- Research article
- Open Access
Molecular docking and biological evaluation of some thioxoquinazolin-4(3H)-one derivatives as anticancer, antioxidant and anticonvulsant agents
- Danah S. Al-Shamary1,
- Monirah A. Al-Alshaikh1,
- Nabila Abdelshafy Kheder2, 3,
- Yahia Nasser Mabkhot4Email author and
- Syed Lal Badshah5Email authorView ORCID ID profile
- Received: 18 November 2016
- Accepted: 16 May 2017
- Published: 31 May 2017
Abstract
Background
The quinazoline are an important class of medicinal compounds that possess a number of biological activities like anticancer, anticonvulsant and antioxidant etc.
Results
We evaluated the previously synthesized quinazoline derivatives 1–3 for their anticancer activities against three cancer cell lines (HepG2, MCF-7, and HCT-116). Among the tested compounds, quinazolines 1 and 3 were found to be more potent than the standard drug Vinblastine against HepG2 and MCF-7 cell lines. All the tested compounds had less antioxidant activity and did not exhibit any anticonvulsant activity. Also, molecular docking studies were performed to get an insight into the binding modes of the compounds with human cyclin-dependent kinase 2, butyrylcholinesterase enzyme, human gamma-aminobutyric acid receptor. These compounds showed better docking properties with the CDK2 as compared to the other two enzymes.
Conclusions
The overall study showed that thioxoquinazolines are suitable antitumor agents and they should be explored for other biological activities. Modification in the available lot of quinazoline and synthesis of its novel derivatives is essential to explore the potential of this class of compounds. The increase in the threat and with the emergence of drug resistance, it is important to explore and develop more efficacious drugs.
Keywords
- Thioxoquinazolin-4(3H)-one
- Anticancer activity
- Antioxidant activity
- Anticonvulsant activity
- Molecular docking
Background
a Examples of some the marketed drugs that contain quinazoline ring and their uses. b The tested quinazoline derivatives 1–3
It is reported that during metabolism and respiration in human body, the free radicals and reactive oxygen species (ROS) are produced that causes a number of devastating effects on human health [41, 42]. Over production of ROS is responsible for oxidative damage to DNA that leads to different kinds of cancers [43, 44]. The oxidative damage by free radicals and ROS is blocked by the antioxidants [45]. Antioxidants act by several ways, scavenging free radicals is one of them. To reduce the effects of oxidation on human body, novel and effective antioxidants are required [42]. Here we intended to study the bioactivities of some thioxoquinazolinone derivatives as anticancer, antioxidant and anticonvulsant agents with an aim to find new drugs of synthetic origin. A docking study was performed to fit the proposed quinazolines 1–3 into the active site of human cyclin-dependent kinase 2 enzyme, human butyrylcholinesterase enzyme, and human gamma-aminobutyric acid receptor in order to study the interaction between binding model and their anticancer, antioxidant and anticonvulsant activities.
Methods
Chemistry
Quinazolinone derivatives were prepared according to the following literature procedures [31, 32].
Pharmacology
Anticancer activity
Antioxidant assay
The antioxidant activity of the compounds was determined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay [48]. Fresh 0.004% (w/v) methanol solution of DPPH was prepared and stored at 10 °C in the dark. A methanol solution of the test compounds were also made. A 40 μl aliquot of the methanol solution of the test compound was added to 3 ml of DPPH solution. Absorbance measurements were recorded immediately with a Milton Roy Spectronic 201 UV–visible spectrophotometer. The decrease in absorbance at 515 nm was determined continuously, with data being recorded at 1 min intervals until the absorbance stabilized (16 min). Ascorbic acid was used as a reference standard and dissolved in distilled water to make the stock solution with the same concentration. The absorbance of the DPPH radical without antioxidant was also measured as control and 95% methanol was used as blank. All the determinations were performed in three replicates and averaged.
Anticonvulsant activity
The anticonvulsant activity was measured according to the reported methods [42, 43]. A total number of animals used for the study consisted of 53 Wister Albino Mice, 20 adult Wister Albino Rats, and 20 day-old Chicks. Stimulator, constant current unit, and corneal electrode were used for the evaluation of the anticonvulsant activity. All of the under investigation quinazolines compounds were suspended in 30% aqueous solution of PEG 400 and administered intraperitoneally in a volume of 0.01 mg/kg at body weight to the mice. Control animals received 30% aqueous form of PEG 400. The quinazolines 1−3 were tested for their anticonvulsant activity against MES-induced seizures and the rotorod toxicity test. Rotorod toxicity test was performed on a 1-in. diameter knurled wooden rod; rotating at 6 rpm.
