Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Antifungal Activity
2.3. Molecular Docking Study
3. Materials and Methods
3.1. General Information
3.2. Chemistry
- Ethyl 2-(2-formyl-1H-pyrrol-1-yl) acetate (8b). At 0 °C and under N2 atmosphere, NaH (60%, 0.051 g, 1.27 mmol) was added to a solution of 6 (0.100 g, 1.05 mmol) and anhydrous DMF (2.0 mL), and the mixture was stirred for 20 min. Then, 7b (0.210 g, 1.26 mmol) was added, and the solution was stirred at room temperature (rt) for 4 h. The reaction mixture was extracted with hexane/EtOAc (1:1, 15.0 mL). The organic layer was washed with brine (5.0 mL × 3) and dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 9:1) to obtain 8b (0.179 g, 94%) as a pale violet oil. Rf 0.64 (hexane/EtOAc, 1:1). IR (film): ῡ 3130, 2993, 2978, 2798, 1735, 1656, 1482, 1402, 1315, 1218, 1027, 752 cm−1. 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 4.22 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 5.05 (s, 2H, CH2), 6.29 (dd, J = 4.0, 2.4 Hz, 1H, H-4′), 6.90–6.93 (m, 1H, H-5′), 6.98 (dd, J = 4.0, 1.6 Hz, 1H, H-3′), 9.52 (d, J = 0.8 Hz, 1H, CHO). 13C NMR (100 MHz, CDCl3): δ 14.1 (CO2CH2CH3), 50.2 (CH2), 61.6 (CO2CH2CH3), 110.2 (C-4′), 124.6 (C-3′) 131.7 (C-2′), 132.0 (C-5′), 168.3 (CO2CH2CH3), 179.7 (CHO). HRMS (EI): m/z [M+] calcd. for C9H11NO3: 181.0739; found: 181.0733.
- 1-(2-Oxo-2-phenylethyl)-1H-pyrrole-2-carbaldehyde (8c). Following the method described for 8b, a mixture of 6 (0.100 g, 1.05 mmol), NaH (60%, 0.505 g, 1.26 mmol), and 7c (0.251 g, 1.26 mmol) furnished 8c (0.200 g, 89%) as white needles. Rf 0.19 (hexane/EtOAc, 9:1); mp 114–115 °C. IR (film): ῡ 3112, 2938, 2812, 1702, 1648, 1402, 1366, 1330, 1222, 1080, 1019, 1005, 748, 690 cm−1. 1H NMR (300 MHz, CDCl3): δ 5.81 (s, 2H, CH2), 6.36 (dd, J = 4.2, 2.5 Hz, 1H, H-4), 6.94–6.98 (m, 1H, H-5), 7.04 (dd, J = 4.2, 1.5 Hz, 1H, H-3), 7.48–7.55 (m, 2H, H-3″), 7.59–7.67 (m, 1H, H-4″), 7.98–8.03 (m, H-2″), 9.51 (d, J = 0.9 Hz, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 54.7 (CH2), 110.3 (C-4), 124.7 (C-3), 128.0 (C-2″), 128.9 (C-3″), 131.6 (C-2), 132.5 (C-5), 133.8 (C-4″), 134.8 (C-1″), 179.8 (CHO), 192.9 (CO). HRMS (EI): m/z [M+] calcd. for C13H11NO2: 213.0790; found: 213.0790.
- 1-(2-(3-Methoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carbaldehyde (8d). Following the method described for 8b, a mixture of 6 (0.060 g, 0.63 mmol), NaH (60%, 0.030 g, 0.76 mmol), and 7c (0.174 g, 0.76 mmol) afforded 8d (0.070 g, 45%) as white needles. Rf 0.48 (hexane/EtOAc, 1:1); mp 106–107 °C. IR (KBr): ῡ 2939, 2799, 1694, 1649, 1591, 1403, 1260, 1192, 1024, 857, 754 cm−1. 1H NMR (750 MHz, CDCl3): δ 3.85 (s, 3H, CH3O), 5.79 (s, 2H, CH2), 6.35 (dd, J = 3.9, 2.6 Hz, 1H, H-4), 6.95 (br s, 1H, H-5), 7.03 (dd, J = 3.9, 1.5 Hz, 1H, H-3), 7.16 (ddd, J = 8.3, 2.6, 1.1 Hz, H-4″), 7.42 (t, J = 8.3 Hz, 1H, H-5″), 7.50 (dd, J = 2.6, 1.5 Hz, 1H, H-2″), 7.58 (dt, J = 7.5, 1.5 Hz, 1H, H-6″), 9.51 (d, J = 0.8 Hz, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 54.9 (CH2), 55.5 (CH3O), 110.3 (C-4), 112.4 (C-2″), 120.4 (C-4″), 120.5 (C-6″), 124.8 (C-3), 129.9 (C-5″), 131.6 (C-2), 132.5 (C-5), 136.1 (C-1″), 160.0 (C-3″), 179.8 (CHO), 192.8 (CO). HRMS (EI): m/z [M+] calcd. for C14H13NO3: 243.0895; found: 243.0891.
