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Polycyclic Aromatic Compounds
ISSN: 1040-6638 (Print) 1563-5333 (Online) Journal homepage: https://www.tandfonline.com/loi/gpol20
Investigation of Some 3H-Quinazolin-4-One
Derivatives in Vitro Antimicrobial Effect and
Cytotoxicity on Human Gingival Fibroblasts
Ural Ufuk Demirel, Aydan Yilmaz, Hatice Türkdağı, Bahadır Öztürk & Uğur
Arslan
To cite this article: Ural Ufuk Demirel, Aydan Yilmaz, Hatice Türkdağı, Bahadır Öztürk & Uğur Arslan (2019): Investigation of Some 3H-Quinazolin-4-One Derivatives in Vitro Antimicrobial Effect and Cytotoxicity on Human Gingival Fibroblasts, Polycyclic Aromatic Compounds, DOI: 10.1080/10406638.2019.1689513
To link to this article: https://doi.org/10.1080/10406638.2019.1689513
Published online: 13 Nov 2019.
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Investigation of Some 3H-Quinazolin-4-One Derivatives
in Vitro Antimicrobial Effect and Cytotoxicity on Human
Gingival Fibroblasts
Ural Ufuk Demirela, Aydan Yilmazb, Hatice T€urkdagıc, Bahadır €Ozt€urkd, and Ugur Arslanc
a
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Altınbas¸ University, _Istanbul, Turkey;bFaculty of Science, Department of Chemistry, Selc¸uk University, Konya, Turkey;cMedical Faculty, Department of Clinical Microbiology, Selc¸uk University, Konya, Turkey;dMedical Faculty, Department of Biochemistry, Selc¸uk University, Konya, Turkey
ABSTRACT
The aim of this study is to synthesize and investigate antimicrobial and cytotoxic activity of 3 H-quinazolinone (1), and its derivatives, which are 3-(4-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (2), 3-(3-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (3), 3-(pyridin-3-ylmethy)-3,4-3-(3-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (4) and derivatives of 2-methyl-3H-quinazolinone, which are 2-methyl-3-phenyl-3,4-dihydroquinazolin-4-one (6), 2-methyl-3(4-hydroxyphenyl)-3,4- dihy-droquinazolin-4-one (7), 2-methyl-3(4-nitrophenyl)-3,4-dihydroquinazolin-4-one (8), compounds. Compounds 2 and 3 were synthesized newly. All compounds were characterized via infrared, 1H-NMR, 13C-NMR, elemental and mass spectral analysis. The compounds were screened for their anti-microbial activity in vitro against E. faecalis ATCC 29212, P. aeruginosa ATCC 27853, S. aureus ATCC 29213, E. Coli ATCC 25922 bacteria and com-pared with commercial antibiotics (Ampicillin and Gentamicin). The deter-mination of the antimicrobial activity was done by using the broth microdilution methods. The antimicrobial test results indicated that the compounds (1, 4, 6, and 8) have MIC values against P. aeruginosa ATCC 27853 lower than ampicillin. But clear cytotoxic effects on proliferation of the gingival fibroblasts applications were observed in 1, 4, 6, and 8 when compared to the control group.
ARTICLE HISTORY Received 29 January 2019 Accepted 3 November 2019 KEYWORDS Antibacterial; Cytotoxicity; Gingival fibroblast; Quinazolinone Introduction
Quinazolinones are the building blocks for approximately 150 naturally occurring alkaloids iso-lated to date from a number of families of the plant kingdom, from animals and from microor-ganisms.1 Quinazolinones have been used as medicine for a long time. Interest in the medicinal chemistry of quinazolinone derivatives was sparked in the early 1950s with the elucidation of a quinazolinone alkaloid, 3-[b-keto-g-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone, from an Asian plant, Dichroa febrifuga, which is an ingredient in a traditional Chinese herbal remedy that is effective against malaria.2 Quinazolinones are important compounds possessing wide range of biological applications.3 Some of these could be listed as antimalarial,4,5 anticonvulsant,6,7 anti-inflammatory and analgesic agents,8 antiviral,9–11 CNS depressant,12 antimicrobial,13,14 and antibacterial.15,16
CONTACTAydan Yilmaz aydan@selcuk.edu.tr; aydanyilmaz@gmail.com Department of Chemistry, Faculty of Science, Selcuk University, Konya-42075, Turkey.
