Next Article in Journal
On the Traceability of the Hazelnut Production Chain by Means of Trace Elements
Previous Article in Journal
Fluorescent Zn(II)-Based Metal-Organic Framework: Interaction with Organic Solvents and CO2 and Methane Capture
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 12
10.3390/molecules27123853
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity

by
Nader M. Boshta
1,*,†,
Farag A. El-Essawy
2,
Mohammed B. Alshammari
3,
Safaa G. Noreldein
1 and
Osama M. Darwesh
4
1
Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam 32511, Egypt
2
Preparatory Year Deanship, Basic Science Department, Prince Sattam Bin Abdulaziz University, P.O. Box 151, Alkharj 11942, Saudi Arabia
3
College of Sciences and Humanities, Prince Sattam Bin Abdulaziz University, P.O. Box 151, Alkharj 11942, Saudi Arabia
4
Environmental Microbiology and Nanotechnology Group, Agricultural Microbiology Department, National Research Centre, Cairo 12622, Egypt
*
Author to whom correspondence should be addressed.
†
Current address: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Molecules 2022, 27(12), 3853; https://doi.org/10.3390/molecules27123853
Submission received: 7 May 2022 / Revised: 6 June 2022 / Accepted: 11 June 2022 / Published: 15 June 2022
Browse Figures
Versions Notes

Abstract

:
In this paper, we report on the design and synthesis of a novel series of quinazoline-2,4(1H,3H)-dione derivatives as fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV to identify and develop antimicrobial agents to prevent bacterial resistance problems. Their structures were confirmed using spectroscopic analyses (IR, NMR, and EI-MS). The novel quinazoline-2,4(1H,3H)-dione derivatives were evaluated for their antimicrobial activities against Gram-positive and Gram-negative bacterial strains using the Agar well diffusion method to study the antimicrobial activities and compared them with the standard drugs. Most compounds displayed moderate activity. Among the tested compounds, the most promising compounds 13 and 15 provided broad bioactive spectrum against Gram-positive and Gram-negative strains compared to the standard drugs.

Graphical Abstract

1. Introduction

Nitrogen heterocycles are among the most notable scaffolds for pharmaceuticals, in which quinazoline is one of those scaffolds that exists in a total of nine U.S. FDA approved pharmaceuticals. Several reports have revealed that the unique quinazoline scaffolds possess several and diverse pharmacological activities such as antimicrobial, antimalarial, anticonvulsant, anti-inflammatory, antihypertensive, cholinesterase inhibitory, anti-diabetic, and anticancer activities [1]. Among the most important quinazoline families are quinazoline-2,4(1H,3H)-dione derivatives, and the various studies have reported several analogues representing a wide variety of biological activities, for example, antimicrobial [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18], anticancer [19,20,21,22,23,24,25,26,27,28,29,30,31,32], antiplatelet [33], antihypertensive [34], antioxidant [35], anticonvulsant [36,37,38], anti-inflammatory [39], phosphodiesterase (PDE) 4 inhibition [40], 5-HT3A receptor antagonist [41], and cyclin-dependent kinase 5 (CDK5) inhibition [42].
Fluoroquinolones, for example, I and II, are fatal and decisive antibacterial agents to exceedingly control many bacterial diseases [43]. However, many bacterial strains are resistant to such fluoroquinolone-like compounds [44,45,46]. Therefore, one way to avoid the resistance problems is to identify new derivatives to address the resistant mutant. On the other hand, a comprehensive study proved that quinazoline-2,4(1H,3H)-dione derivatives are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV [5,47]. In a continuation of our previous work on the synthesis and structural-activity relationships (SAR) of a novel series of 1,3-disubistituted quinoline derivatives [48] due to the current need to identify and develop inhibitors to prevent the bacterial resistance. Therefore, we selected the quinazoline-2,4(1H,3H)-dione scaffold to study and check the substituents’ effect at the same 1- and 3-positions on the quinazoline-dione ring (Figure 1). The most active compound discovered in our previous work was compound III, as shown in Figure 1.

2. Results and Discussion

2.1. Chemistry

The structural–activity relationship study of the previous 1,3-disubistituted quinoline derivatives suggested that the antibacterial activity could be increased by performing synthetic modification at the 1- and 3-positions, interestingly, the incorporation of the oxadiazole rings at both positions led to a significantly more potent compound (compd. III, Figure 1). Therefore, one part of this study aimed to investigate the incorporation of the same heterocyclic ring at the 1- and 3-positions of the quinazoline-2,4(1H,3H)-dione scaffold, as depicted in Scheme 1. Appropriately, quinazoline-2,4(1H,3H)-dione (1) was either commercially available or synthesized from anthranilic acid [49], followed by N-alkylation with ethyl chloroacetate in stirring dimethyl formamide in the presence of potassium carbonate at room temperature. The key intermediate 2,2′-(2,4-dioxoquinazoline-1,3(2H,4H)-diyl)di(acetohydrazide) (3) was afforded via the hydrazinolysis reaction of 2 at the reflux condition. Alternatively, synthesized from 2,2′-(2,4-dioxoquinazoline-1,3(2H,4H)-diyl)diacetonitrile (4), the hydrolysis of the respective nitrile groups to afford the acid derivative 5, was followed by esterification in the presence of sulfuric acid and methanol. The resulting dimethyl 2,2′-(2,4-dioxoquinazoline-1,3(2H,4H)-diyl)diacetate (6) underwent the hydrazinolysis reaction to afford the key intermediate 3 in a good yield of 72%. The crucial derivative 7 was prepared from dihydrazide 3 by treatment with carbon disulfide in the presence of potassium hydroxide. Finally, the target compounds 8a and 8b were synthesized via the alkylation reaction of compound 7 with benzyl chloride or methyl iodide, respectively. The structure of the synthesized derivatives was confirmed using mass spectrometry and NMR. The structure of the key intermediate 3 was obviously confirmed by the 1H-NMR spectrum, which showed the demise of the triplet signals at 1.21 ppm as well as the multiple signal at 4.17 ppm arising from the two COOEt groups of compound 2. Moreover, the appearance of signals assignable to the new (CONHNH2) groups at 9.30, 9.21, and 4.27 ppm. The cyclization of compound 3 resulted into compound 7 which was confirmed by the absence of the last-mentioned signals for (NH & NH2) groups in the 1H-NMR spectrum. Compounds 8a and 8b were confirmed by the appearance of new signals at 4.44 ppm arising from the new methylene fragments in the 1H-NMR spectrum for 8a and in parallel with the appearance of a new signal at 2.67 ppm arising from the new methyl fragments for 8b.
The key intermediate 3 could provide the opportunity for further novel quinazoline-2,4(1H,3H)-dione derivatives and have been prepared based on the synthetic producers displayed in Scheme 2. The reaction of compound 3 with diethyl ethoxymethylenemalonate or ethyl ethoxymethylene cyanoacetate under the reflux condition in acetic acid affording the malonate derivative 9a or cyanoacetate derivative 9b as a mixture of E/Z isomers, respectively. Furthermore, the direct condensation of diacetohydrazide 3 with aromatic aldehyde benzaldehyde, 2-hydroxybenzaldehyde, or 4-methoxybenzaldehyde to afford the corresponding arylidene 10a, 10b, or 10c, respectively, as mixtures of E/Z isomers. Comparably, the condensation reaction with cyclic ketone cyclopentanone, cyclohexanone, or cycloheptanone afforded the corresponding cycloalkylidene derivatives 11a, 11b, or 11c, respectively. The structure of the novel products 9a and 9b were confirmed by the demise of the two –NH2 groups in compound 3 and the appearance of new signals corresponding to the new methine protons (HN–CH=) at 7.69 and 8.20–8.21 ppm, respectively, in the 1H-NMR spectrum, in addition to the appearance of the characteristic signals of the new COOEt groups. Compounds 10a, 10b, and 10c were confirmed by the 1H-NMR spectrum, in which the signals matching to the two amino groups in compound 3 were replaced by singlet signals assignable to the new Schiff base protons (N=CH–Ar) in the region of 8.12–8.44 ppm, in addition to the new aromatic protons because of the insertion of the aryl group of the appropriate aldehydes in the range of 6.87–8.36 ppm. Compounds 11a, 11b, and 11c showed signals attributable to the new aliphatic protons as a result of the installation of cyclic aliphatic moieties of the appropriate cyclic ketones at the range 1.51–2.68 ppm.
The reaction of diacetohydrazide 3 with phenyl isocyanate or phenyl isothiocyanate in ethanol under the reflux condition affords the corresponding disemicarbazide derivative 12a or dithiosemicarbazide derivative 12b in a good yield. Consequently, such derivatives could be practical as a template for further modifications to synthesize more substituted analogues at the 1- and 3-positions of the quinazoline-2,4(1H,3H)-dione scaffold, particularly with hetero cyclic moieties. The triazole, oxadiazole, or thiadiazole derivatives can be afforded during the cyclization reaction of 12b based on the reaction medium. The cyclization of the last product 12b in the presence of NaOH under reflux conditions afforded 1,3-bis((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazoline-2,4(1H,3H)-dione (13). Otherwise, the cyclization of the dithiosemicarbazide derivative 12b in the presence of mercuric oxide HgO under reflux conditions gave 1,3-bis((5-(phenylamino)-1,3,4-oxadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione 14a while the cyclization via stirring at 0 °C in the presence of sulfuric acid provided 1,3-bis((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazoline-2,4(1H,3H)-dione 14b. On the other hand, disemicarbazide derivative 12a was easily intermolecular-cyclized, either with 2-chloroacetonitrile or ethyl bromoacetate in the presence of anhydrous sodium acetate in absolute ethanol, and provided compounds 15 and 16, respectively, in a very good yield (Scheme 3). Compounds 12a and 12b were confirmed by 1H-NMR, in which the signals corresponding to the (NH2) protons in compound 3 were replaced by signals assignable to the new (CONHPh or CSNHPh) protons at the range of 9.30–11.00 ppm and the new aromatic protons at the range of 7.19–8.10 ppm. The cyclization of compound 12b afforded compound 13, which was confirmed by the absence of signal (CSNHPh) protons with the appearance of new typical signals of the (SH) proton at 13.79 ppm. Compounds 14a and 14b were confirmed by the absence of singlet signals at the range of 9.41–11.00 ppm, which was related to the (NHNHCSNH) protons and by the presence of new singlet signals at the range of 10.44–10.53 ppm related to (NHPh) in the 1H-NMR spectrum. Similarly, compounds 15 and 16 were confirmed by the absence of singlet signals at the range of 8.32–10.09 ppm, which was related to the (NHNHCONH) protons and by the presence of new signal at 4.25 ppm, which was related to the new (NH2) group for compound 15, and new signals at 4.52 and 4.72 ppm, which were related to the new (–OCH2CO) groups for compound 16.

