In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic
Abstract
:1. Introduction
- Synthesize the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
- Evaluation of in vitro antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties.
- Study the in silico bioinformatics analysis (physicochemical properties, the bioavailability radar, drug-likeness, and medicinal chemistry) of Schiff bases bearing pyrazole scaffold (22a, b and 23a, b).
- Study the molecular lipophilicity potential (MLP) and the molecular polar surface area (PSA) of the derivatives 22a, b and 23a, b.
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Biological Activities
2.2.1. Antioxidant Activities
- 5-(2, 5-Dimethoxybenzylideneamino)-3-(4-methoxyphenylamino)-1H-pyrazole derivative 22b exhibited the highest antioxidant activities among all the compounds, which had total antioxidant capacity (TAC) = 42.47 ± 0.09 mg gallic acid/gm, iron-reducing power (IRP) = 24.02 ± 0.05 µg/mL, DPPH radical-scavenging activity (IC50 = 13.20 ± 0.03 µg/mL), and ABTS radical-scavenging activity (%) = 35.11 ± 0.08. After compound 22b in the activity, there was compound 23a, 5-(4-chloro-3-nitrobenzylideneamino)-3-(4-methoxyphenylamino)-N-phenyl-1H-pyrazole derivative, which has total antioxidant capacity (TAC) = 36.85 ± 0.08 mg gallic acid/gm, iron-reducing power (IRP) = 20.84 ± 0.05 µg/mL, DPPH radical-scavenging activity (IC50 = 15.21 ± 0.03 µg/mL), and ABTS radical-scavenging activity (%) = 30.46 ± 0.07.
- The two compounds 22a and 23b have almost the same antioxidant activities (TAC = 34.75 ± 0.08 and 34.56 ± 0.08 mg gallic acid/gm, IRP = 19.65 ± 0.04 and 19.54 ± 0.04 µg/mL, DPPH (IC50) = 16.22 ± 0.04 and 16.13 ± 0.04 µg/mL, and ABTS (%) = 28.73 ± 0.06 and 28.56 ± 0.06, respectively).
2.2.2. Anti-Diabetic and Anti-Alzheimer’s Activities
- In the case of α-amylase inhibition (anti-diabetic activity) and using acarbose as the standard reference (% = 69.11 ± 0.15), we observe that compound 22b showed inhibitor activity of α-amylase (%) = 36.06 ± 0.08, and the next in the activity series is compound 23a with α-amylase inhibition (%) equal to 31.28 ± 0.07. The two compounds 22a and 23b showed almost matching α-amylase inhibition activities equivalent to 29.50 ± 0.06 and 29.34 ± 0.06, respectively.
- In the case of anti-Alzheimer’s activity and using acetylcholinesterase (ACE) inhibition as an indicator for the activity, we observe that compound 22b showed inhibitor activity of acetylcholinesterase (ACE, %) = 20.71 ± 0.05, and the next is 23a with percentage inhibition of acetylcholinesterase equal to 17.97 ± 0.04. The inhibitor activities of the two derivatives 22a and 23b are almost the same and equal to 16.95 ± 0.04 and 16.85 ± 0.04, respectively.
2.2.3. Anti-Arthritic Activity
- -
- In the case of the protein denaturation inhibition, the more potent compound is 23a with an inhibitor percentage equal to 22.56 ± 0.05, and then compound 22b which shows activity equal to 19.57 ± 0.04.
- -
- In the case of the inhibition of proteinase, we also find that compound 23a (inhibition of proteinase% = 20.71 ± 0.05) is the most active among the Schiff bases bearing pyrazole scaffold, then compound 22b (inhibition of proteinase% = 17.97 ± 0.04), then the compound 18a (inhibition of proteinase% = 16.95 ± 0.04), and finally the compound 23b (inhibition of proteinase% = 16.85 ± 0.04), compared to the standard drug, diclofenac sodium (inhibition of proteinase% = 41.88 ± 0.09). Therefore, the order of activities is diclofenac sodium > 23a > 22b > 22a > 23b.