- 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carbaldehyde (8e). Following the method described for 8b, a mixture of 6 (0.200 g, 2.10 mmol), NaH (60%, 0.100 g, 2.52 mmol), and 7e (0.577 g, 2.52 mmol) provided 8e (0.413 g, 72%) as white needles. Rf 0.70 (hexane/EtOAc, 1:1); mp 118–119 °C. IR (KBr): ῡ 2939, 1652, 1601, 1406, 1366, 1226, 1178, 1024, 846, 754 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.88 (s,1H, CH3O), 5.77 (s, 2H, CH2), 6.35 (dd, J = 3.9, 2.4 Hz, 1H, H-4), 6.95 (br s, 1H, H-5), 6.96–6.99 (m, 2H, H-3″), 7.02 (dd, J = 3.9, 1.8 Hz, 1H, H-3), 7.97–8.00 (m, 2H, H-2″), 9.50 (d, J = 0.6 Hz, 1H, CHO). 13C NMR (150 MHz, CDCl3): δ 54.3 (CH2), 55.5 (CH3O), 110.2 (C-4), 114.1 (C-3″), 124.7 (C-3), 127.8 (C-1″), 130.4 (C-2″), 131.6 (C-2), 132.6 (C-5), 164.1 (C-4″), 179.8 (CHO), 191.3 (CO). HRMS (EI): m/z [M+] calcd. for C14H13NO3: 243.0895; found: 243.0885.
- 1-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carbaldehyde (8f). Following the method described for 8b, a mixture of 6 (0.030 g, 0.32 mmol), NaH (60%, 0.015 g, 0.38 mmol), and 7f (0.098 g, 0.38 mmol) gave 8f (0.070 g, 81%) as white needles. Rf 0.13 (hexane/EtOAc, 1:1); 148–149 °C. IR (film): ῡ 3011, 1707, 1356, 1219, 1417, 762 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.93 (s, 3H, CH3O), 3.97 (s, 3H, CH3O), 5.79 (s, 2H, CH2), 6.35 (dd, J = 3.9, 2.7 Hz, 1H, H-4), 6.94 (d, J = 8.1 Hz, 1H, H-5″), 6.96 (br s, 1H, H-5), 7.03 (dd, J = 3.9, 1.8 Hz, 1H, H-3), 7.53 (d, J = 2.1 Hz, 1H, H-2″), 7.66 (dd, J = 8.1, 2.1 Hz, 1H, H-6″), 9.52 (d, J = 0.6 Hz, 1H, CHO). 13C NMR (150 MHz, CDCl3): δ 54.2 (CH2), 56.0 (CH3O), 56.1 (CH3O), 110.2 (C-2″, C-4), 110.3 (C-5″), 122.6 (C-6″), 124.8 (C-3), 128.0 (C-1″), 131.7 (C-2), 132.6 (C-5), 149.3 (C-3″), 154.0 (C-4″), 179.9 (CHO), 191.5 (CO). HRMS (EI): m/z [M+] calcd. for C15H15NO4: 273.1001; found: 273.1002.
- 2-(2-Formyl-1H-pyrrol-1-yl)acetonitrile (8g). Following the method described for 8b, a mixture of 6 (0.050 g, 0.53 mmol), NaH (60%, 0.025 g, 0.63 mmol), and 7g (0.076 g, 0.63 mmol) produced 8g (0.036 g, 51%) as pale violet oil. Rf 0.64 (hexane/EtOAc, 1:1). IR (film): ῡ 3113, 2864, 2253, 1652, 1475, 1406, 1362, 1308, 1222, 1028, 748 cm−1. 1H NMR (750 MHz, CDCl3): δ 5.35 (s, 2H, CH2), 6.34 (dd, J = 3.9, 2.6 Hz, 1H, H-4′), 7.00 (dd, J = 3.9, 1.5 Hz, 1H, H-3′), 7.08 (br s, 1H, H-5′), 9.57 (d, J = 0.8 Hz, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 36.2 (CH2), 111.5 (C-4′), 114.5 (CN), 125.2 (C-3′), 130.7 (C-5′), 131.0 (C-2′), 179.9 (CHO). HRMS (EI): m/z [M+] calcd. for C7H6N2O: 134.0480; found: 134.0477.
- Ethyl (Z)-3-(dimethylamino)-2-(2-formyl-1H-pyrrol-1-yl)acrylate (1b). In a threaded ACE glass pressure tube equipped with a magnetic stirring bar and sealed with a Teflon screw cap, a mixture of 8b (0.100 g, 0.55 mmol) and DMFDMA (0.329 g, 2.75 mmol) in anhydrous DMF (2.0 mL) was heated at 100 °C for 20 h. A mixture of CH2Cl2/toluene (10.0 mL/1.0 mL) was added, and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 7:3), resulting in 1b (0.057 g, 44%) as a yellow oil. Rf 0.16 (hexane/EtOAc, 1:1). IR (film): ῡ 2934, 1663, 1618, 1303, 1209, 1078, 749 cm−1. 1H NMR (750 MHz, CDCl3): δ 1.16 (t, J = 6.8 Hz, 3H, CO2CH2CH3), 2.65 (br, 6H, N(CH3)2), 4.04–4.16 (m, 2H, CO2CH2CH3), 6.29 (dd, J = 3.8, 2.3 Hz, H-4′), 6.82 (br t, J = 2.3 Hz, 1H, H-5′), 7.01 (dd, J = 3.8, 1.5 Hz, H-3′), 7.51 (s, 1H, H-3), 9.56 (s, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 14.5 (CO2CH2CH3), 34.9 (N(CH3)2), 60.1 (CO2CH2CH3), 97.9 (C-2), 110.2 (C-4′), 120.9 (C-3′), 134.2 (C-5′), 134.9 (C-2′), 146.0 (C-3), 166.9 (CO2Et), 179.8 (CHO). HRMS (EI): m/z [M+] calcd. for C12H16N2O3: 236.1161; found: 236.1159.