2.2. Antibacterial Activity

The antimicrobial activities of the synthesized compounds were examined against some targeted pathogenic microorganisms obtained from the American Type of Culture Collection (ATCC; Rockville, MD, USA). The compounds were evaluated for antimicrobial activity against Staphylococcus aurous ATCC-47077 (St.), Listeria monocytogenes ATCC-35152 (List.), Escherichia coli ATCC-25922 (E.C.), Salmonella typhi ATCC-15566 (Salm.), and Candida albicans ATCC-10231 (C. Alb.) [50,51]. The stock cultures of pathogens used in this study were maintained on nutrient agar slants at 4°. The Agar well diffusion method was employed to study the antimicrobial activities according to the method described by Kheiralla et al. [52] and Abdelhameed et al. [53] in which the zone of inhibition for the tested compound was measured by a ruler to determine its size (in mm) and compared with that produced by the reference antibacterial drugs ampicillin and vancomycin. The minimum inhibitory concentration (MIC) calculation of the synthesized compounds was also performed according to a slightly modified previous method [54,55] in which the MIC was defined as the concentration at which the bacteria and yeast did not show visible growth with respect to the positive control.
The synthesized intermediate 3 and compound 9b both showed no activity against most of the tested Gram-positive and Gram-negative strains, except for the Candida albicans strain, which is quite sensitive to those derivatives with an inhibition zone value of 11 mm and MIC value of 80 mg/mL, and so more effective than the reference antibacterial drug ampicillin. Compounds 13 and 15 gave broad bioactive spectrum against Gram-positive and Gram-negative strains in which compound 13 with triazole moieties at the 1- and 3-poisitions of the quinazoline-2,4-dione backbone showed moderate activity with a measured inhibition zone value of 9 mm against the Staphylococcus aurous strain when compared with the reference antibacterial drugs ampicillin and vancomycin. It also showed a specific activity against the Escherichia coli strain with inhibition zone values of 15 mm and MIC value of 65 mg/mL, which are equipotent to the reference drugs. Compound 13 significantly inhibited the growth of the Candida albicans strain with an inhibition zone value of 11 mm, and surpassed the efficacy of the reference antibacterial drug ampicillin. It was worthwhile to note that compound 15 showed moderate activities against Staphylococcus aurous, Escherichia coli, and Candida albicans strains with inhibition zone values in the range of 10–12 mm and MIC values of 80, 75, and 77 mg/mL, respectively. On the other hand, the synthesized quinazoline-2,4-dione derivatives 14a and 14b with oxadiazole and thiadiazol moieties at the 1- and 3-poisitions of the quinazoline backbone could effectively inhibit the growth of Staphylococcus aurous and Candida albicans strains in which both compounds exhibited moderate activity against Staphylococcus aurous with inhibition zone values of 12 and 13 mm and MIC values of 70 and 75 mg/mL, respectively. The Candida albicans strain was quite sensitive to compound 14a with an inhibition zone value of 12 mm, which was more effective than the standard drug ampicillin, as depicted in Table 1.
In this context and concerning the structure–activity relationship (SAR), the synthesized compounds 13, 14a, 14b, and 15 indicated that the integration of triazole (compound 13), oxadiazole (compound 14a), thiadiazole (compound 14b), or oxazole (compound 15) across different linkers at position N-1 and N-3 of the quinazoline nucleus was essential for antimicrobial activity. It is worthwhile mentioning that our previous work that included the synthesis and SAR of a novel series of 1,3-disubistituted quinoline derivatives [49] concluded the same results. Therefore, molecular hybridization via incorporating these moieties (triazole, oxadiazole, thiadiazole or oxazole) and others in the 1,3-positions of the quinoline or quinazoline nucleus might be thought to attain more potent antibacterial compounds.

3. Experimental

General Methods: All solvents and reagents were of analytical grade. The reactions were monitored by aluminum oxide thin layer chromatography TLC (silica gel 60F254, Merck, Darmstadt, Germany). Melting points were determined and were uncorrected on a melting point apparatus (Stuart Scientific, Stone, Staffordshire, UK). Mass spectra were measured on a GC MS-QP 1000 EX Mass Spectrometer (Shimadzu, Tokyo, Japan). NMR spectra were carried out with a 300 MHz at Cairo University with 400 MHz at Ulm University, Germany. Chemical shifts (δ) are reported in parts per million (ppm) relative to the respective solvent as the internal standard and the standard abbreviations were used. The required starting material 1 was prepared by adopting the earlier reported procedures [40]. Compounds 2, 3, 4, and 5 were known before and explored in scientific research [56,57].
The spectral data for the target compounds are shown in the Electronic Supplementary Materials.

3.1. Diethyl 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)diacetate (2)

A mixture of 1 (1.0 g, 6.2 mmol) and potassium carbonate anhydrous (K2CO3) (1.7 g, 12.4 mmol) in dimethylformamide (DMF) (10 mL) was stirred for about 15 min at room temperature. Then, ethyl chloroacetate (1.5 g, 12.4 mmol) was added. The reaction mixture was stirred for 24 h at room temperature, poured onto ice water, and the solid product was collected by filtration, washed with water, and dried to give 2 (1.5 g, 73%) as a white powder; m.p. 118–120 °C; 1H-NMR (400 MHz, DMSO-d6) δ 1.21 (t, J = 7.07 Hz, 6H, 2(-CH3)), 4.17 (q, 4H, 2(-CH2-CH3)), 4.72 (s, 2H, -CH2-), 4.99 (s, 2H, -CH2-), 7.37 (t, J = 7.05 Hz, 1H, Ar-H), 7.45 (d, J = 8.21 Hz, 1H, Ar-H), 7.80 (t, J = 6.92 Hz, 1H, Ar-H), 8.11 (d, J = 8.66 Hz, 1H, Ar-H) ppm. M.S (EI, m/z, 70 eV): Calcd. = 334.33 and Found = 335.2 [M+ + 1].

3.2. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)di(acetohydrazide) (3)

A mixture of 2 (1.0 g, 3.0 mmol) and hydrazine hydrate (0.3 g, 6.0 mmol) in a 25 mL one-necked flask was dissolved in (10 mL) absolute ethanol. The mixture was heated under reflux for 9 h, subsequently, the solvent was concentrated under high vacuum. The resulting precipitate was filtered off, washed with ethanol, and dried to give 3 (0.8 g, 88%) as a white powder; m.p. 262–264 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.27 (br.s, 4H, 2(-NH2)), 4.52 (s, 2H, -CH2-), 4.74 (s, 2H, -CH2-), 7.24 (d, J = 8.76 Hz, 1H, Ar-H), 7.33 (t, J = 6.98 Hz, 1H, Ar-H), 7.76 (t, J = 7.01 Hz, 1H, Ar-H), 8.06 (d, J = 8.59 Hz, 1H, Ar-H), 9.21 (s, 1H, -NH-), 9.30 (s, 1H, -NH-) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.62, 45.03, 115.07, 122.99, 127.89, 135.29, 140.40, 150.45, 161.03, 165.88, 166.17, 169.87 ppm.