ß 2019 Taylor & Francis Group, LLC
More than 300 kinds of bacteria in the mouth cavity were isolated.17 Some of these bacteria are helpful, while others are harmful. These harmful bacteria, not only can cause damage to teeth and gum tissue, but also can negatively affect in other areas of the body, such as contributing to heart disease. For this reason, many patients, such as cardiac patients, need to use antibiotics, prior to dental treatment. Pathogenic bacteria increasingly often lead to infection and due to their advanced degree of antibiotic resistance are becoming a major problem.18 In the last years, the majority of clinically relevant bacteria species have acquired resistance to antibiotics, so the devel-opment of new antimicrobial drugs to enter into clinical treatment has become inevitable. In this study, some quinazolinone derivatives are examined in terms of their antimicrobial and cyto-toxic activities.
Materials and methods Chemistry
Materials
Chemicals and solvents were obtained from commercial sources (Aldrich, Fluka, Merck and Sigma) and used without further purification. Measurements of 1H-NMR and 13C-NMR spectra were recorded in DMSO on a Varian MR 400 MHz spectrometer (UK) using TMS as an internal standard. A Perkin Elmer 1605 FT-IR spectrophotometer was used to record the infrared spectra of all compounds (4000–400 cm1). Elemental analysis (C, H, and N) was performed using a Leco 932 CHNS analyzer (USA). FAB-MS spectra were taken on a Varian MAT 312 spectrometer (Netherland). Melting points were determined in open capillaries on a B€uchi B-540 apparatus. Analytical TLC was carried out on precoated silica gel plates (SiO2, Merck PF254).
Synthesis
Compounds 1, 5–8 have been prepared according to the published methods,19,20 respectively. Compounds 2–4 were synthesized from reacting anthranilic acid, triethyl orthoformate, and p-amino phenol/m-p-amino phenol/3-p-aminomethyl pridine (Scheme 1).
General procedure for synthesis of 2–4.To a 50 mL round-bottom flask, anthranilic acid 4-ami-nophenol or 3-ami4-ami-nophenol or 3-aminopyridine (7.3 mmol) and triethyl orthoformate (5 mL) was added and refluxed in sand bath at 5 h. After cooling the mixture to room temperature, extracted with EtOAc (3 15 mL), the organic phase washed with 10% NaHCO3 and water, respectively.
The solvent was removed under vacuum and recrystallized from ethanol/water system.
3-(4-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (2). Yield 70%, mp 210–212C IR: 1681 (C¼ O), 1614 (C ¼ N), 3163 (OH) cm1. 1H-NMR (DMSO): d ppm 9.81 (s, 1 H, OH), 8,25 (s, 1 H, N¼ CH), 8,15 (d, J ¼ 8.0 Hz, 1 H, ArH), 7,83 (t, J ¼ 7.4 Hz, 1 H, ArH), 7,69 (d, J ¼ 8.0 Hz, 1 H, ArH), 7,55 (t, J¼ 7.4 Hz, 1 H, ArH), 7,28 (d, J ¼ 8.8 Hz 2 H, Ph-H), 6,87 (d, J ¼ 8.8 Hz, 2 H, Ph-H).
13
C NMR (DMSO, 100 MHz): d ppm 116.2, 122.0, 123.1, 127.5, 128.8, 129.0, 131.4, 133.9, 149.6, 151.7, 154.8, 160.8 (C¼ O). FAB-MS m/z: 260.98 (M þ Na)þ. Anal. Calcd for C14H10O2N2
(238.12): C 70.5, H 4.2, N 19.7%. Found C 70.9, H 4.5, N 19.2%.
