Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Vasodilation Properties
2.2.2. Toxicological Bioassay
3. Experimental Section
3.1. General Information
3.1.1. Synthesis of 2-((3-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)malononitrile (2)
3.1.2. Synthesis of 2-Alkoxy-4-(3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)-6-phenylpyridine-3-carbonitriles (4a–x)
General Procedure
3.2. Vasodilation Activity Screening
2D-QSAR Study
3.3. Toxicological Bioassay
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of which all the compounds are available from the authors. |
3b; R = 4-ClC6H4 | 4b; R = Ph |
3c; R = 4-BrC6H4 | 4c; R = 4-ClC6H4 |
3d; R = 4-FC6H4 | 4d; R = 4-ClC6H4 |
3e; R = 4-H3CC6H4 | 4e; R = 4-BrC6H4 |
3f; R = 4-H3COC6H4 | 4f; R = 4-BrC6H4 |
3g; R = 1,2,3,4-Tetrahydronaphthalen-6-yl | 4g; R = 4-FC6H4 |
3h; R = 2-Pyrrolyl | 4h; R = 4-FC6H4 |
3i; R = 2-Furanyl | 4i; R = 4-H3CC6H4 |
3j; R = 2-Thienyl | 4j; R = 4-H3CC6H4 |
3k; R = 2-Pyridinyl | 4k; R = 4-H3COC6H4 |
3l; R = 1-Methyl-1H-benzo[d]imidazol-2-yl | 4l; R = 4-H3COC6H4 |
4m; R = 1,2,3,4-Tetrahydronaphthalen-6-yl, R′ = Me | |
4n; R = 1,2,3,4-Tetrahydronaphthalen-6-yl, R′ = Et | |
4o; R = 2-Pyrrolyl, R′ = Me | |
4p; R = 2- Pyrrolyl, R′ = Et | |
4q; R = 2-Furanyl, R′ = Me | |
4r; R = 2-Furanyl, R′ = Et | |
4s; R = 2-Thienyl, R′ = Me | |
4t; R = 2-Thienyl, R′ = Et | |
4u; R = 2-Pyridinyl, R′ = Me | |
4v; R = 2-Pyridinyl, R′ = Et | |
4w;R = 1-Methyl-1H-benzo[d]imidazol-2-yl, R′ = Me | |
Entry | Compound | R | R′ | Potency (IC50), mM |
---|---|---|---|---|
1 | 4a | Ph | Me | 0.281 |
2 | 4b | Ph | Et | 0.343 |
3 | 4c | 4-ClC6H4 | Me | 0.295 |
4 | 4d | 4-ClC6H4 | Et | 0.397 |
5 | 4e | 4-BrC6H4 | Me | 0.253 |
6 | 4f | 4-BrC6H4 | Et | 0.267 |
7 | 4g | 4-FC6H4 | Me | 0.275 |
8 | 4h | 4-FC6H4 | Et | 0.330 |
9 | 4i | 4-H3CC6H4 | Me | 0.330 |
10 | 4j | 4-H3CC6H4 | Et | 0.452 |
11 | 4k | 4-H3COC6H4 | Me | 0.322 |
12 | 41 | 4-H3COC6H4 | Et | 0.291 |
13 | 4m | 1,2,3,4-Tetrahydronaphthalen-6-yl | Me | 0.286 |
14 | 4n | 1,2,3,4-Tetrahydronaphthalen-6-yl | Et | 0.337 |
15 | 4o | 2-Pyrrolyl | Me | 0.356 |
16 | 4p | 2-Pyrrolyl | Et | 0.400 |
17 | 4q | 2-Furanyl | Me | 0.321 |
18 | 4r | 2-Furanyl | Et | 0.254 |
19 | 4s | 2-Thienyl | Me | 0.268 |
20 | 4t | 2-Thienyl | Et | 0.298 |
21 | 4u | 2-Pyridinyl | Me | 0.333 |
22 | 4v | 2-Pyridinyl | Et | 0.370 |
23 | 4w | 1-Methyl-1H-benzo[d]imidazol-2-yl | Me | 0.223 |
24 | 4x | 1-Methyl-1H-benzo[d]imidazol-2-yl | Et | 0.299 |
25 | Amiodarone.HCl | - | - | 0.300 |
Entry | ID | Coefficient | s | t | Descriptor |