- (Z)-1-(1-(Dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)-1H-pyrrole-2-carbaldehyde (2a). Following the method described for 1b, a mixture of 8c (0.030 g, 0.14 mmol) and DMFDMA (0.084 g, 0.70 mmol) in anhydrous DMF (1.0 mL) delivered 2a (0.020 g, 53%) as a yellow oil. Rf 0.16 (hexane/EtOAc, 1:1). IR (film): ῡ 3097, 2928, 1637, 1543, 1413, 1388, 1323, 1095, 950, 878, 766, 708 cm−1. 1H NMR (750 MHz, CDCl3): δ 2.68 (br, 6H, N(CH3)2), 6.33 (dd, J = 3.9, 2.6 Hz, 1H, H-4), 6.89 (br s, 1H, H-5), 7.02 (dd, J = 3.9, 1.5 Hz, 1H, H-3), 7.31–7.36 (m, 3H, H-1′, H-3″), 7.37–7.40 (m, 1H, H-4″), 7.48–7.52 (m, 2H, H-2″), 9.60 (d, J = 0.9 Hz, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 29.6 (br, N(CH3)2), 110.6 (C-2′, C-4), 122.6 (C-3), 127.90 (C-2″), 127.93 (C-3″), 129.9 (C-4″), 134.39 (C-2), 134.43 (C-5), 139.9 (C-1″), 150.2 (C-1′), 179.4 (CHO), 190.9 (CO). HRMS (EI): m/z [M+] calcd. for C16H16N2O2: 268.1212; found: 268.1213.
- (Z)-1-(1-(Dimethylamino)-3-(3-methoxyphenyl)-3-oxoprop-1-en-2-yl)-1H-pyrrole-2-carbaldehyde (2b). Following the method described for 1b, a mixture of 8d (0.050 g, 0.21 mmol) and DMFDMA (0.125 g, 1.05 mmol) in anhydrous DMF (1.0 mL) formed 2b (0.035 g, 56%) as a pale violet oil. Rf 0.45 (hexane/EtOAc, 1:1). IR (film): ῡ 2925, 1663, 1588, 1424, 1322, 1042, 748 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.70 (br, 6H, N(CH3)2), 3.79 (s, 3H, CH3O), 6.31–6.34 (m, 1H, H-4), 6.88 (br s, 1H, H-5), 6.92 (dm, J = 8.0 Hz, 1H, H-4″), 7.01–7.04 (m, 2H, H-2″, H-3), 7.06–7.10 (m, 1H, H-6″), 7.23 (t, J = 8.0 Hz, 1H, H-5″), 7.37 (br s, 1H, H-1′), 9.60 (s, 1H, CHO). 13C NMR (125 MHz, CDCl3): δ 36.5 (br, N(CH3)2), 55.2 (CH3O), 110.6 (C-4), 111.1 (C-2′), 112.7 (C-2″), 116.3 (C-4″), 120.3 (C-6″), 122.5 (C-3), 128.9 (C-5″), 129.5 (C-2), 134.4 (C-5), 141.1 (C-1″), 150.4 (C-1′), 159.2 (C-3″), 179.4 (CHO), 190.6 (CO). HRMS (EI): m/z [M+] calcd. for C17H18N2O3: 298.1317; found: 298.1311.
- (Z)-1-(1-(Dimethylamino)-3-(4-methoxyphenyl)-3-oxoprop-1-en-2-yl)-1H-pyrrole-2-carbaldehyde (2c). Following the method described for 1b, a mixture of 8e (0.100 g, 0.41 mmol) and DMFDMA (0.245 g, 2.05 mmol) in anhydrous DMF (1.0 mL) provided 2c (0.111 g, 90%) as a yellow oil. Rf 0.16 (hexane/EtOAc, 1:1). IR (film): ῡ 2939, 1663, 1600, 1584, 1560, 1386, 1325, 1243, 1096, 1021, 840, 765, 738 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.67 (br, 6H, N(CH3)2), 3.79 (s, 3H, CH3O), 6.31 (dd, J = 4.2, 2.4 Hz, 1H, H-4), 6.80 (d, J = 8.4 Hz, 2H, H-3″), 6.87 (br s, 1H, H-5), 7.01 (dd, J = 4.2, 1.8 Hz, 1H, H-3), 7.35 (s, 1H, H-1′), 7.45 (d, J = 8.4 Hz, 1H, H-2″), 9.56 (s, 1H, CHO). 13C NMR (125 MHz, CDCl3): δ 34.8 (br, N(CH3)2), 55.2 (CH3O), 110.1 (C-2′), 110.6 (C-4), 113.2 (C-3″), 122.3 (C-3), 130.0 (C-2″), 132.1 (C-1″), 134.3 (C-2), 134.4 (C-5), 149.7 (C-1′), 161.2 (C-4″), 179.5 (CHO), 189.7 (CO). HRMS (EI): m/z [M+] calcd. for C17H18N2O3: 298.1317; found: 298.1314.