3-(3-hydroxyphenyl)-3,4-dihydroquinazolin-4-one (3). Yield 65%, mp 254–260C. IR: 1685 (C¼ O), 1618 (C ¼ N), 3213(OH) cm1. 1H-NMR (DMSO, 400 MHz):d ppm 9.59 (bs, 1 H, OH), 8.84 (bs, 1 H, N¼ CH), 7.97 (d, J ¼ 7.6 Hz, 1 H, ArH), 7.76 (bs, 1 H, ArH), 7.52 (t, J ¼ 7.6 Hz, 1 H, ArH), 7.09–7.22 (m, 2 H, ArH), 6.82 (bs, 1 H, ArH), 6.75 (s, 1 H, ArH), 6.51 (d, J ¼ 7.6 Hz, 1 H,
ArH). 13C NMR (DMSO, 100 MHz): d ppm 107.3, 116.3, 120.9, 121.1, 127.1, 127.4, 128.1, 129.8, 133.9, 134.4, 149.7, 151.6, 158.8, 160.7 (C¼ O). FAB-MS m/z: 260.93 (M þ Na)þ. Anal. Calcd for C14H10O2N2(238.12): C 70.5, H 4.2, N 19.7%. Found C 71.0, H 4.4, N 19.5%.
3-(pyridin-3-ylmethy)-3,4-dihydroquinazolin-4-one (4).Yield 60%, mp 128C. IR: 1665 (C¼ O), 1654 (C¼ N) cm1. 1H-NMR (DMSO, 400 MHz):d ppm 8.64 (s, 1 H, Pyr-H), 8.55–8.45 (m, 1 H, ArH), 8.29-8.18 (m, 1 H, ArH), 8.10 (s, 1 H, N¼ CH-N), 7.76–7.60 (m, 3 H, ArH), 7.51–7.41 (m, 1 H, ArH), 7.27-7.17 (m, 1 H, ArH), 5.16 (s, 2 H, N-CH2). 13C NMR (DMSO, 100 MHz):d ppm
47.3 (CH2), 122.0, 124.1, 126.4, 127.6, 127.7, 132.8, 134.9, 136.1, 148.2, 148.3, 149.3, 149.7, 160.6
(C¼ O). FAB-MS m/z: 259.92 (M þ Na)þ. Anal. Calcd for C14H11ON3(237.17): C 70.9, H 4.6, N
17.7%. Found C 71.4, H 4.5, N 17.5%.
Antimicrobial studies
The minimal inhibitory concentration (MIC) was determined by broth microdilution method according to the Clinical and Laboratory Standarts Instıtute (CLSI) guidelines (2011) in Mueller–Hinton broth (MHB) (Becton Dickinson, Sparks, MD) with an inoculum of approxi-mately 5 105 colony-forming units (CFU)/mL.21 The invitro antibacterial activity of the com-plexes was evaluated against standard strains; Staphylococcus aureus ATCC (American-Type Culture Collection) 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853. All the synthesized complexes were weighed (10.24 mg) and dissolved in DMSO (10 mL) to prepare the stock solutions. The serial dilution from 256 to 0.25lg/mL was made in a 96-wells microplate. To each well 100 lL of a bacterial suspension, obtained from a 24 h culture, containing 5 105 CFU/mL was added. The plate was incubated at 35C for 24 h. The data were reported as MICs, the lowest concentration of antibiotic and complexes inhibiting visible growth after 24 h of incubation at 35C. For quality control of the method ampicillin (IE Ulugay, Turkey) and gentamicin (IE Ulugay, Turkey) was tested as anti-microbial agent. These experiments were carried out in duplicate.
Antimicrobial activity tests
In antimicrobial activity studies were used microdilution methods.21In this study, the compounds 1–4 and 6–8 were examined antimicrobial activity against some selected Gram-negative and Gram-positive bacteria and compared with commercial antibiotics such as ampicillin and genta-micin. Results are given inTable 1.
Cytotoxicity studies Cell culture
During the study human gingival fibroblasts (HGF) provided by Dr Sema Hakkı (Selcuk University Faculty of Dentistry, Konya, Turkey) was used. First, the optimal seeding concentra-tion for proliferaconcentra-tion experiments of the HGFs (10,000 cells/well) was determined. For experi-ments, cells were allowed to adhere almost 1 day in DMEM with 10% fetal bovine serum (FBS), after which media were changed to DMEM with %5 FBS containing1, 4, 6, and 8. Cells used in these experiments were between passage 10 and 15. xCELLigence cell index (CI) impedance measurements were performed according to the instructions of the supplier. Cell proliferation experiments were repeated twice.
