A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023
Abstract
:1. Introduction
2. Chemistry of Chromones
3. SAR Studies of Chromone as MAO-B Inhibitors
4. The Role of 3-Styryl Chromones’ Substituents in Inhibiting MAO-B
5. Conclusions
- The methyl group at the R4 position of chromone was shown to be a beneficial substitution.
- The R4 position of the chromone with a bromine group demonstrated a large increase in MAO inhibition and fluorine substitution at R2 of the phenyl ring.
- NO2 and CH3 groups in R3 decreased MAO activity, whereas the electronegative halogens chlorine and fluorine caused a marked increase in activity.
- Electronegative groups, such as Cl and F substitutions at the para position of styryl chromones, demonstrated higher MAO-B inhibition, as seen in the cases of compounds 207 and 206.
- The amino chromone derivatives exhibited more powerful MAO-B inhibition than the ester derivatives 126 and 131. As demonstrated for compounds 131 and 132, phenyl-to-benzyl chain elongation increased MAO-B inhibition, but further chain elongation diminished activity, as seen for compound 135. The inhibition of MAO-B was reduced by compounds containing pyridyl side chains.
- Derivatives with meta substituents on the exocyclic ring showed increased potency.
- In the future perspective of view, researchers could modify and extend the alkyl chains at the R1 and R5 positions of the chromone ring to develop potent MAO-B inhibitors. The introduction of heterocyclic-based amide on the C-3 position of chromone was not explored so far for the development of MAO-B inhibition. This information will be beneficial for discovering and creating a novel category of powerful and specific MAO-B blockers based on chromones.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | IC50 (μM) hMAO-B | Compound | IC50 (μM) hMAO-B |
---|---|---|---|
32 | 15.32 ± 1.02 | 52 | 21.35 ± 1.10 |
33 | 7.52 ± 1.05 | 53 | 17.10 ± 1.17 |
34 | 5.07 ± 1.25 | 54 | 4.20 ± 1.08 |
35 | 45.40 ± 1.30 | 55 | 78.22 ± 1.30 |
36 | 13.90 ± 1.30 | 56 | 151.6 ± 5.14 |
37 | 11.08 ± 1.20 | 57 | 45.42 ± 2.32 |
38 | 621.70 ± 1.8 | 58 | 512.6 ± 2.81 |
39 | 5.95 ± 1.28 | 59 | 41.8 ± 2.2 |
40 | 47.24 ± 1.12 | 60 | 21.80 ± 1.21 |
41 | 9.03 ± 1.07 | 61 | 3.94 ± 1.08 |
42 | 228.6 ± 1.26 | 62 | 113.5 ± 1.10 |
43 | 19.43 ± 1.19 | 63 | 210.8 ± 8.1 |
44 | 18.90 ± 1.01 | 64 | 10.31 ± 1.55 |
45 | * | 65 | 674.2 ± 1.72 |
Deprenyl | 16.73 ± 1.48 | Safinamide | 23.07 ± 2.07 |
Rasagiline | 49.66 ± 2.26 | Clorgyline | * |
Code | R | IC50 (µM) | |
---|---|---|---|
MAO-A | MAO-B | ||
132 | C6H5 | 79.6 | 0.947 |
133 | C6H5CH2 | 77.9 | 0.638 |
134 | C6H5(CH2)2 | 101 | 0.897 |
135 | C6H5(CH2)3 | 312 | 1.43 |
136 | C6H5(CH2)4 | 155 | 142 |
137 | 4Cl-C6H5 | 72.1 | 3.08 |
138 | 4-Cl-C6H5cH2 | 288 | NI |
139 | 3-Cl-C6H5(CH2)2 | NI | NI |
140 | C5H4N | 73.1 | 38.7 |
141 | C5H4N(CH2)2 | 41.6 | 16.66 |
Compound | R1 | R2 | R3 | R4 | TC50 (µM) MAO-A | IC50 (µM) MAO-B |
---|---|---|---|---|---|---|
142 | H | H | H | H | 0.95 | 0.24 |
143 | H | H | H | F | 0.59 | 0.17 |
144 | H | H | H | Cl | 0.29 | 0.079 |
145 | H | H | H | Br | 0.33 | 0.069 |
146 | H | H | H | OMe | 2.3 | 0.049 |
147 | H | H | OMe | OMe | 25 | 2.8 |
