m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. COX Inhibition Studies
- (a)
- Amino esters in 1 lack significant activity, although some of them (1c and 1d) slightly inhibited COX-1 at 50 μM.
- (b)
- The corresponding amino acids in 2 do not achieve significant inhibition levels either, although they are slightly more active. They seem to be selective towards COX-1.
- (c)
- Amino-m-terphenyls in 3 were the most interesting derivatives, and most of them showed COX-1 inhibition at IC50 values in the μM range. Moreover, three of these compounds (3b, 3c, and 3e) showed a complete selectivity towards COX-1, and a fourth (3a) showed a COX-1/COX-2 inhibition ratio around 7. COX-1 inhibition and COX-1/COX-2 selectivity are not connected with the electron density of the aromatic rings since similar results have been obtained for compounds bearing no substitution (3a), electron-withdrawing groups (3c, 3d) and electron-releasing groups (3e). This level of selectivity had not been previously observed for this type of compound and is similar to or better than the one found in other families of COX-1 inhibitors currently being developed, such as diarylisoxazoles [33].
- (d)
- Urea derivatives in 4 and 5 are essentially inactive. The only example with some activity (compound 4f) did not show COX-1 selectivity.
2.3. Blockade of Microglia Inflammatory and Oxidative Responses
2.4. Compound Protects against LPS Challenge in Organotypic Hippocampal Slices
2.5. In Silico Prediction of the ADME Properties of Compounds
3. Materials and Methods
3.1. General Experimental Information
3.2. General Procedure for the Synthesis of Compounds by Saponification of Anthranilic Esters
- 6-Amino-2,4-diphenylbenzoic acid (2a). Prepared from ethyl 6-amino-2,4-diphenylbenzoate 1a (305 mg, 1.2 mmol). Yield: 161 mg (58%), as a pale brown solid. Mp: 162–163 °C. Elemental analysis (%) calcd for C19H15NO2 (M = 289.33): C, 78.87; H, 5.23; N, 4.84; found: C, 78.83; H, 5.27; N, 4.82. IR νmax (film): 3481, 3376, 3024, 1666, 1596, 1560 cm−1. 1H NMR (250 MHz, MeOD) δ 7.59 (d, J = 6.9 Hz, 2H), 7.46–7.23 (m, 10H), 7.03 (d, J = 1.7 Hz, 1H), 6.80 (d, J = 1.7 Hz, 1H). 13C NMR (63 MHz, MeOD) δ 173.1, 149.9, 145.3, 144.9, 144.3, 141.7, 129.8, 129.3, 128.9, 128.8, 128.0, 127.9, 119.4, 116.1, 114.7.
- 6-Amino-2-phenyl-4-(4-tolyl)benzoic acid (2b). Prepared from ethyl 6-amino-2-phenyl-4-(4-tolyl) benzoate 1b (305 mg, 1.2 mmol). Yield: 218 mg (75%), as an off-white solid. Mp: 164–165 °C. Elemental analysis (%) calcd for C20H17NO2 (M = 303.35): C, 79.19; H, 5.65; N, 4.62; found: C, 79.23; H, 5.62; N, 4.58. IR νmax (film): 3485, 3377, 3022, 2857, 1684, 1603 cm−1. 1H NMR (250 MHz, DMSO) δ 7.54 (d, J = 8.1 Hz, 2H), 7.44–7.32 (m, 5H), 7.27 (d, J = 8.4 Hz, 3H), 6.88 (d, J = 1.4 Hz, 1H), 2.33 (s, 3H). 13C NMR (63 MHz, DMSO) δ 169.6, 145.6, 143.2, 142.3, 142.2, 137.6, 136.5, 129.6, 128.1, 128.1, 127.0, 126.6, 118.7, 115.8, 114.3, 20.8.
- 6-Amino-2-phenyl-4-(4-chlorophenyl)benzoic acid (2c). Prepared from ethyl 6-amino-2-phenyl-4-(4-chlorophenyl) benzoate 1c (338 mg, 1.2 mmol). Yield: 268 mg (69%), as a pale brown solid. Mp: 229–230 °C. Elemental analysis (%) calcd for C19H14ClNO2 (M = 323.77): C, 70.48; H, 4.36; N, 4.33; found: C, 70.53; H, 4.32; N, 4.29. IR νmax (film): 3444, 3400, 2923, 2851, 1692 cm−1. 1H NMR (250 MHz, DMSO) δ 7.74–7.64 (m, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.45–7.32 (m, 3H), 7.29 (s, 1H), 6.96 (d, J = 1.3 Hz, 1H). 13C NMR (63 MHz, DMSO) δ 169.4, 150.9, 144.6, 143.2, 141.8, 141.1, 138.1, 133.0, 129.0, 128.6, 128.2, 128.1, 127.2, 119.3, 114.9.