3.3. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)diacetonitrile (4)

A mixture of 1 (1.0 g, 6.2 mmol) and potassium carbonate anhydrous (K2CO3) (1.7 g, 12.4 mmol) in DMF (10 mL) was stirred for about 15 min at room temperature. Then, chloroacetonitrile (0.94 g, 12.4 mmol) was added. The reaction mixture was stirred for 24 h at room temperature, poured onto ice water, where the solid product was collected by filtration, washed with water, and dried to give 4 (1 g, 68%) as an off white powder; m.p. 208–210 °C; 1H-NMR (500 MHz, DMSO-d6) δ 4.94 (s, 2H, -CH2-), 5.33 (s, 2H, -CH2-), 7.42 (t, J = 6.95 Hz, 1H, Ar-H), 7.63 (d, J = 8.68 Hz, 1H, Ar-H), 7.89 (t, J = 7.05 Hz, 1H, Ar-H), 8.12 (d, J = 8.22 Hz, 1H, Ar-H) ppm. M.S (EI, m/z, 70 eV): Calcd. = 240.22, Found = 240.05, 240.95 [M+], 241.95 [M+ + 1], 242.95 [M+ + 2].

3.4. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)diacetic acid (5)

A mixture of 4 (1.0 g, 4.2 mmol) and diluted hydrochloric acid (1:1) (10 mL) was refluxed for 9 h, then the reaction mixture was cooled. The solid form was filtered off, washed with water, and dried to give 5 (1.0 g, 87%) as a yellow powder; m.p. 226–228 °C; 1H-NMR (300 MHz, DMSO-d6) δ 4.62 (s, 2H, -CH2-), 4.89 (s, 2H, -CH2-), 7.34 (t, J = 8.76 Hz, 1H, Ar-H), 7.41 (d, J = 8.59 Hz, 1H, Ar-H), 7.78 (t, J = 6.97 Hz, 1H, Ar-H), 8.09 (d, J = 8.75 Hz, 1H, Ar-H) ppm.

3.5. Dimethyl 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)diacetate (6)

A mixture of 5 (1.0 g, 3.6 mmol) in methanol (10 mL) and the catalytic amount of conc. sulfuric acid were refluxed for 6 h. The reaction mixture was cooled to form a solid that was filtered off, washed with water, and dried to give 6 (0.8 g, 73%) as a white powder; m.p. 122–124 °C; 1H-NMR (300 MHz, DMSO-d6) δ 3.71 (s, 6H, 2(-CH3-), 4.73 (s, 2H, -CH2-), 5.01 (s, 2H, -CH2), 7.37 (t, J = 7.04 Hz, 1H, Ar-H), 7.46 (d, J = 8.66 Hz, 1H, Ar-H), 7.80 (t, J = 7.12 Hz, 1H, Ar-H), 8.11 (d, J = 8.80 Hz, 1H, Ar-H) ppm.

3.6. 1,3-Bis((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione (7)

To a solution of potassium hydroxide (0.74 g, 13.2 mmol) in ethanol/water (7 mL/7 mL) were hydrazide 3 (2.0 g, 6.6 mmol) and carbon disulfide (1.0 g, 13.2 mmol) added. The reaction mixture was heated under reflux for 8 h, and subsequently, the solvent was concentrated under high vacuum before adding water and acidified with conc. hydrochloric acid. The formed solid was filtered off, washed with water, and the obtained compound was further purified by crystallizing from ethanol and dried to give 7 (1.9 g, 75%) as a white solid; m.p. 180–182 °C; 1H-NMR (500 MHz, DMSO-d6) δ 5.23 (s, 2H, -CH2-), 5.50 (s, 2H, -CH2-), 7.39 (t, J = 6.95 Hz, 1H, Ar-H), 7.64 (d, J = 8.59 Hz, 1H, Ar-H), 7.84 (t, J = 8.76 Hz, 1H, Ar-H), 8.11(d, J = 8.81 Hz, 1H, Ar-H) ppm. M.S (EI, m/z, 70 eV): Calcd. = 390.39, Found = 392.30 [M+ + 2].

3.7. General Procedure for the Synthesis of 8a and 8b

A mixture of 7 (0.3 g, 0.8 mmol) and K2CO3 (0.22 g, 1.6 mmol) in DMF (3 mL) was stirred for about 30 min at room temperature. Then, benzyl chloride or methyl iodide (0.8 mmol) was added. The reaction mixture was stirred for 24 h at room temperature, poured onto ice water, and the solid product was collected by filtration and the obtained compounds were further purified by crystallizing from ethanol.

3.7.1. 1,3-Bis((5-(benzylthio)-1,3,4-oxadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione (8a)

Yield (0.32 g, 74%) as a white solid; m.p. 126–128 °C; 1HNMR (500 MHz, DMSO-d6) δ 4.44 (s, 4H, 2(-CH2-)), 5.36 (s, 2H, (-SCH2-)), 5.63 (s, 2H, (-SCH2-)), 7.22 (t, J = 7.07 Hz, 1H, Ar-H), 7.31–7.36 (m, 10H, Ar-H), 7.60 (d, J = 9.88 Hz, 1H, Ar-H), 7.83 (t, J = 7.06 Hz, 1H, Ar-H), 8.13 (d, J = 8.99 Hz, 1H, Ar-H) ppm.

3.7.2. 1,3-Bis((5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione (8b)

Yield (0.3 g, 94%) as a white solid; m.p. 178–180 °C; 1H-NMR (400 MHz, DMSO-d6) δ 2.67 (s, 6H, 2(-CH3)), 5.37 (s, 2H, -CH2-), 5.63 (s, 2H, -CH2-), 7.39 (t, J = 7.04 Hz, 1H, Ar-H), 7.64 (d, J = 8.87 Hz, 1H, Ar-H), 7.83 (t, J = 7.08 Hz, 1H, Ar-H), 8.13 (d, J = 8.66 Hz, 1H, Ar-H) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 14.42, 36.19, 38.65, 114.75, 115.11, 123.95, 128.39, 136.10, 139.44, 149.91, 160.60, 162.99, 163.33, 164.83, 165.39 ppm.

3.8. General Procedure for the Synthesis of 9a and 9b

To a solution of 3 (0.2 g, 0.7 mmol) in absolute ethanol (2 mL), diethyl ethoxymethylenemalonate or ethyl ethoxymethylene cyanoacetate (1.4 mmol) was added and the reaction mixture was refluxed for 20 h. The reaction mixture was cooled to reach room temperature, poured into ice water, then the solid product was collected by filtration and washed with ethanol to give 9a and 9b, respectively.

3.8.1. Tetraethyl 2,2′-(((2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(acetyl))bis(hydrazine-2,1-diyl))bis(methanylylidene))dimalonate (9a)

Yield (0.3 g, 71%) as a white solid; m.p. 128–130 °C; 1H-NMR (500 MHz, DMSO-d6) δ 1.16–1.21 (m, 12H, 4(-CH3)), 4.00 (q, 2H, -CH2CH3), 4.01–4.23 (m, 4H, 2(-CH2CH3)), 4.2 (q, 2H, -CH2CH3), 4.65 (s, 2H,-CH2-), 4.88 (s, 2H, -CH2-), 7.35 (t, J = 6.92 Hz, 1H, Ar-H), 7.69 (s, 2H, 2(-CH=)), 7.71 (d, J = 8.66 Hz, 1H, Ar-H), 7.8 (t, J = 7.08 Hz, 1H, Ar-H), 8.08 (d, J = 8.59 Hz, 1H, Ar-H), 10.06 (s, 1H, -NH-), 10.09 (s, 1H, -NH-), 11.04 (s, 1 H, -NH-), 11.06 (s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 646.61, Found = 648 [M+ + 2].

3.8.2. Ethyl-2-cyano-3-(2-(2-(1-(2-(2-(-2-cyano-3-ethoxy-3-oxoprop-1-en-1-yl)hydrazinyl)-2-oxoethyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetyl)hydrazinyl)acrylate (9b)

Yield (0.3 g, 83%) as a white solid; m.p. 158–160 °C; 1H-NMR (500 MHz, DMSO-d6) δ 1.26 (t, J = 6.95 Hz, 6H, 2(-CH3)), 4.22 (q, 4H, 2(-CH2CH3)), 5.38 (s, 2H, -CH2-), 5.64 (s, 2 H, -CH2-), 7.39 (t, J = 7.02 Hz, 1H, Ar-H), 7.65 (d, J = 8.66 Hz, 1H, Ar-H), 7.75 (t, J = 7.07 Hz, 1H, Ar-H), 7.89 (s, 1H, -CH=), 7.92 (s, 1H, -CH=), 8.1 (d, J = 8.77 Hz, 1H, Ar-H) ppm. M.S (EI, m/z, 70 eV): Calcd. = 552.50, Found = 553 [M+ + 1], 554 [M+ + 2].

