2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General Methods
2.1.2. Synthesis of 2-Hydroxy-N-phenylbenzamides 1–4
2.1.3. Synthesis of Phosphorus-Based Derivatives 5
2.1.4. Determination of Physicochemical Parameters
2.2. Determination of Cholinesterases Inhibition
3. Results and Discussion
3.1. Chemistry
3.2. In Vitro Inhibition of Acetylcholinesterase and Butyrylcholinesterase
- Slightly better inhibition is associated with derivatives of 5-substituted salicylic acid (series 2 and 4).
- The substitution of the position 3 at the aniline ring led to improved activity when compared to the position 4 (majority of the series 3 and the pair 2h and 2i are partial exceptions).
- The order of preferred aniline substituents in the case of monosubstitution is as follows: CF3 > F > Br > Cl (series 4); Cl > Br > F > CF3 (series 3); F > Br > CF3 > Cl (series 2).
- The di- and tri-substitution of aniline (both by chlorine c–e and trifluoromethyl group l) resulted predominantly in significantly more potent inhibition of AChE when compared to monosubstituted analogues.
- Regarding polychlorinated anilides, the derivatives of 3,5-dichloroaniline d are superior to 3,4-dichloroanilides c and also to 3,4,5-trichloroanilides e; the additional substitution of the 3,5-dichloro compounds d by 4-chlorine (i.e., providing trichloro structures e) is detrimental but it is still superior to 3,4-dichloroanilides c. Series 3 is a partial exception.
- The most potent inhibition was exhibited by the derivatives of 5-bromosalicylic acid (series 4) followed by 5-chlorosalicylic acid (2).
- The order of preferred atoms on monosubstituted aniline ring is as follows: Br > CF3 > F > Cl (series 2); Cl > F > Br > CF3 (series 3); CF3 > F > Br > Cl (series 4; i.e., the identical results as obtained for AChE). There was no sharp difference in the activity of 3- and 4-substituted anilines.
- The presence of di- and tri-substituted anilines increases the BuChE inhibition predominantly, especially for trifluoromethyl derivatives.
- Regarding polychlorinated anilides within the series 3 and 4, the derivatives of 3,4-dichloroaniline c are superior to 3,5-dichloroanilides d and also to 3,4,5-trichloroanilides e. However, the reverse SAR was found in the series 2.
Mechanism and Type of Inhibition
3.3. Prediction of Physicochemical Parameters, Drug-Likeness and CNS Delivery
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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| |||||
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Code | R1 | R2 | IC50 (EeAChE) [µM] | IC50 (EqBuChE) [µM] | Selectivity AChE/BuChE |
1 | H | H | 49.71 ± 3.73 | 205.73 ± 12.15 | 0.24 |
2a | 5-Cl | 3-Cl | 59.50 ± 3.80 | 228.42 ± 11.29 | 0.26 |
2b | 5-Cl | 4-Cl | 76.53 ± 2.17 | 169.60 ± 3.09 | 0.45 |
2c | 5-Cl | 3,4-diCl | 60.79 ± 6.88 | 186.47 ± 15.69 | 0.33 |
