compound (B1). Figure 8. 13 C NMR spectrum for compound (B1). Figure 9. 1 HNMR spectrum for compound (B2). IHJPAS. 2025, 38(3) 252 Figure 10. 13 C NMR spectrum for compound (B2). Figure 11. 1 HNMR spectrum for compound (F1). 3.1. Biological activity The compounds studied had modest effects on the bacteria. Compounds B2, C2, D1, and F1 were the most effective against Escherichia coli bacteria, while they were less effective against gram-positive bacteria Staphylococcus aureus, which were affected the same way by all compounds. For comparison, Amikacin was used as the antibiotic, and DMSO served as the carrier (Table 4). Table 4. Antibacterial zone of inhibition (mm) of synthesized derivatives Comp. code Gram positive bacteria Staphylococcus aureus Gram negative bacteria Escherichia coli B1 8 8 B2 8 10 C1 8 8 C2 8 11 D1 8 13 D2 8 8 F1 8 11 F2 8 8 Amikacin 15 32 4. Conclusion The synthesis of several novel quinazolinone derivatives was carried out in three stages, and the compounds were characterized using various spectroscopic methods. The synthetic IHJPAS. 2025, 38(3) 253 compounds exhibited a diverse portfolio of potentially promising antibacterial properties. Compounds D1, C2, and F1 exhibited a strong inhibition zone against gram-positive bacteria. Acknowledgment The authors thank the head of the Department of Chemistry at the College of Science, University of Baghdad, for providing a laboratory for the preparation of scientific research, and the head of the postgraduate laboratory in the Biology Department for measuring antimicrobial activity. 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