- (Z)-1-(3-(3,4-Dimethoxyphenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)-1H-pyrrole-2-carbaldehyde (2d). Following the method described for 1b, a mixture of 8f (0.050 g, 0.18 mmol) and DMFDMA (0.109 g, 0.90 mmol) in anhydrous DMF (1.0 mL) afforded 2d (0.050 g, 83%) as a brown solid. Rf 0.03 (hexane/EtOAc, 1:1); 138–140 °C. IR (film): ῡ 2929, 1738, 1639, 1564, 1509, 1410, 1311, 1096, 1018, 748 cm−1. 1H NMR (600 MHz, CDCl3): δ 2.69 (br, 6H, N(CH3)2), 3.82 (CH3O), 3.87 (CH3O), 6.31 (dd, J = 4.0, 2.1 Hz, 1H, H-4), 6.76 (d, J = 8.1 Hz, 1H, H-5″), 6.87 (br s, 1H, H-5), 7.02 (dd, J = 4.0, 1.8 Hz, 1H, H-3), 7.04 (br s, 1H, H-2″), 7.09 (br d, J = 8.1 Hz, 1H, H-6″), 7.43 (s, 1H, H-1′), 9.58 (CHO). 13C NMR (150 MHz, CDCl3): δ 42.0 (br, N(CH3)2), 55.8 (CH3O), 55.9 (CH3O), 110.00 (C-5″), 110.02 (C-2′), 110.6 (C-4), 111.2 (C-2″), 121.7 (C-6″), 122.2 (C-3), 132.2 (C-1″), 134.3 (C-5), 134.5 (C-2), 148.4 (C-3″), 149.6 (C-1′), 150.1 (C-4″), 179.4 (CHO), 189.4 (CO). HRMS (EI): m/z [M+] calcd. for C18H20N2O4: 328.1423; found: 328.1426.
- (Z)-3-(Dimethylamino)-2-(2-formyl-1H-pyrrol-1-yl)acrylonitrile (3a). (E)-3-(Dimethylamino)-2-(2-formyl-1H-pyrrol-1-yl)acrylonitrile (3a’). Following the method described for 1b, a mixture of 8g (0.077 g, 0.57 mmol) and DMFDMA (0.339 g, 2.85 mmol) in anhydrous DMF (2.0 mL) generated an inseparable mixture of 3a/3a’ (54:46, 0.030 g, 28%) as a pale violet oil. Rf 0.16 (hexane/EtOAc, 1:1). IR (film): ῡ 3095, 2922, 2803, 2184, 1650, 1365, 1130, 772 cm−1. 1H NMR (600 MHz, CDCl3): δ 2.63 (br, 6H, N(CH3)2), 3.16 (s, 6H, N(CH3)2), 6.25 (dd, J = 4.2, 2.4 Hz, 1H, H-4′), 6.31 (dd, J = 4.2, 2.4 Hz, 1H, H-4′), 6.68 (s, 1H, H-3), 6.73 (s, 1H, H-3), 6.87–6.89 (m, 1H, H-5′), 6.91–6.93 (m, 1H, H-5′), 6.96 (dd, J = 4.2, 1.8 Hz, 1H, H-3′), 6.99 (dd, J = 4.2, 1.8 Hz, 1H, H-3′), 9.63 (s, 1H, CHO), 9.66 (s, 1H, CHO). 13C NMR (150 MHz, CDCl3): δ 42.3 (br, N(CH3)2), 78.6 (C-2), 78.8 (C-2), 110.7 (C-4′), 111.2 (C-4′), 118.5 (CN), 120.24 (CN), 122.5 (2C-3′), 133.0 (C-5′), 133.2 (C-2′), 133.8 (C-5′), 134.5 (C-2′), 147.4 (C-3), 151.0 (C-3), 178.9 (CHO), 179.2 (CHO). HRMS (EI): m/z [M+] calcd. for C10H11N3O: 189.0902; found: 189.0900.
- Methyl pyrrolo[1,2-a]pyrazine-4-carboxylate (4a). Method A: In a threaded ACE glass pressure tube equipped with a magnetic stirring bar and sealed with a Teflon screw cap, a mixture of NH4OAc (0.052 g, 0.675 mmol) and Li2CO3 (0.050 g, 0.675 mmol) in anhydrous DMF (1.0 mL) was stirred at rt for 20 min. Then, 1a (0.050 g, 0.225 mmol) was added, and the solution was heated at 70 °C for 4 h. The mixture was diluted with hexane/EtOAc (1:1, 15 mL) and washed with brine (5.0 mL × 3). The organic layer was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 8:2) to give 4a (0.036 g, 90%) as a yellow solid. Rf 0.58 (hexane/EtOAc, 1:1); mp 93–95 °C.