2d | 5-Cl | 3,5-diCl | 46.21 ± 0.63 | 111.59 ± 7.98 | 0.41 |
2e | 5-Cl | 3,4,5-triCl | 51.06 ± 0.49 | 102.72 ± 0.97 | 0.50 |
2f | 5-Cl | 3-Br | 50.03 ± 0.15 | 141.04 ± 1.13 | 0.35 |
2g | 5-Cl | 4-Br | 58.25 ± 4.87 | 118.74 ± 6.65 | 0.49 |
2h | 5-Cl | 3-F | 58.65 ± 3.98 | 154.40 ± 8.38 | 0.38 |
2i | 5-Cl | 4-F | 48.27 ± 8.90 | 132.99 ± 15.81 | 0.36 |
2j | 5-Cl | 3-CF3 | 54.41 ± 0.25 | 120.30 ± 3.02 | 0.45 |
2k | 5-Cl | 4-CF3 | 58.47 ± 2.80 | 154.65 ± 3.58 | 0.38 |
2l | 5-Cl | 3,5-bis-CF3 | 50.18 ± 0.88 | 64.44 ± 1.34 | 0.78 |
3a | 4-Cl | 3-Cl | 58.08 ± 1.20 | 134.29 ± 0.24 | 0.43 |
3b | 4-Cl | 4-Cl | 56.19 ± 3.23 | 152.00 ± 3.13 | 0.37 |
3c | 4-Cl | 3,4-diCl | 46.26 ± 0.56 | 100.27 ± 1.15 | 0.46 |
3d | 4-Cl | 3,5-diCl | 50.15 ± 0.26 | 141.10 ± 2.80 | 0.36 |
3e | 4-Cl | 3,4,5-triCl | 57.78 ± 4.05 | 132.36 ± 4.31 | 0.44 |
3f | 4-Cl | 3-Br | 60.03 ± 0.42 | 167.80 ± 2.06 | 0.36 |
3g | 4-Cl | 4-Br | 58.32 ± 1.57 | 173.99 ± 4.02 | 0.34 |
3h | 4-Cl | 3-F | 60.79 ± 1.74 | 145.66 ± 4.07 | 0.42 |
3i | 4-Cl | 4-F | 62.85 ± 1.53 | 151.76 ± 7.58 | 0.41 |
3j | 4-Cl | 3-CF3 | 68.28 ± 3.78 | 163.18 ± 11.68 | 0.42 |
3k | 4-Cl | 4-CF3 | 60.29 ± 2.39 | 199.53 ± 2.02 | 0.30 |
3l | 4-Cl | 3,5-bis-CF3 | 54.72 ± 2.05 | 150.50 ± 0.87 | 0.36 |
4a | 5-Br | 3-Cl | 62.04 ± 6.48 | 134.00 ± 1.63 | 0.46 |
4b | 5-Br | 4-Cl | 85.75 ± 6.10 | 130.61 ± 3.99 | 0.66 |
4c | 5-Br | 3,4-diCl | 60.83 ± 3.65 | 122.60 ± 7.20 | 0.50 |
4d | 5-Br | 3,5-diCl | 33.13 ± 0.47 | 135.92 ± 0.14 | 0.24 |
4e | 5-Br | 3,4,5-triCl | 42.08 ± 2.41 | 140.07 ± 6.20 | 0.30 |
4f | 5-Br | 3-Br | 69.72 ± 9.97 | 145.78 ± 3.53 | 0.48 |
4g | 5-Br | 4-Br | 70.30 ± 2.85 | 112.16 ± 1.79 | 0.63 |
4h | 5-Br | 3-F | 54.44 ± 0.73 | 119.24 ± 2.53 | 0.46 |
4i | 5-Br | 4-F | 61.22 ± 1.08 | 136.57 ± 1.47 | 0.45 |
4j | 5-Br | 3-CF3 | 42.67 ± 0.18 | 116.91 ± 2.23 | 0.36 |
4k | 5-Br | 4-CF3 | 44.79 ± 3.44 | 134.81 ± 0.86 | 0.33 |
4l | 5-Br | 3,5-bis-CF3 | 48.46 ± 1.07 | 53.46 ± 3.20 | 0.91 |
Rivastigmine | 56.10 ± 1.41 | 38.40 ± 1.97 | 1.46 |
| ||||
---|---|---|---|---|
Code | X | IC50 (EeAChE) [µM] | IC50 (EqBuChE) [µM] | Selectivity AChE/BuChE |
5a [22] | O | 86.3 ± 4.9 | 9.84 ± 0.06 | 8.77 |
5b [25] | S | 9.16 ± 0.17 | 18.3 ± 1.0 | 0.50 |
5c | − | 66.37 ± 1.14 | 2.37 ± 0.01 | 28.00 |
5d | O | 48.13 ± 1.70 | 25.00 ± 0.30 | 1.93 |
5e | S | 63.48 ± 1.41 | 170.10 ± 13.58 | 0.37 |
3k | 60.29 ± 2.39 | 199.53 ± 2.02 | 0.30 | |
Rivastigmine | 56.10 ± 1.41 | 38.40 ± 1.97 | 1.46 |
Code | R1 | R2 | MW | LogP | H-bond Donors | H-bond Acceptors | Number of Violations | tPSA [Å2] |
---|---|---|---|---|---|---|---|---|
1 | H | H | 213.24 | 2.45 | 2 | 3 | 0 | 49.33 |
2a | 5-Cl | 3-Cl | 282.12 | 3.57 | 2 | 3 | 0 | 49.33 |
2b | 5-Cl | 4-Cl | 282.12 | 3.57 | 2 | 3 | 0 | 49.33 |
2c | 5-Cl | 3,4-diCl | 316.56 | 4.12 | 2 | 3 | 0 | 49.33 |
2d | 5-Cl | 3,5-diCl | 316.56 | 4.12 | 2 | 3 | 0 | 49.33 |