Anticonvulsant effects in the maximal electroshock seizure (MES) test
Maximal electroshock seizures are elicited in mice with a 60-cycle alternating current of 50 mA intensity delivered for 0.2 s via corneal electrodes. A drop of 0.9% saline is introduced in the eye prior to application of the electrodes in order to prevent the death of the animal. Abolition of the hind limb tonic extension component of the seizure indicated protection against the spread of MES-induced seizures.
Statistical analysis
The data were expressed as mean ± S.D. The statistical significance of the difference between mean values was determined by Student’s unpaired t test. Data were considered statistically significant at a significance level of P < 0.05. The stata statistical analysis package was used for calculation of IC50 from the dose response curve.
Molecular docking
Docking studies were performed using the MOE 2014.09 software package. The protein data bank (PDB) files of the crystal structures of human cyclin-dependent kinase 2 having PDB entry number 1PXO [46], butyrylcholinesterase with PDB ID 4XII and human gamma-aminobutyric acid receptor having PDB ID 4COF were downloaded from the protein data bank website. Regularization and optimization for protein and ligand were performed. Determination of the essential amino acids in binding site were carried out and compared with the present literature. The performance of the docking method was evaluated by redocking the crystal ligands into the assigned active site of the respective enzymes to determine the root mean square deviation (RMSD) values. The interactive docking method was carried out for all the conformers of each compound in the selected active site. Each docked compound was assigned a score according to its fit in the ligand binding pocket (LBP) and its binding mode.
Results
Chemistry
Quinazoline derivatives 1–3 (Fig. 1b) were synthesized according to the procedures reported previously by our group [31, 32].
Pharmacology
Anticancer activity
Viability values of quinazoline derivatives 1–3 and Vinblastine sulfate against HepG2 cell line
Viability values of quinazoline derivatives 1–3 and Vinblastine sulfate against MCF 7 cell line
Viability values of quinazoline derivatives 1–3 and Vinblastine sulfate against HCT-116 cell line
The inhibitory activities of the tested compounds against three tumor cell lines compared with reference standards
Sample number | IC50 (µg/ml) | ||
---|---|---|---|
HepG2 | MCF-7 | HCT-116 | |
1 | 3.0 ± 0.4 | 3.1 ± 0.6 | 4.4 ± 0.9 |
2 | 9.5 ± 1.2 | 9.7 ± 1.8 | 10.6 ± 2.1 |
3 | 3.9 ± 0.6 | 3.3 ± 0.6 | 5.7 ± 0.5 |
Vinblastine sulfate | 4.3 ± 0.7 | 4.6 ± 0.8 | 2.4 ± 0.3 |
Doxorubicin | 0.5 ± 0.1 | 0.4 ± 0.1 | 0.4 ± 0.1 |
The results from Figs. 2, 3, 4 and Table 1 revealed that quinazolines 1 and 3 were more potent than standard drug Vinblastine sulfate against HepG2 and MCF-7 cell lines with IC50 values = 3.0, 3.1, and 3.9, 3.3, respectively. However, all the tested compounds were less potent than doxorubicin
Antioxidant activity
The in vitro antioxidant activity of quinazolines 1–3 in DPPH method
Sample number | IC50 |
---|---|
1 | 78 ± 4 |
2 | 312 ± 13 |
3 | 124 ± 9 |
Ascorbic acid | 11 ± 2 |
Anticonvulsion activity
Quantitative anticonvulsant data for mice using maximal electroshock test
Sample number | Maximal electroshock ED50 (mg/kg) |
---|---|
1 | >200 |
2 | >200 |
3 | >200 |
Phenytoin standard | 10.3 ± 0.6 |
Molecular docking
All dock runs were conducted using MOE 2014.09 software.
