Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Design
2.2. Isosteric Derivatives (3–8)
2.2.1. Chemistry
2.2.2. Pharmacological Evaluation
2.3. Retroisosteric Derivatives (13 and 14)
2.3.1. Chemistry
2.3.2. Pharmacological Evaluation
3. Materials and Methods
3.1. Synthesis of N-Acylhydrazones (3–8, 13, and 14)
3.1.1. N’-(Selenophen-2-yl-methylene)benzo[d][1,3] dioxole-5-carbohydrazide (3)
3.1.2. 3-Methoxy-N’-(thiophen-2-yl-methylene)benzohydrazide (4)
3.1.3. 3-Methoxy-N’-(selenophen-2-yl-methylene)benzohydrazide (5)
3.1.4. N’-(3-Methoxybenzylidene)thiophene-2-carbo-hydrazide (13)
3.1.5. N’-(3-Methoxybenzylidene)selenophene-2-ca-rbohydrazide (14)
3.2. N-Methylation of N-Acylhydrazones (6, 7 and 8)
3.2.1. N-Methyl-N’-(selenophen-2-yl-methylene) benzo[d][1,3]dioxole-5-carbohydrazide (6)
3.2.2. 3-Methoxy-N-methyl-N’-(thiophen-2-yl-methylene)benzohydrazide (7)
3.2.3. 3-Methoxy-N-methyl-N’-(thiophen-2-yl-methylene)benzohydrazide (8)
3.3. Biological Assays
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Ar | X | 1H NMR Shift (ppm) | ||||
---|---|---|---|---|---|---|---|
H-3 | H-4 | H-5 | OCNH | N=CH | |||
LASSBio-294 (1) | S | 7.43–7.45 | 7.13 | 7.66 | 11.56 | 8.62 | |
LASSBio-2062 (3) | Se | 7.62 | 7.35 | 8.23 | 11.68 | 8.60 | |
LASSBio-2092 (4) | S | 7.49–7.44 | 7.15 | 7.68 | 11.68 | 8.66 | |
LASSBio-2093(5) | Se | 7.62 | 7.36 | 8.24 | 11.85 | 8.68 | |
LASSBio-785 (2) | S | 7.39 | 7.09 | 7.54 | - | 8.22 | |
LASSBio-2063 (6) | Se | 7.56 | 7.31 | 8.10 | - | 8.16 | |
LASSBio-2198 (7) | S | 7.38 | 7.09 | 7.52 | - | 8.24 | |
LASSBio-2199 (8) | Se | 7.56 | 7.30 | 8.09 | - | 8.20 |
Compound | IC50 (µM) MgCl2 (I) | IC50 (µM) NaCl (II) | Na+-Shift (II/I) | P |
---|---|---|---|---|
LASSBio-294 (1) | 38.9 (33.1–45.4) | 24.4 (22.0–27.1) | 0.6 | 0.018 |
LASSBio-2062 (3) | 20.9 (17.5–24.9) | 11.3 (10.0–12.8) | 0.5 | 0.010 |
LASSBio-2092 (4) | 10.8 (9.6–12.2) | 7.3 (6.4–8.4) | 0.7 | 0.016 |
LASSBio-2093 (5) | 10.4 (8.7–12.5) | 6.7 (5.6–8.1) | 0.6 | 0.011 |
LASSBio-785 (2) | 47.9 (39.4–58.3) | 107 (84–135) | 2.3 | 0.043 |
LASSBio-2063 (6) | 52.9 (43.4–64.4) | 86.9 (70.6–107) | 1.7 | 0.004 |
LASSBio-2198 (7) | 22.3 (19.8–25.2) | 54.6 (44.7–66.8) | 2.5 | 0.010 |
LASSBio-2199 (8) | 15.4 (13.4–17.6) | 47.9 (37.0–61.9) | 3.1 | 0.039 |
Compound | IC50 (µM) MgCl2 (I) | IC50 (µM) NaCl (II) | Na+-Shift (II/I) | P |
---|---|---|---|---|
LASSBio-2278 (13) | 27.1 (24.6–30.0) | 55.6 (46.7–66.3) | 2 | 0.010 |
LASSBio-2279 (14) | 16.6 (15.3–18.1) | 37.7 (34.5–41.2) | 2.3 | 0.007 |
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Pedreira, J.G.B.; Silva, R.R.; Noël, F.G.; Barreiro, E.J. Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor. Molecules 2021, 26, 7364. https://doi.org/10.3390/molecules26237364
Pedreira JGB, Silva RR, Noël FG, Barreiro EJ. Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor. Molecules. 2021; 26(23):7364. https://doi.org/10.3390/molecules26237364
Chicago/Turabian StylePedreira, Júlia Galvez Bulhões, Rafaela Ribeiro Silva, François G. Noël, and Eliezer J. Barreiro. 2021. "Effect of S–Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor" Molecules 26, no. 23: 7364. https://doi.org/10.3390/molecules26237364