3.9. General Procedure for the Synthesis of Compounds 10a, 10b, 10c, 11a, 11b, and 11c

A mixture of 3 (0.2 g, 0.7 mmol) and aldehyde or ketone (1.4 mmol) in absolute ethanol (10 mL) in the presence of five drops of piperidine, the reaction mixture was refluxed for 16 h. The formed solid was filtered off and dried. The obtained compounds were further purified by crystallizing from ethanol.

3.9.1. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-(-benzylidene)acetohydrazide) (10a)

Yield (0.25 g, 81%) as a white solid; m.p. 320–322 °C; 1H-NMR (500 MHz, DMSO-d6) δ 5.10 (s, 2H, -CH2-), 5.36 (s, 2H, -CH2-), 7.34–8.1 (m, 14H, Ar-H), 8.2 (s, 1H, -N=CH-),), 8.21 (s, 1H, -N=CH-), 11.77 (s, 1H, -NH-), 11.89 (br.s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 482.50, Found = 482.10 [M+].

3.9.2. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-(-2 hydroxybenzylidene)acetohydrazide) (10b)

Yield (0.29 g, 88%) as a white solid; m.p. 312–314 °C; 1H-NMR (500 MHz, DMSO-d6) δ 5.07 (s, 2H, -CH2-), 5.33 (s, 2H, -CH2-), 6.87–8.36 (m, 12H, Ar-H), 8.41 (s, 1H, -N=CH-), 8.44 (s, 1H, -N=CH-), 10.05 (br.s, 1H, -NH-), 10.95 (br.s, 1H, -NH-), 11.68 (br.s, 1H, -OH), 11.95 (br.s, 1H, -OH) ppm. M.S (EI, m/z, 70 eV): Calcd. = 514.50, Found = 514.10 [M+], 515.10 [M+ + 1], 516.10 [M+ + 2].

3.9.3. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-(-4-methoxybenzylidene)acetohydrazide) (10c)

Yield (0.3 g, 86%) as a yellow solid; m.p. 310–312 °C; 1H-NMR (500 MHz, DMSO-d6) δ 3.79 (s, 6H, 2(-CH3)), 5.08 (s, 2H, (-CH2-)), 5.33 (s, 2H, (-CH2-)), 6.98–8.1 (m, 12H, Ar-H), 8.12 (s, 1H, -N=CH-), 8.15 (s, 1H, -N=CH-), 11.60 (br.s, 1H, -NH-), 11.68 (br.s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 542.55, Found = 542.10 [M+], 543.10 [M+ + 1], 544.10 [M+ + 2].

3.9.4. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-cyclopentylideneacetohydrazide) (11a)

Yield (0.22 g, 79%) as a white solid; m.p. 236–238 °C; 1H-NMR (500 MHz, DMSO-d6) δ 1.67–1.71 (m, 4H, 2(-CH2-)), 1.75–1.78 (m, 4H, 2(-CH2-)), 2.28–2.37 (m, 8H, 4(-CH2-)), 4.90 (s, 2H, -CH2-), 5.15 (s, 2H, -CH2-), 7.25 (d, J = 7.91 Hz, 1H, Ar-H), 7.32 (d, J = 8.12 Hz, 1H, Ar-H), 7.75 (d, J = 8.24 Hz, 1H, Ar-H), 8.06 (t, J = 7.05 Hz, 1H, Ar-H), 10.37 (s, 1H, -NH-), 10.49 (s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 438.49, Found = 438.10 [M+], 439.10 [M+ + 1], 440.10 [M+ + 2].

3.9.5. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-cyclohexylideneacetohydrazide) (11b)

Yield (0.25 g, 83%) as a white solid; m.p. 278–280 °C; 1H-NMR (500 MHz, DMSO-d6) δ 1.51–1.69 (m, 12H, 6(-CH2-)), 2.21–2.41 (m, 8H, 4(-CH2-)), 4.93 (d, J = 8.66 Hz, 2H, -CH2-), 5.17 (s, 2H, -CH2-), 7.27 (t, J = 7.05 Hz, 1H, -Ar-H), 7.32 (d, J = 8.72 Hz, 1H, Ar-H), 7.75 (t, J = 6.95 Hz, 1H, Ar-H), 8.06 (d, J = 8.59 Hz, 1H, Ar-H), 10.51 (s, 1H, -NH-), 10.75 (s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 466.54, Found = 466.15 [M+], 467.15 [M+ + 1], 468.20 [M+ + 2].

3.9.6. 2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(N′-cycloheptylideneacetohydrazide) (11c)

Yield (0.29 g, 91%) as a white solid; m.p. 290–292 °C; 1H-NMR (500 MHz, DMSO-d6) δ 1.53–1.63 (m, 16H, 8(-CH2-)), 2.30–2.68 (m, 8H, 4(-CH2-)), 4.93 (s, 2H, -CH2-), 5.17 (s, 2H, -CH2-), 7.26 (d, J = 8.68 Hz, 1H, Ar-H), 7.32 (t, J = 7.12 Hz, 1H, Ar-H), 7.69–7.78 (m, 1H, Ar-H), 8.06 (d, J = 8.55 Hz, 1H, Ar-H), 10.39 (s, 1H, -NH-), 10.50 (s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 494.60, Found = 494.10 [M+], 495.10 [M+ + 1], 496.10 [M+ + 2].

3.10. General Procedure for the Synthesis of Compounds 12a and 12b

In a 25 mL one-necked flask, a mixture of 3 (1.0 g, 3.3 mmol) and phenylisothiocyanate or phenylisocyanate (6.6 mmol) was dissolved in absolute ethanol (10 mL). The reaction mixture was heated to reflux for 10 h and the formed solid was filtered off and washed with ethanol to give 12a or 12b.

3.10.1. 2,2′-(2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(acetyl))bis(N-phenylhydrazine-1-carboxamide) (12a)

Yield (1.5 g, 85%) as a white solid; m.p. 248–250 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.52 (s, 2H, -CH2-), 4.74 (s, 2H, -CH2-), 6.95 (t, J = 6.96 Hz, 1H, Ar-H), 7.15–7.25 (m, 5H, Ar-H), 7.26–7.34 (m, 5H, Ar-H), 7.48 (d, J = 8.84 Hz, 1H, Ar-H), 7.76 (t, J = 7.08 Hz, 1H, Ar-H), 8.08 (d, J = 8.77 Hz, 1H, Ar-H), 8.32 (br.s, 1H, -NH-), 8.58 (br.s, 1H, -NH-), 8.6 (br.s, 1H, -NH-), 9.21 (s, 1H, -NH-), 9.30 (s, 1H, -NH-), 10.09 (br.s, 1H, -NH-) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.61, 45.03, 114.49, 115.06, 118.14, 122.23, 122.98, 127.77, 128.66, 135.28, 140.06, 150.41, 161.03, 165.87, 166.07 ppm. M.S (EI, m/z, 70 eV): Calcd. = 544.18, Found = 545.04 [M+ + 1].

3.10.2. 2,2′-(2,2′-(2,4-Dioxoquinazoline-1,3(2H,4H)-diyl)bis(acetyl))bis(N-phenylhydrazine-1-carbothioamide) (12b)

Yield (1.8 g, 96%) as a white solid; m.p. 270–272 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.77 (s, 2H, -CH2-), 4.98 (s, 2H, -CH2-), 7.19 (d, J = 8.59 Hz, 2H, Ar-H), 7.34–7.38 (m, 5H, Ar-H), 7.45–7.52 (m, 5H, Ar-H), 7.79 (t, J = 6.96 Hz, 1H, Ar-H), 8.10 (d, J = 8.80 Hz, 1H, Ar-H), 9.41 (br.s, 1H, -NH-), 9.70 (br.s, 1H, -NH-), 9.76 (br.s, 1H, -NH-), 9.82 (br.s, 1H, -NH-), 10.41 (s, 1H, -NH-), 11.0 (br.s, 1H, -NH-) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.69, 44.79, 114.49, 114.56, 115.08, 123.29, 125.11, 127.81, 128.15, 135.49, 138.93, 138.97, 140.08, 150.52, 161.04, 166.60 ppm. M.S (EI, m/z, 70 eV): Calcd. = 576.14, Found = 576.99 [M+ + 1].