- Method B: In a threaded ACE glass pressure tube equipped with a magnetic stirring bar and sealed with a Teflon screw cap, a mixture of 8a (0.030 g, 0.18 mmol), DMFDMA (0.114 g, 0.90 mmol), and NH4OAc (0.042 g, 0.54 mmol) was heated at 100 °C for 24 h. The mixture was suspended in CH2Cl2/PhMe (10:1, 11 mL), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 1:1) to furnish 4a (0.018 g, 57%) as a yellow solid. Rf 0.58 (hexane/EtOAc, 1:1); mp 93–95 °C. IR (film): ῡ 3168, 2954, 1720, 1621, 1441, 1430, 1306, 1217, 1203, 1177, 1112, 764, 744 cm−1. 1H NMR (500 MHz, CDCl3): δ 4.01 (s, 3H, CO2CH3), 7.02 (s, 2H, H-7, H-8), 8.46 (s, 1H, H-3), 8.74 (s, 1H, H-6), 8.92 (s, 1H, H-1). 13C NMR (125 MHz, CDCl3): δ 52.4 (CO2CH3), 106.7 (C-8), 116.6 (C-7), 118.3 (C-4), 118.9 (C-6), 129.9 (C-8a), 134.8 (C-3), 148.1 (C-1), 163.3 (CO2CH3). HRMS (EI): m/z [M+] calcd. for C9H8N2O2: 176.0586; found: 176.0592.
- Ethyl pyrrolo[1,2-a]pyrazine-4-carboxylate (4b). Following method A described for 4a, a mixture of 1b (0.030 g, 0.13 mmol), NH4OAc (0.030 g, 0.39 mmol), and Li2CO3 (0.028 g, 0.39 mmol) was heated at 80 °C for 3 h to obtain 4b (0.016 g, 66%) as a yellow solid. Rf 0.67 (hexane/EtOAc, 1:1); mp 68–70 °C. IR (film): ῡ 3177, 3097, 2848, 1699, 1427, 1287, 1178, 1088, 1033, 734 cm−1. 1H NMR (750 MHz, CDCl3): δ 1.45 (t, J = 7.4 Hz, CO2CH2CH3), 4.47 (q, J = 7.4 Hz, CO2CH2CH3), 7.01–7.03 (m, 2H, H-7, H-8), 8.46 (s, 1H, H-3), 8.73–8.74 (m, 1H, H-6), 8.91 (s, 1H, H-1). 13C NMR (187.5 MHz, CDCl3): δ 14.3 (CO2CH2CH3), 61.6 (CO2CH2CH3), 106.6 (C-8), 116.5 (C-7), 118.9 (C-6), 129.9 (C-8a), 134.6 (C-3), 134.8 (C-4), 148.0 (C-1), 162.8 (CO2CH2CH3). HRMS (EI): m/z [M+] calcd. for C10H10N2O2: 190.0742; found: 190.0742.
- Phenyl(pyrrolo[1,2-a]pyrazin-4-yl)methanone (4c). Following method A described for 4a, a mixture of 2a (0.050 g, 0.187 mmol), NH4OAc (0.043 g, 0.56 mmol), and Li2CO3 (0.041 g, 0.56 mmol) was heated at 80 °C for 3 h to give 4c (0.036 g, 87%) as a yellow solid. Rf 0.48 (hexane/EtOAc, 1:1); mp 61–62 °C. Following method B described for 4a, a mixture of 8c (0.030 g, 0.141 mmol), DMFDMA (0.084 g, 0.70 mmol), and NH4OAc (0.054 g, 0.70 mmol) produced 4c (0.025 g, 80%) as a yellow solid. Rf 0.48 (hexane/EtOAc, 1:1); mp 61–62 °C. IR (film): ῡ 3101, 3040, 2924, 1633, 1467, 1290, 1203, 1052, 882, 741 cm−1. 1H NMR (750 MHz, CDCl3): δ 7.10 (d, J = 1.5 Hz, 2H, H-7′, H-8′), 7.53 (t, J = 7.5 Hz, 2H, H-3″), 7.63 (t, J = 7.5 Hz, 1H, H-4″), 7.81 (br d, J = 7.5 Hz, 2H, H-2″), 8.10 (s, 1H, H-3′), 8.92 (br m, 1H, H-6′), 8.94 (s, 1H, H-1′). 13C NMR (187.5 MHz, CDCl3): δ 107.4 (C-8′), 117.1 (C-7′), 119.6 (C-6′), 124.5 (C-8a’), 128.5 (C-3″), 129.6 (C-2″), 130.1 (C-4′), 132.5 (C-4″), 137.8 (C-1″), 139.0 (C-3′), 148 (C-1′), 190.9 (CO). HRMS (EI): m/z [M+] calcd. for C14H10N2O: 222.0793; found: 222.0794.
