Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.2. General Procedure for the Synthesis of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides 2a–i and 3a–k
2.3. X-ray Structural Analysis of N-(Pyridin-4-ylmethyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide monohydrate (2c)
2.4. X-ray Structural Analysis of N-(Furan-2-ylmethyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (2d)
2.5. X-ray Structural Analysis of N-(5-Methylfuran-2-ylmethyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (2e)
2.6. X-ray Structural Analysis of N-(Thiophen-2-ylmethyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (2g)
2.7. X-ray Structural Analysis of N-Benzyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (3a)
2.8. X-ray Structural Analysis of N-(2-Chlorobenzyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (3c)
2.9. X-ray Structural Analysis of N-(4-Chlorobenzyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (3d)
2.10. X-ray Structural Analysis of N-(2-Methylbenzyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (3e)
2.11. X-ray Structural Analysis of N-(3-Methylbenzyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide (3f)
2.12. Pharmacology: Analgesic and Anti-Inflammatory Tests
3. Results and Discussion
3.1. Chemistry
3.2. Evaluation of the Analgesic and Anti-Inflammatory Activity
3.3. The Molecular and Crystal Structure Study
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Entry | Product | R | Pain Threshold on Damaged Extremity (g/mm2) | Pain Threshold on Non-Damaged Extremity (g/mm2) | Δ Pain Threshold | Analgesic Activity Compared to Control (%) |
---|---|---|---|---|---|---|
1 | 2a | 432.0 ± 12.5 | 192.0 ± 18.5 | 240.0 ± 17.3 1,2,3 | +24.5 | |
2 | 2b | 470.0 ± 50.9 | 345.0 ± 41.7 | 125.0 ± 36.1 1,2,3 | +60.7 | |
3 | 2c | 522.0 ± 53.4 | 249.0 ± 36.9 | 273.0 ± 65.4 1,2,3 | +14.2 | |
4 | 2d | 436.0 ± 36.6 | 202.0 ± 12.5 | 243.0 ± 55.1 1,2,3 | +26.4 | |
5 | 2e | 440.0 ± 35.8 | 306.0 ± 27.9 | 134.0 ± 30.5 1,2 | +57.9 | |
6 | 2f | 460.0 ± 27.4 | 219.0 ± 16.6 | 241.0 ± 43.3 1,2,3 | +24.2 | |
7 | 2g | 404.0 ± 37.1 | 288.0 ± 43.1 | 116.0 ± 20.0 1,2 | +63.5 | |
8 | 2h | 446.0 ± 49.9 | 306.0 ± 42.3 | 140.0 ± 45.4 1,2 | +56.0 | |
9 | 2i | 451.0 ± 21.1 | 344.0 ± 23.7 | 107.0 ± 32.2 1,2 | +66.4 | |
10 | 3a | 541.0 ± 11.9 | 339.0 ± 26.8 | 202.0 ± 48.2 1,2,3 | +36.5 | |
11 | 3b | 560.0 ± 23.5 | 274.0 ± 26.6 | 286.0 ± 40.4 1,2,3 | + 10.1 | |
12 | 3c | 530.0 ± 40.2 | 224.0 ± 32.6 | 306.0 ± 36.1 1,2,3 | +3.8 | |
13 | 3d | 499.0 ± 11.3 | 195.0 ± 7.36 | 304.0 ± 13.2 | +4.4 | |
14 | 3e | 468.0 ± 29.6 | 380.0 ± 20.0 | 106.0 ± 28.8 | +66.7 | |
15 | 3f | 431.0 ± 19.4 | 183.0 ± 21.9 | 248.0 ± 11.0 1,2,3 | + 40.8 | |
16 | 3g | 446.0 ± 24.0 | 352.0 ± 25.7 | 94.0 ± 18.9 1 | + 70.4 | |
17 | 3h | 493.0 ± 8.56 | 366.0 ± 12.4 | 127.0 ± 7.64 1,2,3 | +60.1 | |
18 | 3i | 621.0 ± 13.9 | 590.0 ± 29.7 | 31.0 ± 15.3 1,3 | +90.3 | |
19 | 3j | 494.0 ± 15.6 | 259.0 ± 14.5 | 235.0 ± 49.2 1,2,3 | +26.1 | |
20 | 3k | 415.0 ± 21.4 | 212.0 ± 9.49 | 203.0 ± 40.4 1,2,3 | +36.2 | |
21 | Lornoxicam | - | 441.0 ± 33.1 | 346.0 ± 30.2 | 95.0 ± 12.7 1 | +70.1 |
22 | Diclofenac | - | 538.0 ± 23.6 | 479.0 ± 32.8 | 59.0 ± 15.3 1 | +81.4 |
23 | Control | - | 593.0 ± 62.7 | 257.0 ± 41.4 | 318.0 ± 58.2 1 | 0 |
Entry | Product | R | Volume of Damaged Extremity (mm3) | Volume of Non-Damaged Extremity (mm3) | Δ Volume (Volume Increase) | Anti-Inflammatory Activity Compared to Control (%) |