3.11. 1,3-bis((5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazoline-2,4(1H,3H)-dione (13)

A mixture of 12b (0.4 g, 0.7 mmol) was added gradually with stirring to a solution of sodium hydroxide (2N, 5 mL). The mixture was heated to reflux for 11 h, after that, the reaction mixture was cooled and acidified with 2 N hydrochloric acid. The resulting precipitate was filtered off, washed with water, and the obtained compound was further purified by crystallizing from ethanol and dried to give 13 (0.3 g, 81%) as a white solid; m.p. 140–142 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.23 (s, 2H, -CH2-), 4.29 (s, 2H, -CH2-), 6.51–6.60 (m, 2H, Ar-H), 7.34–7.37 (m, 1H, Ar-H), 7.45–7.46 (m, 3H, Ar-H), 7.50–7.52 (m, 7H, Ar-H), 8.58–8.62 (m, 1H, Ar-H), 13.79 (br.s, 2H, 2(-SH)) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 34.83, 44.23, 111.42, 114.48, 115.31, 117.76, 127.98, 128.43, 129.40, 132.57, 133.47, 147.80, 148.31, 149.75, 167.98, 168.73, 171.78 ppm.

3.12. 1,3-Bis((5-(phenylamino)-1,3,4-oxadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione (14a)

To a solution of 12b (0.4 g, 0.7 mmol) in methanol (4 mL), mercuric oxide (0.3 g, 1.4 mmol) was added. The resulting mixture was heated under reflux conditions for 6 h. The precipitated mercuric sulfide was filtered off and washed several times with hot methanol. On cooling, the filtrate gave a solid product, which was filtered, washed with methanol, and dried to give 14a (0.2 g, 57%) as a white solid; m.p. 160–162 °C; 1H-NMR (500 MHz, DMSO-d6) δ 5.32 (s, 2H, -CH2-), 5.57(s, 2H, -CH2-), 6.95 (t, J = 7.11 Hz, 1H, Ar-H), 7.28–7.31 (m, 4H, Ar-H), 7.40 (t, J = 6.96 Hz, 2H, Ar-H), 7.49–7.51 (m, 4H, Ar-H), 7.7 (d, J = 8.78 Hz, 1H, Ar-H), 7.85 (t, J = 7.13 Hz, 1H, Ar-H), 8.1 (d, J = 8.63 Hz, 1H, Ar-H), 10.47 (s, 1H, -NH-), 10.53 (s, 1H, -NH-) ppm. M.S (EI, m/z, 70 eV): Calcd. = 508.50, Found = 508.25 [M+], 509.20 [M+ + 1], 510.20 [M+ + 2].

3.13. 1,3-Bis((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl)quinazoline-2,4(1H,3H)-dione (14b)

The 12b (0.4 g, 0.7 mmol) was added gradually and carefully with stirring to ice-cooled conc. sulfuric acid (10.5 mL) over 10 min. At 0 °C, the reaction mixture was stirred for 6 h and carefully poured onto ice water. The solid separated out was filtered off, washed with water, and the obtained compound was further purified by crystallizing from ethanol and dried to give 14b (0.25 g, 68%) as off white solid; m.p. < 360 °C; 1H-NMR (400 MHz, DMSO-d6) δ 5.43 (s, 2H, -CH2-), 5.62 (s, 2H, -CH2-), 7.38 (t, J = 7.07 Hz, 1H, Ar-H), 7.51-7.58 (m, 10H, Ar-H), 7.70 (d, J = 8.66 Hz, 1H, Ar-H), 7.84 (t, J = 7.02 Hz, 1H, Ar-H), 8.13 (d, J = 8.59 Hz, 1H, Ar-H), 10.44 (br.s, 2H, 2(-NH-)) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 40.12, 42.38,114.94, 116.45, 123.63, 126.59, 128.21, 135.83, 139.34, 140.66, 141.58, 150.06, 154.28, 160.67, 165.27 ppm. M.S (EI, m/z, 70 eV): Calcd. = 540.12, Found = 541.20 [M+ + 1].

3.14. General Procedure for the Synthesis of Compounds 15 and 16

A mixture of 12a (0.4 g, 0.8 mmol) and chloroacetonitrile or ethyl bromoacetate (1.6 mmol) in (4 mL) absolute ethanol containing anhydrous sodium acetate (0.26 g, 3.2 mmol) was heated under reflux for 12 h and 16 h, respectively. The reaction mixture was cooled, diluted with water, and allowed to stand overnight. The solid precipitate was filtered off, washed with water, and the obtained compounds were further purified by crystallizing from ethanol/acetone (8:2) and dried to give 15 and 16, respectively.

3.14.1. N′-(-4-Amino-3-phenyloxazol-2(3H)-ylidene)-2-(1-(2-(2-(-4-amino-3-phenyloxazol-2(3H)-ylidene)hydrazinyl)-2-oxoethyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (15)

Yield (0.35 g, 78%) as an off white solid; m.p. 232–234 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.25 (br.s, 4H, 2(-NH2)), 4.52 (s, 2H, -CH2-), 4.74 (s, 2H, -CH2-), 6.95 (t, J = 6.93 Hz, 1H, Ar-H), 7.24–7.26 (m, 5H, Ar-H), 7.28–7.31 (m, 5H, Ar-H), 7.49 (d, J = 8.57 Hz, 1H, Ar-H), 7.78 (t, J = 7.06 Hz, 1H, Ar-H), 8.06 (d, J = 8.77 Hz, 1H, Ar-H), 8.79 (s, 2H, 2(-CH-)), 9.21 (s, 1H, -NH-), 9.29 (s, 1H, -NH-) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.61, 45.03, 114.45, 115.07, 118.41, 121.76, 122.98, 127.77, 128.55, 135.28, 139.68, 140.06, 150.41, 155.99, 161.03, 165.87, 166.07 ppm. M.S (EI, m/z, 70 eV): Calcd. = 622.20, Found = 623.11 [M+ + 1].

3.14.2. 2-(2,4-Dioxo-1-(2-oxo-2-(2-(-4-oxo-3-phenyloxazolidin-2-ylidene)hydrazinyl)ethyl)-1,4-dihydroquinazolin-3(2H)-yl)-N′-(-4-oxo-3-phenyloxazolidin-2-ylidene)acetohydrazide (16)

Yield (0.3 g, 67%) as a white solid; m.p. 234–236 °C; 1H-NMR (400 MHz, DMSO-d6) δ 4.22 (s, 2H, -CH2-), 4.28 (s, 2H, -CH2-), 4.52 (s, 2 H, -OCH2-), 4.74 (s, 2H, -OCH2-), 6.94 (t, J = 7.03 Hz, 1H, Ar-H), 7.22–7.26 (m, 5H, Ar-H), 7.31–7.34 (m, 5H, Ar-H), 7.49 (d, J = 8.76 Hz, 1H, Ar-H), 7.78 (t, J = 6.78 Hz, 1H, Ar-H), 8.06 (d, J = 8.57 Hz, 1H, Ar-H), 9.21 (s, 1H, -NH-), 9.29 (s, 1H, -NH-) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.60, 45.02, 114.64, 115.06, 118.40, 121.73, 122.97, 127.76, 128.58, 135.27, 139.70, 140.05, 150.44, 156, 160.96, 161.02, 165.99, 166.15, 169.84 ppm. M.S (EI, m/z, 70 eV): Calcd. = 624.17, Found = 625.06 [M+ + 1].

4. Biological Methods

Antibacterial Assay

The stock cultures of pathogens used in this study were maintained on nutrient agar slants at 4°. The reference antibacterial drugs ampicillin and vancomycin were evaluated for their antibacterial and antifungal activities and compared with the synthesized compounds. Seventy microliters of bacterial and yeast cells (106 CFU/mL) of each pathogen were spread on the nutrient agar plates. The wells (6 mm diameter) were dug in the inoculated agar plates and 100 µL of the tested compound in DMSO (100 mg/mL) was added to the wells. The reference antibiotic disks (10 µg/disk of ampicillin and 30 µg/disk of vancomycin) were potted onto the surface of agar inoculated plates. Before incubation, the plates were allowed to stand for 2 h at 4 °C to allow for diffusion. Subsequently, the plates were incubated for 24 h at 37 °C, except for the yeast strain, which was incubated for 24 h at 28 °C. Next, we applied the measurement of the diameter of the inhibition zone (mm) and three replicates were averaged [58].
MIC calculation: The MIC was defined as the concentration at which the bacteria and yeast do not show visible growth with respect to the positive control. Serial dilutions were prepared of the tested compounds dissolved in DMSO. In each well of the 96 well microtiter plate, a 150 μL of double strength Mueller Hinton broth medium was loaded followed by 150 μL of the 2-fold appropriate concentration, and mixed well to obtain the final concentration. Overnight broth cultures of the tested bacterial and yeast strains prepared as an inoculum of 5% (V/V) (OD = 0.5 McFarland standard) was inoculated into the respective wells. For the positive-growth control, the same inoculum size of each test strain was inoculated in wells that did not contain any of the tested compounds. The DMSO solution was tested as the negative control. The plates were statically incubated at 37 °C for 24 h. A total of 30 μL of resazurin solution (0.18%) was added to each well to act as an electron acceptor and was reduced to a pink, red, or purple resorufin colored product by active microorganisms (i.e., the inhibition of bacterial growth was appearing as a dark blue well and the presence of growth was detected by the presence of a pink, red, or purple color).