- (3-Methoxyphenyl)(pyrrolo[1,2-a]pyrazin-4-yl)methanone (4d). Following method A described for 4a, a mixture of 2b (0.030 g, 0.10 mmol), NH4OAc (0.023 g, 0.30 mmol), and Li2CO3 (0.022 g, 0.30 mmol) provided 4d (0.021 g, 83%) as a yellow solid. Rf 0.39 (hexane/EtOAc, 1:1); mp 88–89 °C. IR (film): ῡ 2970, 1734, 1594, 1424, 1298, 1250, 1171, 1028, 854, 741 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.88 (s, 3H, CH3O), 7.09 (br s, 2H, H-7′, H-8′), 7.17 (dd, J = 8.0, 2.6 Hz, 1H, H-4″), 7.34 (br d, J = 1.2 Hz, 1H, H-2″), 7.36 (br d, J = 8.0 Hz, 1H, H-6″), 7.43 (t, J = 8.0 Hz, 1H, H-5″), 8.13 (s, 1H, H-3′), 8.91 (s, 1H, H-6′), 8.94 (s, 1H, H-1′). 13C NMR (150 MHz, CDCl3): δ 55.4 (CH3O), 107.5 (C-8′), 114.2 (C-2″), 117.2 (C-7′), 118.9 (C-4″), 119.6 (C-6′), 122.2 (C-6″), 124.6 (C-8a’), 129.5 (C-5″), 130.1 (C-4′), 138.9 (C-3′), 139.0 (C-1″), 147.9 (C-1′), 159.7 (C-3″), 190.6 (CO). HRMS (EI): m/z [M+] calcd. for C15H12N2O2: 252.0899; found: 252.0900.
- (4-Methoxyphenyl)(pyrrolo[1,2-a]pyrazin-4-yl)methanone (4e). Following method A described for 4a, a mixture of 2c (0.050 g, 0.168 mmol), NH4OAc (0.039 g, 0.50 mmol), and Li2CO3 (0.037 g, 0.50 mmol) formed 4e (0.036 g, 84%) as a yellow solid. Rf 0.29 (hexane/EtOAc, 1:1); mp 138–139 °C. IR (KBr): ῡ 2928, 1739, 1590, 1507, 1301, 1265, 1167, 1109, 1030, 845, 759, 719 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.91 (s, 3H, CH3O), 7.00–7.03 (m, 2H, H-3″), 7.05 (br s, 1H, H-8′), 7.06 (br s, 1H, H-7′), 7.84–7.87 (m, 2H, H-2″), 8.05 (br s, 1H, H-3′), 8.74 (s, 1H, H-6′), 8.92 (s, 1H, H-1′). 13C NMR (150 MHz, CDCl3): δ 55.6 (CH3O), 106.9 (C-8′), 113.9 (C-3″), 116.8 (C-7′), 119.0 (C-6′), 124.8 (C-8a’), 130.0 (C-4′), 130.1 (C-1″), 132.2 (C-2″), 137.4 (C-3′), 147.7 (C-1′), 163.6 (C-4″), 189.3 (CO). HRMS (EI): m/z [M+] calcd. for C15H12N2O2: 252.0899; found: 252.0899.
- (3,4-Dimethoxyphenyl)(pyrrolo[1,2-a]pyrazin-4-yl)methanone (4f). Following method A described for 4a, a mixture of 2d (0.079 g, 0.24 mmol), NH4OAc (0.056 g, 0.72 mmol), and Li2CO3 (0.053 g, 0.72 mmol) afforded 4f (0.041 g, 60%) as a yellow solid. Rf 0.16 (hexane/EtOAc, 1:1); mp 148–149 °C. IR (KBr): ῡ 3158, 2943, 1632, 1594, 1509, 1414, 1260, 1171, 1014, 772 cm−1. 1H NMR (750 MHz, CDCl3): δ 3.95 (s, 3H, CH3O), 3.97 (s, 3H, CH3O), 6.94 (d, J = 8.8 Hz, 1H, H-5″), 7.04–7.06 (m, 2H, H-7′, H-8′), 7.44–7.47 (m, H-2″, H-6″), 8.06 (s, 1H, H-3′), 8.69 (br s, 1H, H-6′), 8.91 (s, 1H, H-1′). 13C NMR (187.5 MHz, CDCl3): δ 56.0 (CH3O), 56.1 (CH3O), 106.9 (C-8′), 110.0 (C-5″), 111.8 (C-2″), 116.8 (C-7′), 118.9 (C-6′), 124.7 (C-8a’), 124.8 (C-6″), 129.9 (C-4′), 130.1 (C-1″), 137.2 (C-3′), 147.6 (C-1′), 149.2 (C-3″), 153.4 (C-4″), 189.2 (CO). HRMS (EI): m/z [M+] calcd. for C16H14N2O3: 282.1005; found: 282.1004.
- Pyrrolo[1,2-a]pyrazine-4-carbonitrile (4g). Following method A described for 4a, a mixture of 3a (0.032 g, 0.169 mmol), NH4OAc (0.039 g, 0.51 mmol), and Li2CO3 (0.038 g, 0.51 mmol) furnished 4g (0.013 g, 53%) as a brown solid. Rf 0.55 (hexane/EtOAc, 1:1); mp 128–130 °C. IR (film): ῡ 3010, 2600, 1741, 1366, 1212 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.13 (s, 2H, H-7, H-8), 7.84 (s, 1H, H-6), 8.08 (br s, 1H, H-3), 9.00 (br s, 1H, H-1). 13C NMR (100 MHz, CDCl3): δ 104.5 (CN), 107.9 (C-8), 112.8 (C-4), 116.6 (C-6), 117.0 (C-7), 127.9 (C-8a), 136.3 (C-3), 148.1 (C-1). HRMS (EI): m/z [M+] calcd. for C8H5N3: 143.0483; found: 143.0485.