Cytotoxicity tests
Proliferation experiments. A real-time cell analyzer (xCELLigence, Roche Diagnostics GmbH, Penzbeerg, Germany) was used to evaluate the effects of different chemical substances on the pro-liferation of gingival fibroblasts.22,23 After seeding, 200lL of the cell suspensions in DMEM con-taining 10% fetal bovine serum (FBS) into the wells (10,000 cells/well) of the E-plate 16, gingival fibroblasts cells were monitored every 15 min for a period of 88 h. Cells were allowed to adhere to the E-plate for approximately one day after seeding, when the cells were in the log growth phase, the cells were exposed to 100lL of medium containing the following substances: 1, 4, 6, and 8. Compounds 2, 3, and 7 were not included in the cytotoxicity tests because they did not show a better activity than commercial antibiotics against used bacteria.
Results and discussion
The quinazolin-4-ones were incorporated with some aromatic/aliphatic amines such as 4-hydrox-yaniline, 2-hydrox4-hydrox-yaniline, 3-(aminomethyl)-pyridine from the N3 position by using various methods of synthesis and 2,3-disubstituted 3 H-quinazolin-4-ones in the preparation of the anil-ine, 4-aminophenol and 4-nitrophenol at the N3 position and methyl at the C2 position
Table 1. Antimicrobial activity of compounds 1-4, 6-8 (MIC values against bacteriamg/mL). Bacteria
Gram (þ) Gram (-)
Compounds
E. faecalis
ATCC 29212 ATCC 29213S. aureus P. aeruginosaATCC 27853 ATCC 25922E. coli
1 64 128 64 64 2 256 256 256 256 3 128 128 128 128 4 128 128 64 64 6 128 128 64 128 7 64 128 128 128 8 64 128 64 64 Ampicillin 1 0.125 128 2 Gentamicin 4 0.25 0.25 1 4 U. U. DEMIREL ET AL.
functional group substituted compounds are given inScheme 1. To obtain a simple quinazolinone skeleton 1, anthranilic acid was treated with formamide under microwaves.19 Compounds 2–4 were synthesized from a mixture of anthranilic acid, triethyl orthoformate and amine (p-amino phenol, m-amino phenol, and 3-aminomethyl pyridine, respectively). In the infrared spectra, the examined anthranilic acid carbonyl band was at 1679 cm1. As observed in the formation of com-pounds2–4, the carbonyl bands shifted to 1681, 1685, and 1665 cm1, respectively. In the FT-IR spectrum of compounds, 2–4 had new bands at 1614, 1618, and 1654 cm1, respectively, for C¼ N groups, and the phenol hydroxy bands of the compounds 2 and 3 were observed at 3163 and 3213 cm1, respectively. The characterization of the obtained compounds was supported by mass,1H NMR,13C NMR, and elemental analysis.
2,3-disubstituted-3,4-dihydroquinazolin-4-one derivatives were synthesized from anthranilic acid and different amines. First, the anthranilic acid was treated with acetic anhydride to prepare N-acetyl anthranilic acid5, followed by reactions with different aromatic amines to give quinazo-linones compounds6–8.20
In addition, quinazolinone-4-one 1 and methyl groups at the C2 position and/or different homoaromatic/heteroaromatic groups at the N3 position substituted quinazolinones have been compared to commercial antibiotics for their antimicrobial and cytotoxic effects.
The antimicrobial and cytotoxic activities of certain quinazolinone derivatives, some of which were newly synthesized, were examined and compared with commercial antibiotics and a control group. According to the biological evaluations, studied quinazolinone compounds have low antimicrobial activity against E. faecalis and S. aureus Gram-positive bacteria and E. coli Gram-negative bacteria compared with ampicillin and gentamicin as commercial antibiotics. On the other hand, the MIC value (128mg/mL) of compounds 3 and 7 against P. auriginosa is the same as with ampicillin, while the MIC value (64mg/mL) of compounds 1, 4, 6, and 8 is lower than ampicillin. In addition, all compounds have low antimicrobial activity against P. auriginosa as compared with gentamicin.