5. Conclusions

In conclusion, a series of novel quinazoline-2,4(1H,3H)-dione derivatives were designed and synthesized by installing different moieties into in the 1- and 3-positions of the quinazoline nucleus and their structures were determined based on the spectral data. The synthesized compounds generally showed moderate or no activity against the tested strains Staphylococcus aurous, Listeria monocytogenes, Escherichia coli, Salmonella typhi, and Candida albicans in comparison with the reference drugs ampicillin and vancomycin. Among the tested compounds, 1,3-bis((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazoline-2,4(1H,3H)-dione (13) and N′-(-4-amino-3-phenyloxazol-2(3H)-ylidene)-2-(1-(2-(2-((E)-4-amino-3-phenyloxazol-2(3H) ylidene)hydrazinyl)-2-oxoethyl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide (15) generally exhibited better and broad bioactive spectrum against Gram-positive and Gram-negative strains. For our further studies, derivatives 13 and 15 were selected as promising leads to synthesize more selective derivatives to generate more effective antibacterial agents.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27123853/s1; 1H- and 13C-NMR spectral data of compounds 3–16.

Author Contributions

Conceptualization, N.M.B. and F.A.E.-E.; methodology, N.M.B., S.G.N. and O.M.D.; software, N.M.B. and O.M.D.; validation, N.M.B., F.A.E.-E. and M.B.A.; formal analysis, N.M.B. and F.A.E.-E.; investigation, N.M.B.; resources, N.M.B., F.A.E.-E. and M.B.A.; data curation, N.M.B., S.G.N. and O.M.D.; writing—original draft preparation, N.M.B.; writing—review and editing, N.M.B., F.A.E.-E., M.B.A. and O.M.D.; visualization, N.M.B. and F.A.E.-E.; supervision, N.M.B. and F.A.E.-E.; project administration, N.M.B. and F.A.E.-E.; funding acquisition, F.A.E.-E. and M.B.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Khan, A.; Ibrar, N.; Abbas, A.; Saeed. Recent Advances in The Structural Library of Functionalized Quinazoline and Quinazolinone Scaffolds: Synthetic Approaches and Multifarious Applications. Eur. J. Med. Chem. 2014, 76, 193–244. [Google Scholar] [CrossRef]
  2. Zaranappa; Vagdevi, H.M.; Jayanna, N.D. Synthesis, Characterization and Evaluation of Antibacterial Activity of Some 3- Substitutedphenylquinazoline-2,4-diones. Pharma Chem. 2012, 4, 1754–1758. [Google Scholar]
  3. German, N.; Malik, M.; Rosen, J.D.; Drlica, K.; Kerns, R.J. Use of Gyrase Resistance Mutants to Guide Selection of 8-methoxyquinazoline-2,4-diones. Antimicrob. Agents Chemother. 2008, 52, 3915–3921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Huband, M.D.; Cohen, M.; Zurack, M.; Hanna, D.L.; Skerlos, L.; Sulavik, M.C.; Gibson, G.W.; Gage, J.W.; Ellsworth, E.; Stier, M.; et al. In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities Versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups. Antimicrob. Agents Chemother. 2007, 51, 1191–1201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Malik, M.; Maritks, K.R.; Mustaev, A.; Zhao, X.; Chavda, K.; Kerns, R.J.; Drlica, K. Fluoroquinolone and Quinazolinedione Activities against Wild-Type and Gyrase Mutant Strains of Mycobacterium Smegmatis. Antimicrob. Agents Chemother. 2011, 55, 2335–2343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Oppegard, L.M.; Streck, K.R.; Rosen, J.D.; Schwanz, H.; Drlica, K.; Kerns, R.J.; Hiasa, H. Comparison of In Vitro Activities of Fluoroquinolone-Like 2,4- and 1,3-diones. Antimicrob. Agents Chemother. 2010, 54, 3011–3014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Malik, M.; Hoatam, G.; Chavda, K.; Kerns, R.J.; Drlica, K. Novel Approach for Comparing the Abilities of Quinolones to Restrict The Emergence of Resistant Mutants During Quinolone Exposure. Antimicrob. Agents Chemother. 2010, 54, 149–156. [Google Scholar] [CrossRef] [Green Version]
  8. Pan, X.S.; Gould, K.; Fisher, L.M. Probing the Differential Interactions of Quinazolinedione PD 0305970 and Quinolones with Gyrase and Topoisomerase IV. Antimicrob. Agents Chemother. 2009, 53, 3822–3831. [Google Scholar] [CrossRef] [Green Version]
  9. Pan, X.S.; Fisher, L.M. Probing the Differential Interactions of Quinazolinedione PD 0305970 and Quinolones with Gyrase and Topoisomerase IV. Antimicrob. Agents Chemother. 1998, 42, 2810–2816. [Google Scholar] [CrossRef] [Green Version]
  10. Strahilevitz, J.; Hooper, D.C. Dual Targeting of Topoisomerase IV and Gyrase to Reduce Mutant Selection: Direct Testing of the Paradigm by Using WCK-1734, A 167 New Fluoroquinolone, and Ciprofloxacin. Antimicrob. Agents Chemother. 2005, 49, 1949–1956. [Google Scholar] [CrossRef] [Green Version]
  11. Okumura, R.; Hirata, T.; Onodera, Y.; Hoshino, K.; Otani, T.; Yamamoto, T.J. Dual-Targeting Properties of the 3-aminopyrrolidyl Quinolones, DC-159a and Sitafloxacin, against DNA Gyrase and Topoisomerase IV: Contribution to Reducing In Vitro Emergence of Quinolone-Resistant Streptococcus Pneumoniae. Antimicrob. Chemother. 2008, 62, 98–104. [Google Scholar] [CrossRef] [PubMed]
  12. Hassan, M.A.; Mohamed, A.; Younes, A.M.M.; Taha, M.M.; Bakr, A.; Abdel, H. Synthesis and Reactions of 3-aminotetrachloroquinazolin-2,4-dione. Eur. J. Chem. 2011, 2, 514–518. [Google Scholar] [CrossRef]
  13. Clark, R.L.; Clements, C.J.; Barrett, M.P.; Mackay, S.P.; Rathnam, R.P.; Owusu-Dapaah, G.; Spencer, J.; Huggan, J.K. Identification and Development of the 1,4-benzodiazepin-2-one and Quinazoline2,4-dione Scaffolds as Submicromolar Inhibitors of HAT. Bioorg. Med. Chem. 2012, 20, 6019–6033. [Google Scholar] [CrossRef] [PubMed]
  14. Ji, Q.G.; Yang, D.; Deng, Q.; Ge, Z.Q.; Yuan, L.J. Design, Synthesis, and Evaluation of Novel 1-methyl-3-substituted Quinazoline-2,4-dione Derivatives as Antimicrobial Agents. Med. Chem. Res. 2013, 23, 2169–2177. [Google Scholar] [CrossRef]
  15. Hassan, M.A.; Younes, A.M.M.; Taha, M.M.; Abdel-Monsef, A. Synthesis and Reactions of 3-(2-chloromethyl-carbonylamino)-tetrachloroquinazolin-2,4-dione. Org. Chem. Int. 2012, 2, 1–4. [Google Scholar] [CrossRef] [Green Version]
  16. Malancona, S.; Donghi, M.; Ferrara, M.; Martin Hernando, J.I.; Pompei, M.; Pesci, S.; Ontoria, J.M.; Koch, U.; Rowley, M.; Summa, V. Allosteric Inhibitors of Hepatitis C Virus NS5B Polymerase Thumb Domain Site II: Structure-based Design and Synthesis of New Templates. Bioorg. Med. Chem. 2010, 18, 2836–2848. [Google Scholar] [CrossRef]
  17. Kuran, B.; Krawiecka, M.; Kossakowski, J.; Pindel, Ł.; Młynarczyk, G.; Cieślak, M.; Kaźmierczak-Barańska, J. Synthesis and Biological Activity of a Novel Series of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione Derivatives. Acta Pol. Pharm. 2012, 69, 145–148. [Google Scholar]