2.3. In Silico Bioinformatics Analysis
2.3.1. Physicochemical Properties
- -
- Molecular weight (MW): sum of the atomic weight values of the atoms in a molecule (optimal: 100~600).
- -
- Volume: van der Waals volume.
- -
- Density: density = MW/volume.
- -
- The number of hydrogen bond acceptors (nHA): sum of all O and N (optimal: 0~12).
- -
- The number of hydrogen bond donors (nHD): sum of all OHs and NHs (optimal: 0~7).
- -
- The number of rotatable bonds (nRot): (optimal: 0~11).
- -
- Number of rings (nRing): smallest set of smallest rings (optimal: 0~6).
- -
- Number of atoms in the biggest ring (MaxRing): number of atoms involved in the biggest ring (optimal: 0~18).
- -
- Number of heteroatoms (nHet): number of non-carbon atoms (hydrogens included, optimal: 1~15).
- -
- The formal charge (fChar) (optimal: −4~4).
- -
- Number of rigid bonds (nRig): number of non-flexible bonds, as opposed to rotatable bonds (optimal: 0~30).
- -
- Flexibility: flexibility = nRot/nRig.
- -
- Stereocenters: number of stereocenters (optimal: ≤2).
- -
- Topological polar surface area (TPSA): sum of tabulated surface contributions of polar fragments (optimal: 0~140).
- -
- logS: the logarithm of aqueous solubility value (optimal: −4~0.5 log mol/L).
- -
- logP: the logarithm of the n-octanol/water distribution coefficient (optimal: 0~3 log mol/L).
- -
- logD7.4: the logarithm of the n-octanol/water distribution coefficients at pH = 7.4 (optimal: 1~3 log mol/L).
2.3.2. Drug-Likeness
- -
- Lipinski rule: this rule held four parameters and its requirements are MW ≤ 500, logP ≤ 5, nHA ≤ 10, and nHD ≤ 5 [43].
- -
- GSK rule: this rule depends on molecular weight (MW) and logP parameters (optimal: MW ≤ 400; logP ≤ 4) [44].
- -
- Pfizer rule: the rule focuses on high logP > 3 and low topological polar surface area (TPSA) < 75 factors [45].
2.3.3. Medicinal Chemistry
2.3.4. Molecular Lipophilicity Potential (MLP)
2.3.5. Molecular Polar Surface Area (PSA)
3. Materials and Methods
3.1. Chemistry
3.2. In Vitro Biological Activities
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Derivatives | Antioxidant Activity | Scavenging Activity | ||
---|---|---|---|---|
TAC (mg Gallic Acid/gm) | IRP (µg/mL) | DPPH (IC50 µg/mL) | ABTS (%) | |
22a | 34.75 ± 0.08 | 19.65 ± 0.04 | 16.22 ± 0.04 | 28.73 ± 0.06 |
22b | 42.47 ± 0.09 * | 24.02 ± 0.05 * | 13.20 ± 0.03 * | 35.11 ± 0.08 * |
23a | 36.85 ± 0.08 | 20.84 ± 0.05 | 15.21 ± 0.03 | 30.46 ± 0.07 |
23b | 34.56 ± 0.08 | 19.54 ± 0.04 | 16.13 ± 0.04 | 28.56 ± 0.06 |
STD | - | - | 4.05 ± 0.01 | 39.09 ± 0.09 |
Ascorbic Acid |
Derivatives | Anti-Diabetic Activity | Anti-Alzheimer’s Activity | Anti-Arthritic Activity | |
---|---|---|---|---|