- 6-Amino-2,4-di-(4-chlorophenyl)benzoic acid (2d). Prepared from ethyl 6-amino-2,4-di-(4-chlorophenyl) benzoate 1d (371 mg, 1.2 mmol). Yield: 215 mg (50%), as a pale brown solid. Mp: 178–179 °C. Elemental analysis (%) calcd for C19H13Cl2NO2 (M = 358.22): C, 63.71; H, 3.66; N, 3.91; found: C, 63.68; H, 3.72; N, 3.86. IR νmax (film): 3496, 3371, 1657, 1605, 1581, 1491 cm−1. 1H NMR (250 MHz, MeOD) δ 7.53 (d, J = 8.3 Hz, 2H), 7.42–7.33 (m, 3H), 7.33–7.23 (m, 4H), 6.99 (s, 1H), 6.70 (s, 1H). 13C NMR (63 MHz, MeOD) δ 172.1, 150.7, 144.7, 143.9, 143.1, 140.0, 135.0, 133.9, 130.8, 129.9, 129.5, 129.0, 118.8, 114.9, 114.5.
- 6-Amino-2-phenyl-4-(4-methoxyphenyl)benzoic acid (2e). Prepared from ethyl 6-amino-2-(4-methoxyphenyl)-2-phenylbenzoate 1e (334 mg, 1.2 mmol). Yield: 238 mg (62%), as a pale-yellow solid. Mp: 195–196 °C. Elemental analysis (%) calcd for C20H17NO3 (M = 319.35): C, 75.22; H, 5.37; N, 4.39; found: C, 75.18; H, 5.35; N, 4.42. IR νmax (film): 3484, 3372, 1647, 1605, 1581 cm−1. 1H NMR (250 MHz, DMSO) δ 7.58 (d, J = 8.7 Hz, 2H), 7.40–7.26 (m, 5H), 7.05–6.96 (m, 3H), 6.68 (d, J = 1.4 Hz, 1H), 3.79 (s, 3H). 13C NMR (63 MHz, DMSO) δ 170.2, 159.3, 149.0, 143.3, 142.8, 142.1, 132.0, 128.0, 128.0, 127.8, 126.8, 116.4, 114.4, 112.9, 112.3, 55.2.
- 6-Amino-2,4-di-(4-bromophenyl)benzoic acid (2f). Prepared from ethyl 6-amino-2,4-di-(4-bromophenyl) benzoate 1f (456 mg, 1.2 mmol). Yield: 397 mg (74%), as an off-white solid. Mp: 239–240 °C. Elemental analysis (%) calcd for C19H13Br2NO2 (M = 447.12): C, 51.04; H, 2.93; N, 3.13; found: C, 51.07; H, 2.89; N, 3.18. IR νmax (film): 2922, 2851, 1674, 1590, 1492 cm−1. 1H NMR (250 MHz, DMSO) δ 7.75–7.49 (m, 7H), 7.31 (d, J = 8.5 Hz, 3H), 6.93 (d, J = 1.2 Hz, 1H). 13C NMR (63 MHz, DMSO) δ 169.1, 150.9, 142.2, 141.3, 141.3, 138.3, 132.0, 131.0, 130.3, 129.4, 128.9, 121.8, 120.6, 113.8, 101.9.
- 6-Phenylamino-2,4-diphenylbenzoic acid (2g). Prepared from ethyl 6-phenylamino-2,4-diphenyl-2,3-dihydro benzoate 1g (378 mg, 1.2 mmol). Yield: 333 mg (76%), as a pale-yellow solid. Mp: 182–183 °C. Elemental analysis (%) calcd for C25H19NO2 (M = 365.42): C, 82.17; H, 5.24; N, 3.83; found: C, 82.13; H, 5.29; N, 3.85. IR νmax (film): 3374, 3055, 3029, 2924, 1656, 1589, 1557 cm−1. 1H NMR (250 MHz, CDCl3) δ 7.45 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.33–7.23 (m, 7H), 7.23–7.16 (m, 4H), 7.12 (d, J = 7.9 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H). 13C NMR (63 MHz, CDCl3) δ 174.56, 146.33, 145.39, 144.90, 142.57, 141.37, 140.10, 129.59, 128.90, 128.30, 128.16, 127.38, 127.30, 123.20, 121.48, 120.97, 113.01.