- Phenyl(pyrrolo[1,2-a]pyrazin-4-yl)methanol (4h). In a round-bottom flask equipped with a magnetic stirring bar, NaBH4 (0.051 g, 1.33 mmol) was slowly added to a solution of 4c (0.030 g, 0.13 mmol) in anhydrous THF (5.0 mL). After heating the reaction mixture at 60 °C for 2 h, MeOH (8.0 mL) was added dropwise and stirred at rt for 5.0 min. Then, a saturated aqueous solution of NH4Cl (8.0 mL) was added and stirred at rt for 20 min. The mixture was extracted with hexane/EtOAc (1:1, 15 mL) and brine (3 × 5.0 mL). The organic layer was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 7:3), resulting in 4h (0.014 g, 48%) as a yellow solid. Rf 0.10 (hexane/EtOAc, 1:1); mp 150–152 °C. IR (film): ῡ 3042, 2820, 1618, 1451, 1318, 1048, 727, 704 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.10 (br, 1H, OH), 5.98 (s, 1H, CHOH), 6.80 (s, 2H, H-7′, H-8′), 7.30–7.39 (m, 4H, H-6′, H-3″, H-4″), 7.43 (br s, 1H, H-3′), 7.44–7.46 (m, 2H, H-2″), 8.58 (s, 1H, H-1′). 13C NMR (187.5 MHz, CDCl3): δ 71.9 (CHOH), 104.5 (C-8′), 114.6 (C-6′), 115.3 (C-7′), 125.5 (C-3′), 126.6 (C-2″), 128.5 (C-4″), 128.83 (C-3″), 128.88 (C-8a’), 130.2 (C-4′), 138.6 (C-1″), 144.3 (C-1′). HRMS (EI): m/z [M+] calcd. for C14H12N2O: 224.0950; found: 224.0948.
- Methyl 2-(4-bromo-2-formyl-1H-pyrrol-1-yl)acetate (8h). In a round-bottom flask at 0 °C with a magnetic stirring bar, a solution of NBS (0.080 g, 0.45 mmol) in anhydrous CH2Cl2 (5.0 mL) was added dropwise to a solution of 8a (0.05 g, 0.30 mmol) in anhydrous DMF (5.0 mL). The mixture was stirred at rt for 2.0 h before adding a 10% aqueous solution of NaHSO3 (1.0 mL). It was then washed with brine (3 × 5.0 mL), the organic phase was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 8:2) to afford 8h (0.066 g, 90%) as a violet oil. Rf 0.74 (hexane/EtOAc, 1:1). IR (film): ῡ 2922, 1692, 1661, 1393, 1215, 998, 768 cm−1. 1H NMR (500 MHz, CDCl3): δ 3.76 (s, 3H, CO2CH3), 5.01 (s, 2H, CH2), 6.90 (br s, 1H, H-5′), 6.95 (d, J = 2.0 Hz, 1H, H-3′), 9.45 (d, J = 0.5 Hz, 1H, CHO). 13C NMR (125 MHz, CDCl3): δ 50.1 (CH2), 52.6 (CO2CH3), 97.5 (C-4′), 125.2 (C-3′) 131.2 (C-5′), 131.6 (C-2′), 168.2 (CO2CH3), 179.3 (CHO). HRMS (EI): m/z [M+] calcd. for C8H8BrNO3: 244.9688; found: 244.9680.
- Methyl (Z)-2-(4-bromo-2-formyl-1H-pyrrol-1-yl)-3-(dimethylamino)acrylate (1c). Following the method described for 1b, a mixture of 8h (0.050 g, 0.20 mmol) and DMFDMA (0.121 g, 1.02 mmol) in anhydrous DMF (1.0 mL) gave 1c (0.041 g, 66%) as a pale violet oil. Rf 0.12 (hexane/EtOAc, 7:3). IR (film): ῡ 2921, 1666, 1621, 1212, 1084, 922, 755 cm−1. 1H NMR (600 MHz, CDCl3): δ 2.67 (br, 6H, N(CH3)2), 3.62 (s, 3H, CO2CH3), 6.81 (br s, 1H, H-5′), 6.99 (br s, 1H, H-3′), 7.50 (s, 1H, H-3), 9.49 (s, 1H, CHO). 13C NMR (125 MHz, CDCl3): δ 34.7 (N(CH3)2), 51.6 (CO2CH3), 96.6 (C-2), 98.2 (C-4′), 121.6 (C-3′), 132.9 (C-5′), 134.8 (C-2′), 146.4 (C-3), 166.9 (CO2CH3), 179.1 (CHO). HRMS (EI): m/z [M+] calcd. for C11H13BrN2O3: 300.0110; found: 300.0108.
