Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. In Vitro PDE5 Inhibitory Activity Assay
2.3. Pharmacology
2.4. Molecular Modeling
2.4.1. Lead Optimization by Scaffold Hopping
2.4.2. Structure-Based Lead Discovery
3. Materials and Methods
3.1. General
3.2. Syntheses
3.2.1. 6-Hydroxy-2-imino-4-methyl-1-(thiazol-2-yl)-1,2-dihydro-pyridine-3-carbonitrile (2)
3.2.2. 4-Methyl-6-(thiazol-2-ylamino)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (3)
3.2.3. 3-Acetyl-6-imino-1-(thiazol-2-yl)piperidin-2-one (5)
3.2.4. Typical Procedure for Preparing 6a–c
3.2.5. 1 3-Oxo-2-(2-phenylhydrazono)-N-(thiazol-2-yl)butanamide (6a)
3.2.6. 2 2-[2-(4-Methoxyphenyl)hydrazono]-3-oxo-N-(thiazol-2-yl)-butanamide(6b)
3.2.7. 3 2-(2-(4-Chlorophenyl)hydrazono)-3-oxo-N-(thiazol-2-yl)-butanamide (6c)
3.2.8. Typical Procedure for Preparing 7a,b
3.2.9. 1 2-Benzylidene-3-oxo-N-(thiazol-2-yl)butanamide (7a)
3.2.10. 2 2-(4-Methoxybenzylidene)-3-oxo-N-(thiazol-2-yl)butanamide (7b)
3.2.11. Typical Procedure for Preparing 8a,b
3.2.12. 4,4′-(1,4-.Phenylene)bis(6-methyl-N-(thiazol-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide) (9)
3.2.13. Typical Procedure for Preparing 10a,b
3.2.14. Typical Procedure for Preparing 11a–c
3.2.15. N-(5-(4-Chlorophenyl)-5H-pyrazolo[4,3-c]pyridazin-3-yl)-thiazol-2-amine (12)
3.2.16. (Z)-N-(5-(4-Chlorophenyl)-2-phenyl-2H-pyrazolo[4,3-c]-pyridazin-3(5H)-ylidene)thiazol-2-amine (13)
3.3. Pharmacological Assessment
3.3.1. PDE5 Enzyme Activity Assay Procedure
3.3.2. ABP Measurement
3.4. Molecular Modeling
3.4.1. Lead Optimization by Scaffold Hopping
3.4.2. Structure-Based Lead Discovery
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound No. | PDE5 (Inhibition %) | MABP |
---|---|---|
1 | 13 | 103.1 ± 1.85 # |
2 | 100 | 64.7 ± 2.98 ### |
3 | 2 | 79.3 ± 2.57 ## |
5 | 100 | 115.95 ± 2.91 ### |
6a | 20 | 110.1 ± 3.5 ## |
6c | 5 | 108.8 ± 3.9 # |
7a | 38 | 87.2 ± 2.68 * |
7b | 62 | 90.4 ± 2.84 ** |
8b | 23 | 88.1 ± 1.62 ** |
9 | 10 | 90.1 ± 1.62 ** |
10a | 100 | 110.3 ± 2.84 # |
10b | 82 | 105.3 ± 2.84 # |
11a | 8 | 120.1 ± 2.96 ### |
11b | 100 | 78.3 ± 2.57 ## |
12 | 7 | 90.3 ± 1.43 ** |
11c | 13 | 81.3 ± 2.57 ## |
13 | 8 | 81.10 ± 3.78 # |
Control | - | 93.10 ± 1.55 |
Nitroprusside | - | 52.10 ± 1.11 ### |
Sildenafil | 100 | 72.50 ± 2.92 ## |
Compound No. | EON ET Combo | EON Rank |
---|---|---|
Sildenafil | 0.494 | 1 |
9 | 0.370 | 2 |
5 | 0.298 | 3 |
6a | 0.290 | 4 |
12 | 0.247 | 5 |
8a | 0.235 | 6 |
13 | 0.234 | 7 |
6b | 0.203 | 8 |
11b | 0.198 | 9 |
11a | 0.186 | 10 |
8b | 0.181 | 11 |
6c | 0.167 | 12 |
7a | 0.147 | 13 |
7b | 0.136 | 14 |
2 | 0.129 | 15 |
11c | 0.115 | 16 |
10a | 0.107 | 17 |
10b | 0.106 | 18 |
3 | 0.041 | 19 |
Comp. No | FRED Chemgauss4 Score |
---|---|
12 | −12.9335 |
3 | −12.3931 |
11b | −11.3665 |
8b | −11.1262 |
11c | −11.0972 |
11a | −10.9461 |
7a | −10.9088 |
10b | −10.1529 |
8a | −9.7921 |
10a | −9.594 |
7b | −9.0632 |
2 | −8.4895 |
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Hussein, A.H.M.; Khames, A.A.; El-Adasy, A.-B.A.; Atalla, A.A.; Abdel-Rady, M.; Hassan, M.I.A.; Abou-Salim, M.A.; Elshaier, Y.A.M.M.; Barakat, A. Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity. Molecules 2021, 26, 902. https://doi.org/10.3390/molecules26040902
Hussein AHM, Khames AA, El-Adasy A-BA, Atalla AA, Abdel-Rady M, Hassan MIA, Abou-Salim MA, Elshaier YAMM, Barakat A. Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity. Molecules. 2021; 26(4):902. https://doi.org/10.3390/molecules26040902
Chicago/Turabian StyleHussein, Abdel Haleem M., Ahmed A. Khames, Abu-Bakr A. El-Adasy, Ahmed A. Atalla, Mohamed Abdel-Rady, Mohamed I. A. Hassan, Mahrous A. Abou-Salim, Yaseen A. M. M. Elshaier, and Assem Barakat. 2021. "Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity" Molecules 26, no. 4: 902. https://doi.org/10.3390/molecules26040902