3.3. General Procedure for the Synthesis of m-Terphenylanilines by Decarboxylation of Compounds
- 5′-Amino-m-terphenyl (3a). Prepared from 6-amino-2,4-diphenylbenzoic acid 2a (289 mg, 1.0 mmol). Yield: 243 mg (99%), as a white solid. Mp: 108–109 °C; lit [55], 107–109 °C. Elemental analysis (%) calcd for C18H15N (M = 245.32): C, 88.13; H, 6.16; N, 5.71; found: C, 88.16; H, 6.14; N, 5.65. IR νmax (film): 3454, 3370, 3055, 1595. 1H NMR (250 MHz, DMSO) δ 7.64 (d, J = 7.1 Hz, 4H), 7.45 (t, J = 7.3 Hz, 4H), 7.35 (t, J = 7.2 Hz, 2H), 7.02 (s, 1H), 6.84 (d, J = 1.5 Hz, 2H), 5.32 (s, 2H). 13C NMR (63 MHz, DMSO) δ 149.6, 141.6, 141.1, 128.8, 127.3, 126.7, 113.3, 111.5. These characterization data were coincident with those found in the literature [28,56].
- 4-Methyl-5′-amino-m-terphenyl (3b). Prepared from 6-amino-2-phenyl-4-(4-tolyl) benzoic acid (303 mg, 1.0 mmol) 2b. Yield: 257 mg (99%), as a white solid. Mp: 98–99 °C. Elemental analysis (%) calcd for C19H17N (M = 259.34): C, 87.99; H, 6.61; N, 5.40; found: C, 88.02; H, 6.63; N, 5.38. IR νmax (film): 3418, 3294, 3025, 1594 cm−1. 1H NMR (250 MHz, CDCl3) δ 7.64 (d, J = 6.9 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.51–7.42 (m, 2H), 7.41–7.34 (m, 1H), 7.26 (s, 1H), 7.23 (t, J = 1.5 Hz, 1H), 6.93–6.89 (m, 2H), 2.43 (s, 3H). 13C NMR (63 MHz, DMSO) δ 149.6, 141.6, 141.5, 141.2, 138.2, 136.5, 129.4, 128.8, 127.3, 126.7, 126.5, 113.1, 111.3, 20.7. These characterization data were coincident with those found in the literature [28,55].
- 4-Chloro-5′-amino-m-terphenyl (3c). Prepared from 6-amino-2-phenyl-4-(4-chlorophenyl)benzoic acid 2c (324 mg, 1.0 mmol). Yield: 201 mg, (72%), as a white solid. Mp: 96–97 °C. Elemental analysis (%) calcd for C18H14ClN (M = 279.76): C, 77.28; H, 5.04; N, 5.01; found: C, 77.25; H, 5.07; N, 5.04. IR νmax (film): 3460, 3374, 3057, 2923, 1597, 1495 cm−1. 1H NMR (250 MHz, MeOD) δ 7.62 (d, J = 8.4 Hz, 4H), 7.45–7.38 (m, 4H), 7.36–7.30 (m, 1H), 7.12 (t, J = 1.6 Hz, 1H), 6.97 (t, J = 1.6 Hz, 1H), 6.95 (t, J = 1.6 Hz, 1H). 13C NMR (63 MHz, MeOD) δ 149.9, 144.1, 142.8, 142.6, 141.7, 134.2, 129.8, 129.7, 129.5, 128.3, 128.0, 116.7, 114.5, 113.9. These characterization data were coincident with those found in the literature [28,55].