---|---|---|---|---|---|---|
1 | 2a | 641.7 ± 72.9 | 321.5 ± 87.2 | 320.1 ± 69.3 1,2,3 | +22.6 | |
2 | 2b | 589.4 ± 17.3 | 339.2 ± 16.5 | 250.1 ± 13.3 1,2,3 | +39.6 | |
3 | 2c | 594.9 ± 24.6 | 291.8 ± 49.6 | 303.1 ± 30.7 1,2,3 | +26.7 | |
4 | 2d | 416.0 ± 50.5 | 330.3 ± 59.8 | 85.7 ± 6.0 1 | +79.3 | |
5 | 2e | 506.4 ± 62.4 | 397.6 ± 64.6 | 108.8 ± 6.3 1 | +73.7 | |
6 | 2f | 473.7 ± 50.2 | 225.6 ± 54.2 | 248.0 ± 49.9 1,2,3 | +40.1 | |
7 | 2g | 431.3 ± 36.7 | 379.4 ± 44.9 | 51.9 ± 10.5 1,2,3 | +87.5 | |
8 | 2h | 603.0 ± 68.6 | 425.3 ± 41.1 | 177.7 ± 37.5 1,2,3 | +57.0 | |
9 | 2i | 561.7 ± 11.6 | 274.1 ± 21.0 | 287.7 ± 28.3 1,2,3 | +30.5 | |
10 | 3a | 537.1 ± 32.5 | 281.7 ± 16.3 | 255.4 ± 43.41 1,2,3 | +38.3 | |
11 | 3b | 580.8 ± 62.7 | 297.6 ± 10.4 | 283.3 ± 53.2 1,2,3 | +31.5 | |
12 | 3c | 669.8 ± 30.2 | 292.3 ± 27.7 | 377.6 ± 28.1 | +8.7 | |
13 | 3d | 794.2 ± 37.1 | 393.8 ± 35.7 | 400.7 ± 41.9 | +4.2 | |
14 | 3e | 453.4 ± 51.3 | 279.1 ± 7.04 | 174.3 ± 50.7 1,2,3 | +57.9 | |
15 | 3f | 696.8 ± 28.6 | 314.4 ± 8.31 | 382.4 ± 31.6 | +7.6 | |
16 | 3g | 600.9 ± 13.6 | 326.2 ± 24.8 | 274.8 ± 27.0 1,2,3 | +33.6 | |
17 | 3h | 421.3 ± 18.5 | 271.1 ± 22.4 | 150.3 ± 26.7 1,2,3 | +63.7 | |
18 | 3i | 369.5 ± 65.4 | 296.6 ± 42.8 | 72.8 ± 24.7 1,2,3 | +82.4 | |
19 | 3j | 779.5 ± 50.2 | 369.7 ± 13.7 | 409.8 ± 54.5 | +0.9 | |
20 | 3k | 377.5 ± 39.2 | 306.6 ± 50.5 | 70.99 ± 16.3 | +82.8 | |
21 | Lornoxicam | - | 360.5 ± 82.5 | 263.9 ± 60.9 | 96.6 ± 22.7 1 | +76.7 |
22 | Diclofenac | - | 397.6 ± 22.4 | 306.6 ± 17.6 | 91.0 ± 16.0 1 | +78.0 |
23 | Control | - | 768.7 ± 61.0 | 354.9 ± 22.9 | 413.7 ± 72.1 1 | 0 |
Entry | Product | R | Conformer | Torsion Angle C(9)–N(2))–C(10))–C(11) | Torsion Angle N(2))–C(10))–C(11))–X | Torsion Angle N(2))–C(10))–C(11))–C(12) |
---|---|---|---|---|---|---|
1 | 2g | 2g-A | −94.2(2) | +77.8(2) 1 | −107.0(2) | |
2g-B | −94.2(2) | −94.2(2) 1 | +79.6(3) | |||
2 | 3e | 3e-A | +146.3(4) | +115.5(3) 2 | −64.4(3) | |
3e-B | +171.0(3) | −73.2(3) 2 | +106.9(3) | |||
3 | 2e | 2e | +177.9(7) | −70.4(9) 3 | +114(1) | |
4 | 3f | 3f | +152.5(2) | +122.2(3) 2 | −79.3(4) | |
5 | 3a | 3a | +135.7(2) | +124.1(2) 2 | −55.8(3) | |
6 | 2d | 2d-A | +111.0(3) | +171.6(2) 3 | −14.3(3) | |
2d-B | +111.0(3) | +83.2(4) 3 | −96.0(5) | |||
7 | 2c | 2c | +87.8(2) | +8.9(3) 4 | −173.1(2) | |
8 | 3c | 3c | +98.2(3) | +21.7(4) 2 | −159.8(3) | |
9 | 3d | 3d-A | −65(1) | −8(2) 2 | +172(1) | |
3d-B | +150(1) | +128(1) 2 | −60(2) |
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Ukrainets, I.V.; Hamza, G.M.; Burian, A.A.; Voloshchuk, N.I.; Malchenko, O.V.; Shishkina, S.V.; Grinevich, L.A.; Grynenko, V.V.; Sim, G. Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides. Sci. Pharm. 2018, 86, 50. https://doi.org/10.3390/scipharm86040050
Ukrainets IV, Hamza GM, Burian AA, Voloshchuk NI, Malchenko OV, Shishkina SV, Grinevich LA, Grynenko VV, Sim G. Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides. Scientia Pharmaceutica. 2018; 86(4):50. https://doi.org/10.3390/scipharm86040050
Chicago/Turabian StyleUkrainets, Igor V., Ganna M. Hamza, Anna A. Burian, Natali I. Voloshchuk, Oxana V. Malchenko, Svitlana V. Shishkina, Lina A. Grinevich, Vasyl V. Grynenko, and Galina Sim. 2018. "Molecular Conformations and Biological Activity of N-Hetaryl(aryl)alkyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides" Scientia Pharmaceutica 86, no. 4: 50. https://doi.org/10.3390/scipharm86040050