148 | OMe | H | H | H | 0.20 | 0.18 |
149 | OMe | H | H | F | 0.12 | 0.064 |
150 | OMe | H | H | Cl | 26 | 0.017 |
151 | OMe | H | H | Br | 0.53 | 0.024 |
152 | OMe | H | H | OMe | 0.21 | 0.19 |
153 | OMe | H | OMe | OMe | 21 | 0.68 |
154 | H | OMe | H | H | 26 | 0.22 |
155 | H | OMe | H | F | 35 | 0.12 |
156 | H | OMe | H | Cl | >100 | 0.27 |
157 | H | OMe | H | Br | >100 | 0.45 |
158 | H | OMe | H | OMe | 72 | 1.4 |
159 | H | OMe | OMe | OMe | >100 | 10 |
hMAO-A | hMAO-B | ||
---|---|---|---|
Compound | R | IC50 (µM) | IC50 (µM) |
160 | H | 63.8 | 17.68 |
161 | 6-OCH3 | 7.5 | 46.27 |
162 | 6-OBn | 11.6 | 0.035 |
163 | 6 cH3 | 48.1 | 19.46 |
164 | 6-Br | 35.5 | 22.82 |
165 | 7-OCH3 | 37.4 | 28.64 |
166 | 7-Br | 31.6 | 19.73 |
167 | H | 29.7 | 33.29 |
168 | H | 68.6 | 35.29 |
169 | 6-OCH3 | 72.4 | 11.23 |
170 | 6-OBn | 67.2 | 0.272 |
171 | 6-CH3 | 30.6 | 52.45 |
172 | 6-Br | 48.2 | 26.13 |
173 | 7-OCH3 | 32.4 | 30.93 |
174 | 7-Br | 30.3 | 29.46 |
175 | H | 29.5 | 20.03 |
Compound | R1 | R2 | IC50 (µM) | |
---|---|---|---|---|
MAO-A | MAO-B | |||
2-(N-Cyclic amino)chromone | ||||
177i | H | H | 38 | 59 |
177ii | OMe | H | 16 | 27 |
177iii | H | OMe | 57 | 36 |
178i | H | H | 31 | 22 |
178ii | OMe | H | 4.1 | 5.6 |
178iii | H | OMe | 8.8 | 7.4 |
183i | H | H | 38 | 22 |
183ii | OMe | H | 2.6 | 2.8 |
183iii | H | OMe | 59 | 12 |
184i | H | H | 66 | 58 |
184ii | OMe | H | 36 | 40 |
184iii | H | OMe | 34 | 31 |
3-(N-Cyclic amino)chromone | ||||
185i | H | H | 23 | 2.0 |
185ii | OMe | H | 23 | 0.99 |
185iii | H | OMe | 18 | 14 |
186i | H | H | >100 | 1.5 |
186ii | OMe | H | >100 | >100 |
186iii | H | OMe | >100 | 0.25 |
187i | H | H | >100 | 0.72 |
187ii | OMe | H | >100 | >100 |
187iii | H | OMe | >100 | 0.015 |
188i | H | H | 57 | 23 |
188ii | OMe | H | 34 | 8.0 |
18Siii | H | OMe | 25 | 7.3 |
Compound | R | IC50 (μM) hMAO-B |
---|---|---|
213 | H | 0.0672 |
214 | 7-methyl | 0.0827 |
215 | 6-methyl | 0.0863 |
216 | 7-methoxy | 0.0670 |
217 | 6-methoxy | 0.0886 |
Pargyline | 0.1113 |
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Ipe, R.S.; Kumar, S.; Benny, F.; Jayan, J.; Manoharan, A.; Sudevan, S.T.; George, G.; Gahtori, P.; Kim, H.; Mathew, B. A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023. Pharmaceuticals 2023, 16, 1310. https://doi.org/10.3390/ph16091310
Ipe RS, Kumar S, Benny F, Jayan J, Manoharan A, Sudevan ST, George G, Gahtori P, Kim H, Mathew B. A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023. Pharmaceuticals. 2023; 16(9):1310. https://doi.org/10.3390/ph16091310
Chicago/Turabian StyleIpe, Reshma Susan, Sunil Kumar, Feba Benny, Jayalakshmi Jayan, Amritha Manoharan, Sachitra Thazhathuveedu Sudevan, Ginson George, Prashant Gahtori, Hoon Kim, and Bijo Mathew. 2023. "A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023" Pharmaceuticals 16, no. 9: 1310. https://doi.org/10.3390/ph16091310
APA StyleIpe, R. S., Kumar, S., Benny, F., Jayan, J., Manoharan, A., Sudevan, S. T., George, G., Gahtori, P., Kim, H., & Mathew, B. (2023). A Concise Review of the Recent Structural Explorations of Chromones as MAO-B Inhibitors: Update from 2017 to 2023. Pharmaceuticals, 16(9), 1310. https://doi.org/10.3390/ph16091310