- 4,4″-Dichloro-5′-amino-m-terphenyl (3d). Prepared from 6-amino-2,4-di-(4-chlorophenyl)benzoic acid (358 mg, 1.0 mmol) 2d. Yield: 212 mg (99%), as an off-white solid. Mp: 253–254 °C. Elemental analysis (%) calcd for C18H13Cl2N (M = 314.21): C, 68.81; H, 4.17; N, 4.46; found: C, 68.86; H, 4.14; N, 4.42. IR νmax (film): 3327, 3012, 2957, 1626, 1544, 1512 cm−1. 1H NMR (250 MHz, CDCl3) δ 7.60–7.51 (m, 4H), 7.43 (d, J = 8.7 Hz, 4H), 7.13 (t, J = 1.6 Hz, 1H), 6.88 (d, J = 1.6 Hz, 2H), 3.89 (bs, 2H). 13C NMR (63 MHz, CDCl3) δ 147.4, 142.0, 139.8, 133.6, 129.0, 128.5, 116.6, 113.0. These characterization data were coincident with those found in the literature [28].
- 4-Methoxy-5′-amino-m-terphenyl (3e). Prepared from 6-amino-2-(4-methoxyphenyl)-2-phenylbenzoic acid 2e (319 mg, 1.0 mmol). Yield: 215 mg (78%), as a white solid. Mp: 118–119 °C. Elemental analysis (%) calcd for C19H17NO (M = 275.34): C, 82.88; H, 6.22; N, 5.09; found: C, 82.83; H, 6.26; N, 5.04. IR νmax (film): 3447, 3369, 3030, 1596, 1514 cm−1. 1H NMR (250 MHz, DMSO) δ 7.63 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.06–6.95 (m, 3H), 6.80 (s, 2H), 5.28 (br s, 2H), 3.79 (s, 3H). 13C NMR (63 MHz, DMSO) δ 158.8, 149.6, 141.6, 141.3, 141.2, 133.4, 128.8, 127.7, 127.2, 126.7, 114.2, 112.9, 111.1, 110.9, 55.2. These characterization data were coincident with those found in the literature [28,55].
- 4,4″-Dibromo-5′-amino-m-terphenyl (3f). Prepared from 6-amino- 2,4-di-(4-bromophenyl)benzoic acid 2f (447 mg, 1.0 mmol). Yield: 294 mg (73%), as an off-white solid. Mp: 163–164 °C. Elemental analysis (%) calcd for C18H13Br2N (M = 403.11): C, 53.63; H, 3.25; N, 3.47; found: C, 53.61; H, 3.26; N, 3.43. IR νmax (film): 3393, 3308, 1598, 1491 cm−1. 1H NMR (250 MHz, DMSO) δ 7.69–7.54 (m, 8H), 7.01 (s, 1H), 6.84 (d, J = 1.4 Hz, 2H), 5.38 (br s, 2H). 13C NMR (63 MHz, DMSO) δ 149.9, 140.4, 140.1, 131.7, 128.8, 120.7, 112.9, 111.5.
- 5′-Phenylamino-m-terphenyl (3g). Prepared from 6-phenylamino- 2,4-diphenylbenzoic acid 2g (365 mg, 1.0 mmol). Yield: 244 mg, (76%), as an off-white solid. Mp: 128–129 °C. Elemental analysis (%) calcd for C24H19N (M = 321.41): C, 89.68; H, 5.96; N, 4.36; found: C, 89.62; H, 5.93; N, 4.37. IR νmax (film): 3401, 3050, 3026, 1594, 1533 cm−1. 1H NMR (250 MHz, CDCl3) δ 7.55 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.44–7.29 (m, 7H), 7.29–7.20 (m, 3H), 7.19–7.11 (m, 3H), 7.01 (d, J = 7.5 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 5.61 (br s, 1H). 13C NMR (63 MHz, CDCl3) δ 143.4, 141.5, 141.0, 140.6, 138.8, 131.5, 130.6, 129.6, 129.5, 129.1, 128.9, 127.7, 127.5, 127.2, 121.4, 120.0, 118.4, 116.1.