MIC values of used compounds against bacteria are between 64 and 256mg/mL. According to the MIC values, compounds1, 7, and 8 showed the lowest MIC value (64 mg/mL) against E. fae-calis strain, but this value is higher than the reference antibiotics (ampicillin and gentamicin). The MIC value of compound 2 against S. aureus is 256 mg/mL, while MIC values for the other compounds are 128mg/mL. These results indicated that compounds 1, 3–8 are more effective than compound2. While compounds 3 and 7 have the same effect as ampicillin against P. aerugi-nosa strain, 1, 4, 6, and 8 showed the lowest MIC value (64 mg/mL) against P. aeruginosa strain
Figure 1. Effects of different chemical substance applications on the proliferation of gingival fibroblasts. Cells were examined for 88 h using a real-time cell analyzer.
and this value is higher than the gentamicin but lower than ampicillin. Compounds1, 4, and 8 showed the lowest MIC value (64mg/mL) against E. coli strain and this value is higher than the reference antibiotics (ampicillin and gentamicin).
Clear cytotoxic effects on proliferation of the gingival fibroblasts were observed in1, 4, 6, and 8 chemical substance applications immediately after treatment when compared to the control group (Figure 1).
Conclusions
Some monosubstituted quinazolin-4-ones at the N3 position (2–4) and disubstituted quinazolin-4-ones at the C2 and at the N3 positions (6–8) were synthesized. Antimicrobial and cytotoxicity studies were performed with the synthesized compounds.
According to the MIC values, compound3 showed twofold activity than compound 2 against all studied bacteria. At the N3 as the phenyl group, meta and ortho substitutions were equally active but para was generally not tolerated against S. aureus.24 In our study, meta-substituted compound3 at the N3 position was more effective than para-substituted compound 2 against E. faecalis, P. aeruginosa, and E. coli as well as against S. aureus. Compound 4, which has hetero-aromatic group, was more effective than compounds 2 and 3 against Gram (-) bacteria P. auriginosa and E. coli. This result indicates that the potential activity of heteroaromatic rings. When the MIC values of N-4-hydroxyphenyl substituted compounds 2 and 7 were compared, compound7 was found to be more effective for all used bacteria. Compound 7 differs from com-pound2 in that the C2 position has methyl group. This difference points out the importance of methyl substation as a small alkyl group. Compounds 6 and 8 showed the same activity against P. aeruginosa and S. aureus but when they compared against E. faecalis and E. coli nitro group provides superiority. When the antimicrobial activity of compounds 7 and 8 was compared against P. aeruginosa and E. coli bacteria, the nitro group at para position appears to enhance the effect than hydroxyl group at para position, while they have the same activity against gram-posi-tive bacteria E. faecalis and S. aureus. This result also showed that the nitro group, a hydrogen bond acceptor, was more effective against at studied gram-negative bacteria. Compounds1 which is unsubstituted quinazolin-4-one and compound 8 which is disubstituted quinazolin-4-ones at the C2 and at the N3 position showed the same activity against used bacteria. When compound1 and8 compared their activities appear to be the same, but the pharmacokinetic and pharmacody-namic properties of the compound8 can be improved by changing the substituents.
All of the compounds were effective against E. faecalis, S. aureus, and E. coli bacteria, but showed a lower effect than the used antibiotics ampicillin and gentamicin. Likewise all com-pounds were effective against P. aeruginosa, especially comcom-pounds 1, 4, 6, and 8 were more effective than ampicillin. These compounds were cytotoxic according to the cytotoxicity studies. These results encourage us to continue the search for more active and noncytotoxic compounds with special focus on modification the quinazolinone unit, especially at C2 and N3.
Disclosure statement
The authors declare no conflict of interest, financial or otherwise.
Acknowledgements
We thank the Research Foundation of Selcuk University, Konya-Turkey (BAP 2011/11201014) for financial support of this work produced from a part of U.U. Demirel’s MS Thesis.
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