α-Amylase Inhibition (%) | Acetylcholinesterase (ACE) Inhibition (%) | Proteinase Denaturation (%) | Inhibition of Proteinase (%) | |
22a | 29.50 ± 0.06 | 16.95 ± 0.04 | 18.45 ± 0.04 | 16.95 ± 0.04 |
22b | 36.06 ± 0.08 * | 20.71 ± 0.05 * | 19.57 ± 0.04 | 17.97 ± 0.04 |
23a | 31.28 ± 0.07 | 17.97 ± 0.04 | 22.56 ± 0.05 * | 20.71 ± 0.05 * |
23b | 29.34 ± 0.06 | 16.85 ± 0.04 | 18.35 ± 0.04 | 16.85 ± 0.04 |
STD | 69.11 ± 0.15 | - | 49.33 ± 0.11 | 41.88 ± 0.09 |
Acarbose | Diclofenac Sodium |
Derivatives | 22a | 22b | 23a | 23b |
---|---|---|---|---|
Molecular Weight (MW) | 471.190 | 505.150 | 490.120 | 524.080 |
Volume | 479.897 | 495.108 | 468.876 | 484.087 |
Density | 0.982 | 1.020 | 1.045 | 1.083 |
nHA | 9 | 9 | 10 | 10 |
nHD | 3 | 3 | 3 | 3 |
nRot | 9 | 9 | 8 | 8 |
nRing | 4 | 4 | 4 | 4 |
MaxRing | 6 | 6 | 6 | 6 |
nHet | 9 | 10 | 11 | 12 |
fChar | 0 | 0 | 0 | 0 |
nRig | 26 | 26 | 27 | 27 |
Flexibility | 0.346 | 0.346 | 0.296 | 0.296 |
Stereocenters | 0 | 0 | 0 | 0 |
TPSA | 113.090 | 113.090 | 137.770 | 137.770 |
logS | −6.608 | −7.121 | −6.434 | −6.807 |
logP | 4.421 | 5.190 | 4.711 | 5.455 |
logD7.4 | 3.783 | 3.910 | 3.915 | 3.807 |
Derivatives | 22a | 22b | 23a | 23b |
---|---|---|---|---|
Molecular Weight (MW) | 471.190 | 505.150 | 490.120 | 524.080 |
nHA | 9 | 9 | 10 | 10 |
nHD | 3 | 3 | 3 | 3 |
TPSA | 113.090 | 113.090 | 137.770 | 137.770 |
logP | 4.421 | 5.190 | 4.711 | 5.455 |
Lipinski Rule | Accepted | Rejected | Accepted | Rejected |
GSK Rule | Rejected | Rejected | Rejected | Rejected |
Pfizer Rule | Accepted | Accepted | Accepted | Accepted |
SA Score | 2.886 | 2.928 | 2.986 | 3.027 |
NP Score | −0.903 | −1.033 | −1.395 | −1.448 |
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Alkahtani, H.M.; Almehizia, A.A.; Al-Omar, M.A.; Obaidullah, A.J.; Zen, A.A.; Hassan, A.S.; Aboulthana, W.M. In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic. Molecules 2023, 28, 7125. https://doi.org/10.3390/molecules28207125
Alkahtani HM, Almehizia AA, Al-Omar MA, Obaidullah AJ, Zen AA, Hassan AS, Aboulthana WM. In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic. Molecules. 2023; 28(20):7125. https://doi.org/10.3390/molecules28207125
Chicago/Turabian StyleAlkahtani, Hamad M., Abdulrahman A. Almehizia, Mohamed A. Al-Omar, Ahmad J. Obaidullah, Amer A. Zen, Ashraf S. Hassan, and Wael M. Aboulthana. 2023. "In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic" Molecules 28, no. 20: 7125. https://doi.org/10.3390/molecules28207125
APA StyleAlkahtani, H. M., Almehizia, A. A., Al-Omar, M. A., Obaidullah, A. J., Zen, A. A., Hassan, A. S., & Aboulthana, W. M. (2023). In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic. Molecules, 28(20), 7125. https://doi.org/10.3390/molecules28207125