- 1-([m-Terphenyl]-5′-yl)-3-cyclopentyl urea (4a). Prepared from 5′-amino-m-terphenyl 3a (172 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 217 mg (87%), as a white solid. Mp: 224–225 °C. Elemental analysis (%) calcd for C24H24N2O (M = 356.46): C, 80.87; H, 6.79; N, 7.86; found: C, 80.92; H, 6.83; N, 7.81. IR νmax (film): 3337, 2919, 2851, 1643, 1559 cm−1. 1H NMR (250 MHz, DMSO) δ 8.50 (s, 1H), 7.69 (d, J = 7.7 Hz, 6H), 7.48 (t, J = 7.3 Hz, 4H), 7.42–7.34 (m, 3H), 6.28 (d, J = 7.1 Hz, 1H), 4.05–3.87 (m, 1H), 1.93–1.77 (m, 2H), 1.73–1.49 (m, 4H), 1.47–1.32 (m, 2H). 13C NMR (63 MHz, DMSO) δ 154.9, 141.7, 141.4, 140.5, 129.0, 127.6, 126.9, 118.2, 115.1, 51.0, 32.8, 23.2. These characterization data were coincident with those found in the literature [27].
- 1-([4-Methyl-m-terphenyl]-5′-yl)-3-cyclopentyl urea (4b). Prepared from 4-methyl-5′-amino-m-terphenyl 3b (182 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 254 mg (98%), as an off-white solid. Mp: 217–218 °C. Elemental analysis (%) calcd for C25H26N2O (M = 370.49): C, 81.05; H, 7.07; N, 7.56; found: C, 81.02; H, 7.11; N, 7.53. IR νmax (film): 3314, 2955, 2857, 1640, 1557 cm−1. 1H NMR (250 MHz, DMSO) δ 8.47 (s, 1H), 7.68 (d, J = 7.1 Hz, 2H), 7.64 (d, J = 1.5 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.3 Hz, 2H), 7.42–7.34 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 7.1 Hz, 1H), 4.06–3.87 (m, 1H), 1.93–1.77 (m, 2H), 1.72–1.49 (m, 4H), 1.39 (dd, J = 11.5, 6.0 Hz, 2H). 13C NMR (63 MHz, DMSO) δ 154.9, 141.6, 141.4, 141.3, 140.6, 137.6, 136.9, 129.5, 128.9, 127.6, 126.9, 126.7, 117.9, 114.8, 51.0, 32.9, 23.2, 20.7.
- 1-([4-Chloro-m-terphenyl]-5′-yl)-3-cyclopentylurea (4c). Prepared from 4-chloro-5′-amino-m-terphenyl (196 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 178 mg (65%), as a white solid. Mp: 203–204 °C. Elemental analysis (%) calcd for C24H23ClN2O (M = 390.91): C, 73.74; H, 5.93; N, 7.17; found: C, 73.71; H, 6.02; N, 7.15. IR νmax (film): 3323, 2919, 2851, 1639, 1556 cm−1. 1H NMR (250 MHz, DMSO) δ 8.34 (s, 1H), 7.55 (dd, J = 14.6, 5.9 Hz, 6H), 7.35 (dd, J = 16.4, 8.1 Hz, 4H), 7.29–7.18 (m, 2H), 6.13 (d, J = 7.1 Hz, 1H), 3.89–3.72 (m, 1H), 1.78–1.62 (m, 2H), 1.56–1.33 (m, 4H), 1.32–1.14 (m, 2H). 13C NMR (63 MHz, DMSO) δ 154.9, 141.7, 141.5, 140.3, 140.0, 139.3, 132.4, 129.0, 128.9, 128.7, 127.7, 126.9, 118.1, 115.4, 114.9, 51.0, 32.8, 23.2.
- 1-([4,4″-Dichloro-m-terphenyl]-5′-yl)-3-cyclopentylurea (4d). Prepared from 4,4″-dichloro-5′-amino-m-terphenyl (220 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 179 mg (60%), as a pale-yellow solid. Mp: 239–240 °C. Elemental analysis (%) calcd for C24H22Cl2N2O (M = 425.35): C, 67.77; H, 5.21; N, 6.59; found: C, 67.82; H, 5.19; N, 6.63. IR νmax (film): 3258, 3092, 2955, 1728, 1633 cm−1. 1H NMR (250 MHz, DMSO) δ 8.42 (s, 1H), 7.63 (d, J = 8.6 Hz, 4H), 7.59 (d, J = 1.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 4H), 7.33 (d, J = 2.0 Hz, 2H), 6.21 (d, J = 7.1 Hz, 1H), 3.94–3.78 (m, 1H), 1.86–1.67 (m, 2H), 1.62–1.39 (m, 4H), 1.37–1.20 (m, 2H). 13C NMR (63 MHz, DMSO) δ 155.2, 142.2, 140.5, 139.5, 132.8, 129.2, 129.0, 118.3, 115.6, 51.3, 33.2, 23.6.