  18. Combrink, K.D.; Gulgeze, H.B.; Thuring, J.W.; Yu, K.L.; Civiello, R.L.; Zhang, Y.; Pearce, B.C.; Yin, Z.; Langley, D.R.; Kadow, K.F.; et al. Respiratory Syncytial Virus Fusion Inhibitors. Part 6: An Examination of The Effect of Structural Variation of The Benzimidazol-2-one Heterocycle Moiety. Bioorg. Med. Chem. Lett. 2007, 17, 4784–4790. [Google Scholar] [CrossRef]
  19. Betti, M.; Genesio, E.; Panico, A.; Coccone, S.S.; Wiedenau, P. Process Development and Scale-Up for The Preparation of The 1- methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461. Org. Process Res. Dev. 2013, 17, 1042–1051. [Google Scholar] [CrossRef]
  20. El-Deeb, I.M.; Bayoumi, S.M.; El-Sherbeny, M.; Abdel-Aziz, M.A. Synthesis and Antitumor Evaluation of Novel Cyclic Arylsulfonylureas: ADME-T and Pharmacophore Prediction. Eur. J. Med. Chem. 2010, 45, 2516–2530. [Google Scholar] [CrossRef] [Green Version]
  21. Zhou, X.; Xie, X.; Liu, G. Quinazoline-2,4(1H, 3H)-diones Inhibit The growth of Multiple Human Tumor Cell Lines. Mol. Divers. 2013, 17, 197–219. [Google Scholar] [CrossRef] [PubMed]
  22. McDonald, A.; Bergnes, G.; Morgans, D.J. Compounds, Compositions and Methods. US Patent WO/2004/064741, 5 August 2004. 2, 62–26 (A2). [Google Scholar]
  23. Choo, H.P.; Kim, M.; Lee, S.K.; Kim, S.W.; Chung, I.K. Solidphase Combinatorial Synthesis and Cytotoxicity of 3-aryl-2,4-quinazolindiones. Bioorg. Med. Chem. 2002, 10, 517–523. [Google Scholar] [CrossRef]
  24. Richter, S.; Gioffreda, B. Synthesis, Molecular Modelling and Biological Evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone Derivatives as Antitumor Agents. Arch. Pharm. 2011, 344, 810–820. [Google Scholar] [CrossRef]
  25. Hashimoto, Y. Structural Development of Biological Response Modifiers Based on Retinoids and Thalidomide. Mini Rev. Med. Chem. 2002, 2, 543–551. [Google Scholar] [CrossRef]
  26. Jin, H.Z.; Du, J.L.; Zhang, W.D.; Yan, S.K.; Chen, H.S.; Lee, J.H.; Lee, J.J. A New Quinazolinedione Alkaloid from the Fruits of Evodia Officinalis. Fitoterapia 2008, 79, 317–318. [Google Scholar] [CrossRef] [PubMed]
  27. Kakuta, H.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y. Specific Nonpeptide Inhibitors of Puromycin-Sensitive Aminopeptidase with a 2,4(1H,3H)-quinazolinedione Skeleton. Chem. Pharm. Bull. 2003, 51, 1273–1282. [Google Scholar] [CrossRef] [Green Version]
  28. Lane, K.T.; Beese, L.S. Thematic Review Series: Lipid Posttranslational Modifications. Structural Biology of Protein Farnesyltransferase and Geranylgeranyltransferase Type I. J. Lipid Res. 2006, 47, 681–699. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Appels, N.M.; Beijnen, J.H.; Schellens, J.H. Development of Farnesyl Transferase Inhibitors: A Review. Oncologist 2005, 10, 565–578. [Google Scholar] [CrossRef] [Green Version]
  30. Tizot, A.; Tucker, G.C.; Pierré, A.; Hickman, J.; Goldstein, S. Controlled Exploration of Structural Databases: The Case of Farnesyl Transferase Inhibitors. Med. Chem. 2009, 5, 208–215. [Google Scholar] [CrossRef]
  31. Leysen, J.E.; Awouters, F.; Kennis, L.; Laduron, P.M.; Vandenberk, J.; Janssen, P.A.J. Receptor Binding Profile of R41468, a Novel Antagonist at 5-HT2 Receptor. Life Sci. 1981, 28, 1015–1022. [Google Scholar] [CrossRef]
  32. Carrico, D.; Blaskovich, M.; Bucher, C.J.; Sebti, S.M.; Hamilton, A.D. Design, Synthesis, and Evaluation of Potent and Selective Benzoyleneurea-Based Inhibitors of Protein Geranylgeranyltransferase I. Bioorg. Med. Chem. 2005, 13, 677–688. [Google Scholar] [CrossRef] [PubMed]
  33. Liverton, N.J.; Armstrong, D.J.; Claremon, D.; Remy, D.C.; Baldwin, J.J.; Lynch, R.J.; Zhang, G.; Gould, R.J. Nonpeptide Glycoprotein IIb/IIIa Inhibitors: Substituted Quinazolinediones and Quinazolinones as Potent Fibrinogen Receptor Antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 483–486. [Google Scholar] [CrossRef]
  34. Hedner, T.; Persson, B.; Berglund, G. Ketanserin. A Novel 5- hydroxytryptamine Antagonist: Monotherapy in Essential Hypertension. Br. J. Clin. Pharmacol. 1983, 16, 121–125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Agdevi, H.M.; Rajanna, M.; Gowdarshivannanavar, B.C. Synthesis and Antioxidant Activity of 3-substituted Schiff Bases of Quinazoline-2,4-diones. Int. J. Chem. Tech. Res. 2012, 4, 1527–1533. [Google Scholar]
  36. Prashanth, M.K.; Madaiah, M.; Revanasiddappa, H.D.; Veeresh, B. Synthesis, Anticonvulsant, Antioxidant and Binding Interaction of Novel N-substituted Methylquinazoline-2,4(1H,3H)-dione Derivatives to Bovine Serum Albumin: A Structure-Activity Relationship Study. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2013, 110, 324–332. [Google Scholar] [CrossRef] [Green Version]
  37. Koller, M.; Lingenhoehl, K.; Schmutz, M.; Vranesic, I.T.; Kallen, J.; Auberson, Y.P.; Carcache, D.; Mattes, H.; Ofner, S.; Orain, D.; et al. Quinazolinedione Sulfonamides: A Novel Class of Competitive AMPA Receptor Antagonists with Oral Activity. Bioorg. Med. Chem. Lett. 2011, 21, 3358–3361. [Google Scholar] [CrossRef]
  38. Orain, D.; Ofner, S.; Koller, M.; Carcache, D.A.; Froestl, W.; Allgeier, H.; Rasetti, V.; Nozulak, J.; Mattes, H.; Soldermann, N.; et al. 6-Amino Quinazolinedione Sulfonamides as Orally Active Competitive AMPA Receptor Antagonists. Bioorg. Med. Chem. Lett. 2012, 22, 996–999. [Google Scholar] [CrossRef]
  39. Handrika, P.M.; Rao, A.R.R.; Narsaiah, B.; Raju, M.B. Quinazoline Derıvatives with Potent Anti-Inflammatory and Anti-Allergic Activities. Int. J. Chem. Sci. 2008, 6, 1119–1146. [Google Scholar]
  40. Redondo, M.; Zarruk, J.G.; Ceballos, P.; Pérez, D.I.; Pérez, C.; Perez-Castillo, A.; Moro, M.; Brea, J.; Val, C.; Cadavid, M.I.; et al. Neuroprotective Efficacy of Quinazoline Type Phosphodiesterase-7 Inhibitors in Cellular Cultures and Experimental Stroke Model. Eur. J. Med. Chem. 2012, 47, 175–185. [Google Scholar] [CrossRef]
  41. Lee, B.H.; Choi, M.J.; Jo, M.N.; Seo, H.J.; Nah, S.Y.; Cho, Y.S.; Nam, G.; Pae, A.N.; Rhim, H.; Choo, H. Quinazolindione Derivatives as Potent 5-HT3A Receptor Antagonists. Bioorg. Med. Chem. 2009, 17, 4793–4796. [Google Scholar] [CrossRef]
  42. Rzasa, R.M.; Kaller, M.R.; Liu, G.; Magal, E.; Nguyen, T.T.; Osslund, T.D.; Powers, D.; Santora, V.J.; Viswanadhan, V.N.; Wang, H.L.; et al. Structureactivity Relationships of 3,4-dihydro-1H-quinazolin-2-one Derivatives as Potential CDK5 Inhibitors. Bioorg. Med. Chem. 2007, 15, 6574–6595. [Google Scholar] [CrossRef] [PubMed]
  43. Linder, J.; Huang, M.E.; Steinman, R.; Gonzales; Stafford, R. Fluoroquinolone Prescribing in The United States: 1995 to 2002. Am. J. Med. 2005, 118, 259–268. [Google Scholar] [CrossRef] [PubMed]
