N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2
Abstract
:1. Introduction
2. Materials and Methods
2.1. General Chemistry Methods
2.2. General Procedure for the Synthesis of Amides 5a–f, 7, 9a,b, 14
2.2.1. N-(Benzo[d]Thiazol-2-yl)-4-(Naphthalen-2-yl)Butanamide (5a)
2.2.2. N-(Benzo[d]Thiazol-2-yl)-3-(Naphthalen-2-yl)Propanamide (5b, GK510)
2.2.3. N-(Benzo[d]Oxazol-2-yl)-3-(Naphthalen-2-yl)Propanamide (5c)
2.2.4. N-(Benzo[d]Oxazol-2-yl)-4-(Naphthalen-2-yl)Butanamide (5d)
2.2.5. N-(1H-Benzo[d]Imidazol-2-yl)-3-(Naphthalen-2-yl)Propanamide (5e)
2.2.6. N-(1H-Benzo[d]Imidazol-2-yl)-4-(Naphthalen-2-yl)Butanamide (5f)
2.2.7. N-(Benzo[d]Thiazol-2-yl)-2-(Naphthalen-2-yloxy)Acetamide (7)
2.2.8. (E)-N-(Benzo[d]Thiazol-2-yl)-3-(Naphthalen-2-yl)Acrylamide (9a)
2.2.9. (E)-N-(Benzo[d]Thiazol-2-yl)-3-(4-Methoxyphenyl)Acrylamide (9b)
2.2.10. N-(3-(Naphthalen-2-yl)Propyl)Benzo[d]Thiazole-2-Carboxamide (14)
2.3. N-(Benzo[d]Thiazol-2-yl)-3-(4-Methoxyphenyl)Propanamide (11)
2.4. General Procedure for the Synthesis of Carbamates 16a,b
2.4.1. 4-Methoxybenzyl Benzo[d]Thiazol-2-ylcarbamate (16a)
2.4.2. Naphthalen-2-ylmethyl Benzo[d]Thiazol-2-ylcarbamate (16b)
2.5. General Procedure for the Synthesis of Hemiaminal Ethers 18a–h
2.5.1. N-(1-Methoxy-3-(Naphthalen-2-yl)Propyl)Benzo[d]Thiazol-2-Amine (18a)
2.5.2. N-(1-Methoxy-3-Phenylpropyl)Benzo[d]Thiazol-2-Amine (18b)
2.5.3. N-(1-Methoxy-3-(4-Methoxyphenyl)Propyl)Benzo[d]Thiazol-2-Amine (18c)
2.5.4. N-(1-Methoxy-3-(Naphthalen-1-yl)Propyl)Benzo[d]Thiazol-2-Amine (18d)
2.5.5. N-(1-Methoxy-3-(Naphthalen-2-yl)Propyl)-6-(Trifluoromethoxy)Benzo[d]Thiazol-2-Amine (18g)
2.5.6. N-(1-Methoxy-3-(Naphthalen-1-yl)Propyl)-6-(Trifluoromethoxy)Benzo[d]Thiazol-2-Amine (18h)
2.6. General Procedure for the Reduction of Hemiaminal Ethers to 2-Aminobenzothiazoles 19a–h
2.6.1. N-(3-(Naphthalen-2-yl)Propyl)Benzo[d]Thiazol-2-Amine (19a, GK543)
2.6.2. N-(3-Phenylpropyl)Benzo[d]Thiazol-2-Amine (19b, GK562)
2.6.3. N-(3-(4-Methoxyphenyl)Propyl)Benzo[d]Thiazol-2-Amine (19c)
2.6.4. N-(3-(Naphthalen-1-yl)Propyl)Benzo[d]Thiazol-2-Amine (19d)
2.6.5. N-(3-(Naphthalen-1-yl)Propyl)Thiazol-2-Amine (19e)
2.6.6. N-(3-Phenylpropyl)Thiazol-2-Amine (19f)
2.6.7. N-(3-(Naphthalen-2-yl)Propyl)-6-(Trifluoromethoxy)Benzo[d]Thiazol-2-Amine (19g)
2.6.8. N-(3-(Naphthalen-1-yl)Propyl)-6-(Trifluoromethoxy)Benzo[d]Thiazol-2-Amine (19h)
2.7. General Procedure for the Synthesis of 2-Aminobenzoxazoles 23a–d
2.7.1. N-(3-(Naphthalen-2-yl)Propyl)Benzo[d]Oxazol-2-Amine (23a)
2.7.2. N-(3-(4-Methoxyphenyl)Propyl)Benzo[d]Oxazol-2-Amine (23b)
2.7.3. N-(2-(Naphthalen-2-yloxy)Ethyl)Benzo[d]Oxazol-2-Amine (23c)