---|---|---|---|---|---|
N = 24, n= 4, R2 = 0.816, R2cvOO = 0.731, R2cvMO = 0.772, F = 21.103, s2 = 6.191 × 10−8 | |||||
1 | 0 | 1.464 | 0.244 | 6.009 | Intercept |
2 | D1 | 0.0004 | 4.751 × 10−5 | 7.789 | Max. e–e repulsion for bond C–O |
3 | D2 | −7.1825 × 10−6 | 1.975 × 10−6 | −3.637 | WNSA-1 Weighted PNSA (PNSA1*TMSA/1000) (MOPAC PC) |
4 | D3 | −0.255 | 0.045 | −5.670 | FHACA Fractional HACA (HACA1/TMSA) (MOPAC PC) |
5 | D4 | −0.0043 | 0.001 | −6.241 | Max. e–n attraction for bond C–N |
1/IC50 (μM) = 1.464 + (0.0004 × D1) − [(7.1825 × 10−6) × D2] − (0.255 × D3) − (0.0043 × D3) |
Entry | Compd. | R | R′ | Observed IC50, μM | Estimated IC50, μM | Error |
---|---|---|---|---|---|---|
1 | 4a | Ph | Me | 281 | 276 | 5 |
2 | 4b | Ph | Et | 343 | 363 | −20 |
3 | 4c | 4-ClC6H4 | Me | 295 | 272 | 23 |
4 | 4d | 4-ClC6H4 | Et | 397 | 392 | 5 |
5 | 4e | 4-BrC6H4 | Me | 253 | 253 | 0 |
6 | 4f | 4-BrC6H4 | Et | 267 | 307 | −40 |
7 | 4g | 4-FC6H4 | Me | 275 | 303 | −28 |
8 | 4h | 4-FC6H4 | Et | 330 | 354 | −24 |
9 | 4i | 4-H3CC6H4 | Me | 330 | 299 | 31 |
10 | 4j | 4-H3CC6H4 | Et | 452 | 369 | 83 |
11 | 4k | 4-H3COC6H4 | Me | 322 | 337 | −15 |
12 | 41 | 4-H3COC6H4 | Et | 291 | 307 | −16 |
13 | 4m | 1,2,3,4-Tetrahydronaphthalen-6-yl | Me | 286 | 265 | 21 |
14 | 4n | 1,2,3,4-Tetrahydronaphthalen-6-yl | Et | 337 | 344 | −7 |
15 | 4o | 2-Pyrrolyl | Me | 268 | 286 | −18 |
16 | 4p | 2-Pyrrolyl | Et | 298 | 311 | −13 |
17 | 4q | 2-Furanyl | Me | 321 | 310 | 11 |
18 | 4r | 2-Furanyl | Et | 254 | 257 | −3 |
19 | 4s | 2-Thienyl | Me | 356 | 328 | 28 |
20 | 4t | 2-Thienyl | Et | 400 | 386 | 14 |
21 | 4u | 2-Pyridinyl | Me | 333 | 336 | −3 |
22 | 4v | 2-Pyridinyl | Et | 370 | 369 | 1 |
23 | 4w | 1-Methyl-1H-benzo[d]imidazol-2-yl | Me | 223 | 227 | −4 |
24 | 4x | 1-Methyl-1H-benzo[d]imidazol-2-yl | Et | 299 | 285 | 14 |
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Khalifa, N.M.; Srour, A.M.; Abd El-Karim, S.S.; Saleh, D.O.; Al-Omar, M.A. Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators. Molecules 2017, 22, 1820. https://doi.org/10.3390/molecules22111820
Khalifa NM, Srour AM, Abd El-Karim SS, Saleh DO, Al-Omar MA. Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators. Molecules. 2017; 22(11):1820. https://doi.org/10.3390/molecules22111820
Chicago/Turabian StyleKhalifa, Nagy M., Aladdin M. Srour, Somaia S. Abd El-Karim, Dalia O. Saleh, and Mohamed A. Al-Omar. 2017. "Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators" Molecules 22, no. 11: 1820. https://doi.org/10.3390/molecules22111820