  44. Frazee, B.W.; Lynn, J.; Charlebois, E.D.; Lambert, L.; Lowery, D.; Perdreau-Remington, F. High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann. Emerg. Med. 2005, 45, 311–320. [Google Scholar] [CrossRef] [PubMed]
  45. Fridkin, S.K.; Hageman, J.C.; Morrison, M.; Sanza, L.T.; Como-Sabetti, K.; Jernigan, J.A.; Harriman, K.; Harrison, L.H.; Lynfield, R.; Farley, M.M. Active Bacterial Core Surveillance Program of the Emerging Infections Program. Engl. J. Med. 2005, 352, 1436–1444. [Google Scholar] [CrossRef] [PubMed]
  46. Moran, G.J.; Amii, R.N.; Abrahamian, F.M.; Talan, D.A. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerg. Infect. Dis. 2005, 11, 928–930. [Google Scholar] [CrossRef] [Green Version]
  47. Oppegard, L.M.; Schwanz, H.A.; Towle, T.R.; Kerns, R.J.; Hiasa, H. Fluoroquinolones Stimulate The DNA Cleavage Activity of Topoisomerase IV by Promoting The Binding of Mg(2+) to The Second Metal Binding Site. Biochim. Biophys. Acta 1860, 3, 569–575. [Google Scholar]
  48. El-Essawy, F.A.; Boshta, N.M.; Alotaibi, M.A.; Elsayed, M.S.; Tarabees, R.; Saleh, E.A. Construction of 1,3-disubstituted 4-oxo-1,4-dihydroquinolines as A Potential Antibacterial Agents. Res. Chem. Intermed. 2016, 42, 8157–8174. [Google Scholar] [CrossRef]
  49. Li, P.; Zhan, C.; Zhang, S.; Ding, X.; Guo, F.; He, S.; Yao, J. Alkali Metal Cations Control over Nucleophilic Substitutions on Aromatic Fused Pyrimidine-2,4-[1H,3H]-diones: Towards New PNA Monomers. Tetrahedron 2012, 68, 8908–8915. [Google Scholar] [CrossRef]
  50. Ali, S.I.; Mohamed, A.A.; Sameeh, M.Y.; Darwesh, O.M.; Abd El-Razik, T.M. Gamma-Irradiation Affects Volatile Oil Constituents, Fatty Acid Composition and Antimicrobial Activity of Fennel (Foeniculum vulgare) Seeds Extract. Pharm. Biol. Chem. Sci. 2016, 7, 524–532. [Google Scholar]
  51. Darwesh, O.M.; Barakat, K.M.; Mattar, M.Z.; Sabae, S.Z.; Hassan, S.H. Production of Antimicrobial Blue Green Pigment Pyocyanin by Marine Pseudomonas Aeruginosa. Biointerface Appl. Chem. 2019, 9, 4334–4339. [Google Scholar]
  52. Kheiralla, Z.H.; Hewedy, M.A.; Mohammed, H.R.; Darwesh, O.M. Isolation of Pigment Producing Actinomycetes from Rhizosphere Soil and Application of It in Textiles Dyeing. Pharm. Biol. Chem. Sci. 2016, 7, 2128–2136. [Google Scholar]
  53. Abdelhameed, R.M.; El-Sayed, H.A.; El-Shahat, M.; El-Sayed, A.A.; Darwesh, O.M. Novel Triazolothiadiazole and Triazolothiadiazine Derivatives Containing Pyridine Moiety: Design, Synthesis, Bactericidal and Fungicidal Activities. Curr. Bioact. Compd. 2018, 14, 169–179. [Google Scholar] [CrossRef]
  54. Mohamed, A.A.; Ali, S.I.; Darwesh, O.M.; El-Hallouty, S.M.; Sameeh, M.Y. Chemical Compositions, Potential Cytotoxic and Antimicrobial Activities of Nitraria Retusa Methanolic Extract Sub-fractions. Int. J. Toxicol. Pharmacol. Res. 2015, 7, 204–212. [Google Scholar]
  55. Sultan, Y.Y.; Ali, M.A.; Darwesh, O.M.; Embaby, M.A.; Marrez, D.A. Influence of Nitrogen Source in Culture Media on Antimicrobial Activity of Microcoleus lacustris and Oscillatoria rubescens. Res. J. Pharm. Biol. Chem. Sci. 2016, 7, 1444–1452. [Google Scholar]
  56. Hassanein, H.H.; Ebraheem, E.; El Ghandour, S. Synthesis of some quinazolinones of potential anticonvulsant activity. Al-Azhar J. Pharm. Sci. 1998, 22, 35–47. [Google Scholar]
  57. Süsse, M.; Johne, S. Chinazolincarbonsäuren, 10. Mitt. Synthese von 1-Methyl-2,4-dioxo-chinazolin-3-yl-essigsäure, 2,4-Dioxo-chinazolin-1-yl-essigsäuren, 2,4-Dioxo-1,3-chinazolindiessigsäuren und deren Estern. Chem. Mon. 1987, 118, 71–79. [Google Scholar] [CrossRef]
  58. Darwesh, O.M.; Elshahawy, I.E. Silver Nanoparticles Inactivate Sclerotial Formation in Controlling White Rot Disease in Onion and Garlic Caused by The Soil Borne Fungus Stromatinia Cepivora. Eur. J. Plant Pathol. 2021, 160, 917–934. [Google Scholar] [CrossRef]
Molecules 27 03853 g001 550
Figure 1. The design of the target compounds based on the relevant previous compound [48].
Figure 1. The design of the target compounds based on the relevant previous compound [48].
Molecules 27 03853 g001
Molecules 27 03853 sch001 550
Scheme 1. The synthesis of the target compounds 3–8.
Scheme 1. The synthesis of the target compounds 3–8.
Molecules 27 03853 sch001
Molecules 27 03853 sch002 550
Scheme 2. The synthesis of the target compounds 9–11.
Scheme 2. The synthesis of the target compounds 9–11.
Molecules 27 03853 sch002
Molecules 27 03853 sch003 550
Scheme 3. The synthesis of the target compounds 12–16.
Scheme 3. The synthesis of the target compounds 12–16.
Molecules 27 03853 sch003
Table
Table 1. The antimicrobial activity as the inhibition zone value (IZ mm) and minimum inhibitory concentration (MICs mg/mL) for the synthesized compounds against Staphylococcus aurous, Listeria monocytogenes, Escherichia coli, Salmonella typhi, and Candida albicans strains.
Table 1. The antimicrobial activity as the inhibition zone value (IZ mm) and minimum inhibitory concentration (MICs mg/mL) for the synthesized compounds against Staphylococcus aurous, Listeria monocytogenes, Escherichia coli, Salmonella typhi, and Candida albicans strains.
SampleS. aureusL. monocytogenesE. coliS. typhiC. albicans
MICs mg/mL, (IZ mm)MICs mg/mL,
(IZ mm)		MICs mg/mL, (IZ mm)MICs mg/mL,
(IZ mm)		MICs mg/mL, (IZ mm)
Control: DMSO0.00.00.00.00.0
3>100>100>100>10080 (11)
7>100>100>100>100>100
8a>100>100>100>100>100
8b>100>100>100>100>100
9a>100>100>100>100>100
9b>100>100>100>10080 (11)
10a>100>100>100>100>100
10b>100>100>100>100>100
10c>100>100>100>100>100
11a>100>100>100>100>100
11b>100>100>100>100>100
11c>100>100>100>100>100
12b>100>100>100>100>100
1390 (9)>10065 (15)>10080 (11)
14a75 (12)>100>100>10075 (12)
14b70 (13)>100>100>10090 (9)
1580 (11)>10075 (12)>10077 (10)
16>100>100>100>100>100
Ampicillin(25)(20)(16)(19)(9)
Vancomycin(14)(15)(15)(17)(15)
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Boshta, N.M.; El-Essawy, F.A.; Alshammari, M.B.; Noreldein, S.G.; Darwesh, O.M. Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity. Molecules 2022, 27, 3853. https://doi.org/10.3390/molecules27123853

AMA Style

Boshta NM, El-Essawy FA, Alshammari MB, Noreldein SG, Darwesh OM. Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity. Molecules. 2022; 27(12):3853. https://doi.org/10.3390/molecules27123853

Chicago/Turabian Style

Boshta, Nader M., Farag A. El-Essawy, Mohammed B. Alshammari, Safaa G. Noreldein, and Osama M. Darwesh. 2022. "Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity" Molecules 27, no. 12: 3853. https://doi.org/10.3390/molecules27123853

Article Metrics

Back to TopTop