Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer’s Disease along with Molecular Docking Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Molecular Docking Studies
2.3. Post Simulation Analysis
2.3.1. RMSD (Root Mean Square Deviation) Analysis
2.3.2. RMSF (Root Mean Square Fluctuation) Analysis
2.4. Binding Energy Calculation
2.5. Pharmacokinetics (ADMET) Properties of Finally Selected Compounds
2.6. Structure-Activity Relationship (SAR)
3. Materials and Methods
3.1. Procedure for the Synthesis of Benzimidazole Analogs (1–21)
3.1.1. 5-Methoxy-2-(4-Nitrophenyl)-1H-Benzo[d]-Imidazole (1)
3.1.2. 5-Methoxy-2-(3-Nitrophenyl)-1H-Benzo[d]-Imidazole (2)
3.2. Inhibition Assay Protocol of Acetylcholinesterase and Butyrylcholinesterase
3.3. Molecular Docking
3.4. Molecular Dynamics simulation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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S.No | Weight | logP | H-donor | H-acceptor |
---|---|---|---|---|
Compound 3 | 293.15 | 4.11 | 1 | 2 |
Compound 10 | 309.15 | 3.65 | 2 | 3 |
Compound 11 | 293.15 | 4.14 | 1 | 2 |
Reference | 380.51 | 1.04 | 1 | 3 |
Complex | vdW | EEL | ESURF | EGB | ΔG TOTAL |
---|---|---|---|---|---|
Compound3_AChE | −59.8288 | −10.1721 | −7.8161 | 5.5700 | −56.4166 |
Compound10_AChE | −57.0777 | −2.0551 | −6.1095 | 12.6979 | −52.5444 |
Donepezil_ache | −55.1897 | −4.2318 | −5.7198 | 14.9143 | −50.6618 |
Compound3_BuChE | −41.5357 | −2.6287 | −4.2604 | 10.9467 | −37.4781 |
Compound10_BuChE | −35.5181 | −5.0815 | −3.4819 | 12.2147 | −31.8668 |
Donepezil_BuChE | −33.1783 | −2.1543 | −3.1661 | 11.2146 | −30.1013 |
Category | Property with Unit | Compound’s ID | |||
---|---|---|---|---|---|
3 | 10 | 11 | Donepezil | ||
Absorption | Water solubility (log mol/L) | −4.959 | −3.705 | −8.852 | −6.483 |
Intestinal absorption (%) | 92.4 | 90.359 | 86.645 | 88.561 | |
Skin permeability(log Kp) | −0.823 | −1.672 | −2.178 | −2.728 | |
Distribution | VDss (human) (log L/kg) | 0.487 | 0.196 | 0.803 | 0.943 |
BBB permeability | 0.458 | 0.21 | 0.453 | 0.514 | |
CNS permeability (log PS) | −1.394 | −1.394 | −0.914 | −0.97 | |
Metabolism | CYP2D6 substrate | No | No | No | No |
CYP3A4 substrate | No | No | Yes | Yes | |
CYP1A2 inhibitor | Yes | Yes | Yes | No | |
CYP2C19 inhibitor | No | No | Yes | No | |
CYP2C9 inhibitor | No | No | Yes | No | |
Excretion | Total Clearance(log ml/min/kg) | 0.281 | 0.225 | −0.294 | 0.685 |
Renal OCT2 substrate | No | No | No | No | |
Toxicity | AMES toxicity | No | No | No | No |
Max. tolerated dose (human) (log mg/kg/day) | 0.888 | 0.702 | 0.81 | 0.404 | |
Oral Rat Acute Toxicity (LD50) (mol/kg) | 2.16 | 2.326 | 2.405 | 3.401 | |
Hepatotoxicity | No | No | No | No | |
Skin Sensitisation | Yes | Yes | No | No |
Code No. | R | AChE IC50 (µM ± SEM) | BuChE IC50 (µM ± SEM) |
---|---|---|---|
1 | 2.10 ± 0.10 | 1.60 ± 0.10 | |
2 | 5.10 ± 0.10 | 5.90 ± 0.10 | |
3 | 0.050 ± 0.001 | 0.080 ± 0.001 | |
4 | 3.40 ± 0.10 | 3.60 ± 0.10 | |
5 | 25.30 ± 0.40 | 25.80 ± 0.40 | |
6 | 4.10 ± 0.10 | 5.10 ± 0.20 | |
7 | 5.80 ± 0.10 | 5.90 ± 0.10 | |
8 | 6.80 ± 0.20 | 4.70 ± 0.10 | |
9 | 2.30 ± 0.10 | 2.10 ± 0.10 | |
10 | 0.10 ± 0.001 | 0.40 ± 0.001 | |
11 | 0.20 ± 0.001 | 0.30 ± 0.001 | |
12 | 5.10 ± 0.10 | 5.80 ± 0.10 | |
13 | N. A. | N. A. | |
14 | N. A. | N. A. | |
15 | 0.80 ± 0.001 | 0.90 ± 0.001 | |
16 | 1.30 ± 0.10 | 2.10 ± 0.10 | |
17 | 6.10 ± 0.10 | 3.90 ± 0.10 | |
18 | 11.30 ± 0.30 | 9.80 ± 0.30 | |
19 | 9.20 ± 0.20 | 6.80 ± 0.20 | |
20 | N. A. | 15.20 ± 0.30 | |
21 | 2.10 ± 0.10 | 2.70 ± 0.10 | |
Donepezil | 0.016 ± 0.12 | 0.30 ± 0.010 |
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Adalat, B.; Rahim, F.; Rehman, W.; Ali, Z.; Rasheed, L.; Khan, Y.; Farghaly, T.A.; Shams, S.; Taha, M.; Wadood, A.; et al. Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer’s Disease along with Molecular Docking Study. Pharmaceuticals 2023, 16, 208. https://doi.org/10.3390/ph16020208
Adalat B, Rahim F, Rehman W, Ali Z, Rasheed L, Khan Y, Farghaly TA, Shams S, Taha M, Wadood A, et al. Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer’s Disease along with Molecular Docking Study. Pharmaceuticals. 2023; 16(2):208. https://doi.org/10.3390/ph16020208
Chicago/Turabian StyleAdalat, Bushra, Fazal Rahim, Wajid Rehman, Zarshad Ali, Liaqat Rasheed, Yousaf Khan, Thoraya A. Farghaly, Sulaiman Shams, Muhammad Taha, Abdul Wadood, and et al. 2023. "Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer’s Disease along with Molecular Docking Study" Pharmaceuticals 16, no. 2: 208. https://doi.org/10.3390/ph16020208