The binding mode of the quinazoline derivatives 1–3 with the human cyclin-dependent kinase 2
a 2-D representation of docking of quinazoline 1 into human cyclin-dependent kinase 2 enzyme. b 2-D representation of docking of quinazoline 2 into human cyclin-dependent kinase 2 enzyme. c 2-D representation of docking of quinazoline 3 into human cyclin dependent kinase 2 enzyme
The molecular docking study of quinazoline 2 into the binding pocket of human cyclin-dependent kinase 2 enzyme revealed two interactions; arene-cation interaction with bond length of 3.78 Å and binding energy of −2.9 (kcal/mol) and hydrogen bond acceptor interaction with bond length of 3.59 Å and binding energy of −1.5 (kcal/mol) with Lys129. It also showed a hydrogen donor interaction with bond length of 3.28 Å and binding energy of −0.8 (kcal/mol) with Asp145, in addition to arene-hydrogen interaction with bond length of 4.64 Å and binding energy of −0.6 (kcal/Mol) with Glu12 (Fig. 5b).
Alignment study of docked quinazoline 3 into the active binding pocket of the human cyclin-dependent kinase 2 enzyme (Fig. 5c) revealed arene-hydrogen interaction with bond length of 4.23 Å and binding energy of −0.6 (kcal/mol) with Ile10. There was a hydrogen acceptor interaction between Gln131 and one of the sulphur atom of the compound with bond length of 4.05 Å and binding energy of −1.1 kcal/mol.
The binding mode of the quinazoline derivatives 1−3 with the human butyrylcholinesterase
a 2-D representation of docking of quinazoline 1 into butyrylcholinesterase. b 2-D representation of docking of quinazoline 2 into butyrylcholinesterase. c 2-D representation of docking of quinazoline 3 with butyrylcholinesterase
The binding mode of the quinazoline derivatives 1–3 with human gamma-aminobutyric acid receptor
a 2-D representation of docking of quinazoline 1 into the human gamma-aminobutyric acid receptor. b 2-D representation showing interactions between human gamma-aminobutyric acid receptor and the quinazoline 2. c 2-D representation showing interactions between human gamma-aminobutyric acid receptor and the compound 3
Drug-likeness analysis
Drug-like properties of the quinazolines 1–3
Sample number | Molecular weight (g/mol) | TPSA | LogS | LogP | HBA | HBD |
---|---|---|---|---|---|---|
1 | 570.49 | 127.15 | −9.26 | 4.86 | 5 | 3 |
2 | 475.39 | 118.41 | −8.31 | 3.52 | 5 | 2 |
3 | 552.48 | 101.62 | −9.63 | 5.55 | 5 | 1 |
Discussion
We tested the three thioxoquinazolines derivative compounds on three different types of cancer cells and they all showed cytotoxicity to them. These thioxoquinazolines were active against the cancer cell lines in different concentrations. The molecular docking studies of the thioxoquinazoline derivatives with the human cyclin dependent kinase showed several interactions and have favorable docking free energies. These docking studies of quinazoline with cyclin dependent kinase 2 are in agreement with other studies [52–54]. Further these analogues also showed favorable interactions inside the active site of human butyrylcholinesterase and gamma-aminobutyric acid receptor. The quinazolines analogues are also working as an antioxidants and they showed IC50 values between 78 μg/ml and 312 μg/ml as compared to the standard ascorbic acid that has a IC50 of 11 μg/ml. Although they are not as much potent antioxidant as ascorbic acid but their antioxidant properties can be increased by attaching suitable substituents with the quinazoline nucleus [55, 56]. Some quinazolines also posses anticonvulsant activities [57] and that is why we tested our synthesized compound for this purpose but unfortunately we did not observe such properties. Therefore, it is necessary to screen such quinazoline compounds for a number of biological activities.
Conclusions
The results showed that the quinazolinones 1 and 3 were more potent than standard drug Vinblastine sulfate against HepG2 and MCF-7 cell lines, all the tested compounds had low antioxidant activity compared with the reference standard ascorbic acid. In the near future, it will be better to utilized QSAR and virtual screening methods to design and select more suitable quinazoline ligands that posses better anticancer and antioxidant activities. The three tested compounds here showed no anticonvulsant activity. This work on testing thioxoquinazoline for biological activities is an initial effort and these and other synthesized compounds will be tested for antimicrobial, antiviral and antimalarial activities.
Declarations
Authors’ contributions
DA and MA conceived, designed and performed the experiments; NK, YM and SB analyzed the data and edited the paper. All authors read and approved the final manuscript.
Acknowledgements
The authors extend their sincere appreciation to the Deanship of Scientific Research at king Saud University for its funding this Prolific Research group (PRG-1437-29). Also, the authors are thankful to Ahmed Abdelshafy Khedr Chemistry department—faculty of science—Cairo University for the molecular docking.
Competing interests
The authors declare that they have no competing interests.
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Authors’ Affiliations
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