- 1-([4-Methoxy-m-terphenyl]-5′-yl)-3-cyclopentylurea (4e). Prepared from 4-methoxy-5′-amino-m-terphenyl (193 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 170 mg (63%), as a white solid. Mp: 208–209 °C. Elemental analysis (%) calcd for C25H26N2O2 (M = 386.49): C, 77.69; H, 6.78; N, 7.25; found: C, 77.73; H, 6.82; N, 7.21. IR νmax (film): 3312, 2954, 1640, 1605, 1556 cm−1. 1H NMR (250 MHz, MeOD) δ 7.66 (t, J = 1.8 Hz, 1H), 7.63 (d, J = 1.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.60–7.54 (m, 3H), 7.48–7.42 (m, 1H), 7.40 (dd, J = 3.4, 1.8 Hz, 2H), 7.38–7.30 (m, 1H), 4.16–4.01 (m, 1H), 3.83 (s, 3H), 2.08–1.90 (m, 2H), 1.82–1.58 (m, 4H), 1.58–1.42 (m, 2H). 13C NMR (63 MHz, MeOD) δ 160.9, 158.0, 143.7, 143.4, 142.6, 141.9, 134.8, 129.8, 129.1, 128.5, 128.1, 120.4, 117.0, 116.9, 115.2, 55.8, 52.9, 34.2, 24.6.
- 1-([4,4″-Dibromo-m-terphenyl]-5′-yl)-3-cyclopentylurea (4f). Prepared from 4,4″-dibromo-5′-amino-m-terphenyl (282 mg, 0.7 mmol) and cyclopentyl isocyanate (0.12 mL, 1.05 mmol). Yield: 259 mg (72%), as an off-white solid. Mp: 222–223 °C. Elemental analysis (%) calcd for C24H22Br2N2O (M = 514.25): C, 56.05; H, 4.31; N, 5.45; found: C, 56.07; H, 4.35; N, 5.42. IR νmax (film): 3294, 2955, 2860, 1631, 1557 cm−1. 1H NMR (250 MHz, DMSO) δ 8.51 (s, 1H), 7.75–7.59 (m, 10H), 7.42 (s, 1H), 6.30 (d, J = 7.1 Hz, 1H), 4.03–3.88 (m, 1H), 1.93. 13C NMR (63 MHz, DMSO) δ 154.9, 141.9, 140.2, 139.5, 131.8, 129.0, 121.1, 117.9, 115.2, 51.0, 32.8, 23.2.
- Ethyl 6-(3′-cyclohexylureido)-2-(4-methoxyphenyl)-4-phenylbenzoate (5). Prepared from ethyl-6-amino-2-(4-methoxyphenyl)-2-phenylbenzoate (243 mg, 0.7 mmol) and cyclohexyl isocyanate (0.13 mL, 1.05 mmol). Yield: 208 mg (63%), as a white solid. Mp: 234–235 °C. Elemental analysis (%) calcd for C29H32N2O4 (M = 472.58): C, 73.70; H, 6.83; N, 5.93; found: C, 73.67; H, 6.84; N, 5.90. IR νmax (film): 3302, 2926, 2850, 1691, 1644, 1542 cm−1. 1H NMR (250 MHz, CDCl3) δ 8.95 (bs, 1H), 8.60 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.46–7.30 (m, 5H), 7.23 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.68 (t, J = 10.5 Hz, 1H), 2.12–1.99 (m, 2H), 1.85–1.60 (m, 3H), 1.53–1.33 (m, 2H), 1.30–1.11 (m, 3H), 0.73 (t, J = 7.2 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 170.4, 160.2, 155.1, 154.7, 144.4, 144.2, 143.4, 134.6, 132.6, 129.0, 128.5, 128.5, 127.4, 122.8, 116.6, 114.6, 68.2, 61.5, 55.8, 34.1, 26.0, 25.4, 13.4.