2.7.4. N-(2-(Naphthalen-1-yloxy)Ethyl)Benzo[d]Oxazol-2-Amine (23d)
2.8. General Procedure for the Synthesis of 2-Aminobenzothiazoles 25a,b
2.8.1. N-(2-(Naphthalen-2-yloxy)Ethyl)Benzo[d]Thiazol-2-Amine (25a)
2.8.2. N-(2-(Naphthalen-1-yloxy)Ethyl)Benzo[d]Thiazol-2-Amine (25b)
2.9. Biological Assays
2.9.1. Cell Culture
2.9.2. Quantification of PGE2
2.9.3. Statistical Analysis
2.9.4. In Vitro PLA2 Activity Assay
2.9.5. Rat-Paw Carrageenan-Induced-Edema Assay
3. Results and Discussion
3.1. Synthesis of Inhibitors
3.2. Study of the Suppression of PGE2 Generation in Mesangial Cells
3.3. Study of the In Vivo Anti-Inflammatory Activity
3.4. Inhibition of Phospholipases A2 by 19a
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Entry | Compound | Structure | % Inhibition (at 3 μM) | EC50 (μM) |
---|---|---|---|---|
1 | 14 | 64 | ||
2 | 5a | 50 | ||
3 | 5b | 96 | 0.173 | |
4 | 9a | 28 | ||
5 | 16b | 39 | ||
6 | 5d | 73 | ||
7 | 5c | 49 | ||
8 | 5f | 66 | ||
9 | 5e | 29 | ||
10 | 11 | 80 | 0.916 | |
11 | 9b | 25 | ||
12 | 16a | 15 | ||
13 | 7 | 41 |
Entry | Compound | Structure | % Inhibition (at 3 μM) | EC50 (μM) |
---|---|---|---|---|
1 | 18a | 46 | ||
2 | 19a | 98 | 0.118 | |
3 | 23a | 95 | 0.336 | |
4 | 25a | 63 | ||
5 | 23c | 87 | 0.894 | |
6 | 19d | 82 | 0.399 | |
7 | 25b | 57 | ||
8 | 23d | 45 | ||
9 | 18c | 0 | ||
10 | 18b | 0 | ||
11 | 19c | 62 | ||
12 | 19b | 96 | 0.177 | |
13 | 23b | 79 | ||
14 | 19e | 88 | ||
15 | 19f | 20 | ||
16 | 19g | 0 | ||
17 | 19h | 0 |
Compound | Structure | % Reduction of Rat-Paw Edema a |
---|---|---|
5b | 48.4 ** ± 2.16 | |
19a | 47.3 * ± 3.06 | |
19c | 41.4 * ± 2.16 | |
Indomethacin | 37.3 * ± 1.3 |
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Theodoropoulou, M.A.; Psarra, A.; Erhardt, M.; Nikolaou, A.; Gerogiannopoulou, A.-D.D.; Hadjipavlou-Litina, D.; Hayashi, D.; Dennis, E.A.; Huwiler, A.; Kokotos, G. N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2. Biomolecules 2022, 12, 267. https://doi.org/10.3390/biom12020267
Theodoropoulou MA, Psarra A, Erhardt M, Nikolaou A, Gerogiannopoulou A-DD, Hadjipavlou-Litina D, Hayashi D, Dennis EA, Huwiler A, Kokotos G. N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2. Biomolecules. 2022; 12(2):267. https://doi.org/10.3390/biom12020267
Chicago/Turabian StyleTheodoropoulou, Maria A., Anastasia Psarra, Martin Erhardt, Aikaterini Nikolaou, Anna-Dimitra D. Gerogiannopoulou, Dimitra Hadjipavlou-Litina, Daiki Hayashi, Edward A. Dennis, Andrea Huwiler, and George Kokotos. 2022. "N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2" Biomolecules 12, no. 2: 267. https://doi.org/10.3390/biom12020267