Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation
Abstract
:1. Introduction
2. Experimental
2.1. General Procedure for the Synthesis of Drug-Derivatives 1,3,4-Thiadiazole (3)
Acetylcholinesterase Inhibition Assay
2.2. Kinetic Study
2.3. Free Radical Scavenging Assay
2.4. Computational Methodology
Retrieval of the Protein Structure from the PDB
2.5. Compound Structure
2.6. Molecular Docking
3. Results and Discussion
3.1. Acetyl Cholinesterase Inhibition Assay
3.2. Kinetic Mechanism
3.3. Free Radical Scavenging
3.4. Biochemical Properties and Lipinski’s Rule of Five (RO5) Validation
3.5. ADMET Assessment of Synthesized Compounds
3.6. Molecular Docking Analyses
3.7. Structure–Activity Relationship (SAR) Analyses between 3b and Target Protein
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples are available from the authors. |
Compounds | Acetylcholine Esterase (from Human Erythrocytes) IC50 ± SEM (nM) |
---|---|
3a | 126.3 ± 3.6 |
3b | 18.1 ± 0.9 |
3c | 576.3 ± 3.6 |
3d | 2241.7 ± 112.0 |
3e | 3806.4 ± 190.3 |
3f | 17274.8 ± 863.0 |
3g | 1182.19 ± 59.1 |
3h | 1710.7 ± 86.5 |
3i | 29228.0 ± 1461.4 |
Neostigmine methyl sulfate | 2186.5 ± 98.0 |
Concentration (µM) | Vmax (ΔA/Sec) | Km (mM) |
---|---|---|
0.00 | 0.001856 | 0.07692 |
0.009 | 0.000467 | 0.51282 |
0.018 | 0.000343 | 0.55555 |
0.036 | 0.000183 | 0.6060 |
Properties | 3a | 3b | 3c | 3d | 3e | 3f | 3g | 3h | 3i |
---|---|---|---|---|---|---|---|---|---|
Mol. weight (g/mol) | 414 | 402 | 416 | 261 | 285 | 443 | 563 | 548 | 587 |
No. HBA | 6 | 6 | 6 | 3 | 4 | 6 | 6 | 6 | 6 |
No. HBD | 3 | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
Mol. Log P | 1.40 | 1.25 | 1.87 | 3.83 | 3.67 | 3.23 | 3.47 | 3.47 | 4.38 |
No of stereo centers | 0 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 |
Mol. Vol (A3) | 401 | 373 | 394 | 546 | 256 | 408 | 525 | 525 | 537 |
Drug likeness Score | 0.90 | 0.40 | 0.97 | 0.85 | 0.50 | 2.46 | 0.94 | 1.05 | 0.90 |
ADMET Properties | 3a | 3b | 3c | 3d | 3e | 3f | 3g | 3h | 3i | |
---|---|---|---|---|---|---|---|---|---|---|
Absorption | WS (log mol/L) | −3.031 | −3.295 | −3.814 | −3.693 | −2.925 | −4.184 | −3.903 | −3.712 | −3.766 |
IS (%abs) | 96.491 | 83.841 | 95.331 | 93.288 | 83.648 | 93.375 | 95.172 | 93.294 | 89.651 | |
SP (log Kp) | −2.743 | −2.815 | −2.785 | −2.741 | −2.743 | −2.895 | −2.74 | −2.741 | −2.731 | |
Distribution | BBBP (Log BB) | −1.267 | −1.167 | 0.143 | −0.926 | −1.287 | 0.234 | −1.261 | −0.92 | −1.114 |
CNSP (Log PS) | −3.105 | −3.134 | −2.108 | −3.346 | −3.131 | −2.087 | −3.277 | −3.346 | −2.449 | |
VDss (log L/kg) | 0.693 | 0.964 | 0.389 | 0.508 | 0.631 | 0.573 | 0.42 | 0.463 | 1.47 | |
Metabolism | CYP3A4 inhibitor | No | No | No | Yes | No | No | Yes | Yes | Yes |
CYP1A2 inhibitor | No | No | Yes | No | Yes | Yes | No | No | No | |
CYP2C19 inhibitor | No | No | Yes | Yes | No | Yes | Yes | Yes | No | |
CYP2C9 inhibitor | No | No | Yes | Yes | No | No | Yes | Yes | No | |
Excretion | TC (log mL/min/kg) | 0.508 | 0.871 | 0.097 | 0.009 | 0.585 | −0.03 | 0.126 | 0.011 | 0.842 |
Toxicity | AMES toxicity | No | No | Yes | No | No | No | No | No | No |
Max. tolerat. dose | −0.245 | −0.377 | 0.143 | −0.07 | −0.237 | 0.864 | −0.057 | −0.092 | 0.244 | |
ORAT(LD50) | 2.528 | 2.924 | 2.914 | 2.605 | 2.483 | 2.669 | 2.593 | 2.606 | 2.698 | |
HT | Yes | Yes | No | Yes | Yes | No | Yes | Yes | Yes | |
SS | No | No | No | No | No | No | No | No | No |
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Ujan, R.; Saeed, A.; Channar, P.A.; Larik, F.A.; Abbas, Q.; Alajmi, M.F.; El-Seedi, H.R.; Rind, M.A.; Hassan, M.; Raza, H.; et al. Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules 2019, 24, 860. https://doi.org/10.3390/molecules24050860
Ujan R, Saeed A, Channar PA, Larik FA, Abbas Q, Alajmi MF, El-Seedi HR, Rind MA, Hassan M, Raza H, et al. Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules. 2019; 24(5):860. https://doi.org/10.3390/molecules24050860
Chicago/Turabian StyleUjan, Rabail, Aamer Saeed, Pervaiz Ali Channar, Fayaz Ali Larik, Qamar Abbas, Mohamed F. Alajmi, Hesham R. El-Seedi, Mahboob Ali Rind, Mubashir Hassan, Hussain Raza, and et al. 2019. "Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation" Molecules 24, no. 5: 860. https://doi.org/10.3390/molecules24050860
APA StyleUjan, R., Saeed, A., Channar, P. A., Larik, F. A., Abbas, Q., Alajmi, M. F., El-Seedi, H. R., Rind, M. A., Hassan, M., Raza, H., & Seo, S. -Y. (2019). Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules, 24(5), 860. https://doi.org/10.3390/molecules24050860