2e | 5-Cl | 3,4,5-triCl | 351.00 | 4.68 | 2 | 3 | 0 | 49.33 |
2f | 5-Cl | 3-Br | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
2g | 5-Cl | 4-Br | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
2h | 5-Cl | 3-F | 265.67 | 3.17 | 2 | 3 | 0 | 49.33 |
2i | 5-Cl | 4-F | 265.67 | 3.17 | 2 | 3 | 0 | 49.33 |
2j | 5-Cl | 3-CF3 | 315.68 | 3.93 | 2 | 3 | 0 | 49.33 |
2k | 5-Cl | 4-CF3 | 315.68 | 3.93 | 2 | 3 | 0 | 49.33 |
2l | 5-Cl | 3,5-bis-CF3 | 383.67 | 4.85 | 2 | 3 | 0 | 49.33 |
3a | 4-Cl | 3-Cl | 282.12 | 3.57 | 2 | 3 | 0 | 49.33 |
3b | 4-Cl | 4-Cl | 282.12 | 3.57 | 2 | 3 | 0 | 49.33 |
3c | 4-Cl | 3,4-diCl | 316.56 | 4.12 | 2 | 3 | 0 | 49.33 |
3d | 4-Cl | 3,5-diCl | 316.56 | 4.12 | 2 | 3 | 0 | 49.33 |
3e | 4-Cl | 3,4,5-triCl | 351.00 | 4.68 | 2 | 3 | 0 | 49.33 |
3f | 4-Cl | 3-Br | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
3g | 4-Cl | 4-Br | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
3h | 4-Cl | 3-F | 265.67 | 3.17 | 2 | 3 | 0 | 49.33 |
3i | 4-Cl | 4-F | 265.67 | 3.17 | 2 | 3 | 0 | 49.33 |
3j | 4-Cl | 3-CF3 | 315.68 | 3.93 | 2 | 3 | 0 | 49.33 |
3k | 4-Cl | 4-CF3 | 315.68 | 3.93 | 2 | 3 | 0 | 49.33 |
3l | 4-Cl | 3,5-bis-CF3 | 383.67 | 4.85 | 2 | 3 | 0 | 49.33 |
4a | 5-Br | 3-Cl | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
4b | 5-Br | 4-Cl | 326.57 | 3.84 | 2 | 3 | 0 | 49.33 |
4c | 5-Br | 3,4-diCl | 361.02 | 4.4 | 2 | 3 | 0 | 49.33 |
4d | 5-Br | 3,5-diCl | 361.02 | 4.4 | 2 | 3 | 0 | 49.33 |
4e | 5-Br | 3,4,5-triCl | 395.46 | 4.95 | 2 | 3 | 0 | 49.33 |
4f | 5-Br | 3-Br | 371.03 | 4.11 | 2 | 3 | 0 | 49.33 |
4g | 5-Br | 4-Br | 371.03 | 4.11 | 2 | 3 | 0 | 49.33 |
4h | 5-Br | 3-F | 310.12 | 3.44 | 2 | 3 | 0 | 49.33 |
4i | 5-Br | 4-F | 310.12 | 3.44 | 2 | 3 | 0 | 49.33 |
4j | 5-Br | 3-CF3 | 360.13 | 4.2 | 2 | 3 | 0 | 49.33 |
4k | 5-Br | 4-CF3 | 360.13 | 4.2 | 2 | 3 | 0 | 49.33 |
4l | 5-Br | 3,5-bis-CF3 | 428.13 | 5.12 | 2 | 3 | 1 | 49.33 |
5a | - | - | 451.76 | 5.08 | 1 | 6 | 1 | 73.86 |
5b | - | - | 467.82 | 5.82 | 1 | 5 | 1 | 56.79 |
5c | - | - | 435.76 | 4.70 | 1 | 5 | 0 | 56.79 |
5d | - | - | 437.74 | 5.64 | 0 | 4 | 1 | 46.61 |
5e | - | - | 453.80 | 6.37 | 0 | 3 | 1 | 29.54 |
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Krátký, M.; Štěpánková, Š.; Houngbedji, N.-H.; Vosátka, R.; Vorčáková, K.; Vinšová, J. 2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase. Biomolecules 2019, 9, 698. https://doi.org/10.3390/biom9110698
Krátký M, Štěpánková Š, Houngbedji N-H, Vosátka R, Vorčáková K, Vinšová J. 2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase. Biomolecules. 2019; 9(11):698. https://doi.org/10.3390/biom9110698
Chicago/Turabian StyleKrátký, Martin, Šárka Štěpánková, Neto-Honorius Houngbedji, Rudolf Vosátka, Katarína Vorčáková, and Jarmila Vinšová. 2019. "2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase" Biomolecules 9, no. 11: 698. https://doi.org/10.3390/biom9110698