3.4. Docking Studies
3.5. Cyclooxygenase Colorimetric Inhibitor Screening Assay
3.6. Microglia BV2 Cell Line
3.7. Griess Reaction
3.8. ROS Measurement
3.9. Preparation of Organotypic Hippocampal Cultures (OHCs)
3.10. Quantification of Cell Death in OHCs: Propidium Iodide (PI) Uptake
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Entry | Compound | oCOX-1; IC50 (µM) (% Inhibition at 50 µM) a | hCOX-2; IC50 (µM) (% Inhibition at 50 µM) |
---|---|---|---|
1 | Mofezolac | 0.023 ± 0.0013 (100) | >50 (42) |
2 | Celecoxib | >50 (40) | 0.24 (95) |
3 | 1a | >50 | >50 |
4 | 1b | >50 | NM (6) |
5 | 1c | NM (11) | >50 |
6 | 1d | NM (11) | NM (5) |
7 | 1e | NM (9) | >50 |
8 | 1f | >50 | >50 |
9 | 1g | >50 | >50 |
10 | 2a | NM (32) | NM (3) |
11 | 2b | NM (46) | NM (2) |
12 | 2c | >50 | NM (4) |
13 | 2d | >50 | NM (13) |
14 | 2e | >50 | NM (20) |
15 | 2f | NM (8) | NM (12) |
16 | 2g | NM (7) | NM (13) |
17 | 3a | 0.80 ± 0.39 (86) | 5.4 (70) |
18 | 3b | 1.10 ± 0.18 (83) | >50 |
19 | 3c | 4.70 ± 3.04 (100) | >50 |
20 | 3d | NM (36] | >50 |
21 | 3e | 0.90 ± 0.76 (73) | NM (8) |
22 | 3f | >50 | >50 |
23 | 3g | >50 | >50 |
24 | 4a | >50 | >50 |
25 | 4b | >50 | >50 |
26 | 4c | >50 | >50 |
27 | 4d | >50 | >50 |
28 | 4e | >50 | >50 |
29 | 4f | NM (10) | NM (30) |
30 | 5 | >50 | >50 |
Compound | Binding Energy (kcal/mol) |
---|---|
Mofezolac | 7.97 |
Celecoxib | 5.06 |
3a | 6.68 |
3b | 6.68 |
3c | 6.54 |
3e | 5.54 |
Treatment | Concentration | Nitrite Release after 24 h | Nitrite Release after 48 h |
---|---|---|---|
Basal | 0 | 100 | 100 |
LPS | 1 μg/mL | 150 ± 8 ### | 188 ± 15 ### |
SC-560 | 100 nM | 114 ± 9 * | 135 ± 8 * |
3a | 1 μM | 130 ± 14 | 145 ± 17 |
3b | 1 μM | 123 ± 8 | 140 ± 14 |
3c | 1 μM | 135 ± 6 | 181 ± 9 |
3e | 1 μM | 124 ± 9 | 144 ± 15 |
3a | 3 μM | 110 ± 7 * | 119 ± 10 ** |
3b | 3 μM | 100 ± 4 *** | 123 ± 10 ** |
3c | 3 μM | 117 ± 8 | 163 ± 5 |
3e | 3 μM | 110 ± 6 ** | 133 ± 13 * |
3a | 10 μM | 122 ± 10 | 120 ± 15 ** |
3b | 10 μM | 105 ± 6 ** | 128 ± 10 * |
3c | 10 μM | 110 ± 6 * | 138 ± 7 |
3e | 10 μM | 103 ± 9 ** | 131 ± 13 * |
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Rocchi, D.; González, J.F.; Martín-Cámara, O.; Perrone, M.G.; Miciaccia, M.; Scilimati, A.; Decouty-Pérez, C.; Parada, E.; Egea, J.; Menéndez, J.C. m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity. Molecules 2023, 28, 5374. https://doi.org/10.3390/molecules28145374
Rocchi D, González JF, Martín-Cámara O, Perrone MG, Miciaccia M, Scilimati A, Decouty-Pérez C, Parada E, Egea J, Menéndez JC. m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity. Molecules. 2023; 28(14):5374. https://doi.org/10.3390/molecules28145374
Chicago/Turabian StyleRocchi, Damiano, Juan F. González, Olmo Martín-Cámara, Maria Grazia Perrone, Morena Miciaccia, Antonio Scilimati, Celine Decouty-Pérez, Esther Parada, Javier Egea, and J. Carlos Menéndez. 2023. "m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity" Molecules 28, no. 14: 5374. https://doi.org/10.3390/molecules28145374