- Methyl 7-bromopyrrolo[1,2-a]pyrazine-4-carboxylate (4i). Following method A described for 4a, a mixture of 1c (0.030 g, 0.10 mmol), NH4OAc (0.031 g, 0.40 mmol), and Li2CO3 (0.029 g, 0.40 mmol) provided 4i (0.017 g, 74%) as a yellow solid. Rf 0.38 (hexane/EtOAc, 1:1); mp 93–95 °C. IR (film): ῡ 3173, 3126, 2957, 1720, 1442, 1308, 1200, 1175 cm−1. 1H NMR (500 MHz, CDCl3): δ 4.01 (s, 3H, CO2CH3), 7.10 (br s, 1H, H-8), 8.45 (br s, 1H, H-3), 8.78 (s, 1H, H-6), 8.87 (br s, 1H, H-1). 13C NMR (125 MHz, CDCl3): δ 52.8 (CO2CH3), 107.2 (C-7), 109.2 (C-8), 117.7 (C-4), 119.5 (C-6), 129.6 (C-8a), 133.7 (C-3), 145.9 (C-1), 162.5 (CO2CH3). HRMS (EI): m/z [M+] calcd. for C9H7BrN2O2: 253.9691; found: 253.9681.
- Methyl 6-bromopyrrolo[1,2-a]pyrazine-4-carboxylate (4j). In a round-bottom flask at 0 °C with a magnetic stirring bar, a solution of NBS (0.040 g, 0.23 mmol) in anhydrous CH2Cl2 (5.0 mL) was added dropwise to a solution of 4a (0.040 g, 0.23 mmol) in anhydrous CH2Cl2 (5.0 mL). The mixture was stirred at rt for 2.0 h before adding a 10% aqueous solution of NaHSO3 (1.0 mL). It was then washed with brine (3 × 5.0 mL), the organic phase was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 1:1) to obtain 4j (0.032 g, 55%) as a pale orange solid. Rf 0.32 (hexane/EtOAc, 1:1); mp 115–117 °C. IR (film): ῡ 3144, 2953, 1724, 1417, 1294, 1175, 957, 857, 773 cm−1. 1H NMR (600 MHz, CDCl3): δ 4.00 (s, 3H, CO2CH3), 7.03 (d, J = 2.4 Hz, 1H, H-8), 8.46 (s, 1H, H-3), 8.67 (dd, 1H, J = 2.4, 0.6 Hz, H-7), 8.92 (br s, 1H, H-1). 13C NMR (150 MHz, CDCl3): δ 52.6 (CO2CH3), 94.3 (C-6), 118.5 (C-8), 118.8 (C-7), 127.1 (C-4), 129.5 (C-8a), 135.2 (C-3), 147.2 (C-1), 162.8 (CO2CH3). HRMS (EI): m/z [M+] calcd. for C9H7BrN2O2: 253.9691; found: 253.9701.
- Methyl 6,7-dibromopyrrolo[1,2-a]pyrazine-4-carboxylate (4k). Following the method described for 4j, a mixture of 4a (0.030 g, 0.17 mmol) and NBS (0.063 g, 0.36 mmol) produced 4k (0.023 g, 40%) as an orange solid. Rf 0.61 (hexane/EtOAc, 1:1); mp 106–108 °C. IR (film): ῡ 3123, 2952, 2918, 2850, 1733, 1601, 1464, 1420, 1312, 1294, 1200, 1172, 1095, 862, 753 cm −1. 1H NMR (500 MHz, CDCl3): δ 4.02 (s, 3H, CO2CH3), 7.04 (s, 1H, H-8), 8.00 (s, 1H, H-3), 8.80 (s, 1H, H-1). 13C NMR (125 MHz, CDCl3): δ 53.0 (CO2CH3), 95.0 (C-6), 99.6 (C-7), 121.1 (C-4), 122.0 (C-8), 128.7 (C-8a), 133.1 (C-3), 145.8 (C-1), 161.6 (CO2CH3). HRMS (EI): m/z [M+] calcd. for C9H6N2O2Br2: 331.8796; found: 331.8792.
- Methyl (E)-3-(1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl)acrylate (10a). At 0 °C and under N2 atmosphere, NaH (60%, 0.032 g, 0.80 mmol) was added to a solution of 9a (0.100 g, 0.66 mmol) in anhydrous DMF (2.0 mL), and the mixture was stirred for 15 min. Then, 7a (0.124 g, 0.80 mmol) was added, and the solution was stirred at rt for 3 h. The reaction mixture was extracted with a hexane/EtOAc (1:1, 15.0 mL), the organic layer was washed with brine (5.0 mL × 3) and dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 9:1), resulting in 10a (0.088 g, 60%) as a white solid. Rf 0.32 (hexane/EtOAc, 7:3); mp 116–118 °C. IR (film): ῡ 2960, 1753, 1688, 1623, 1467, 1294, 1171, 1080, 987, 745 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.76 (s, 3H, =CHCO2CH3), 3.77 (s, 3H, CH2CO2CH3), 4.75 (s, 2H, CH2), 6.15 (d, J = 15.6 Hz, 1H, H-2), 6.24–6.26 (m, 1H, H-4′), 6.72 (dd, J = 3.8, 1.4 Hz, 1H, H-3′), 6.78 (br t, J = 1.4 Hz, 1H, H-5′), 7.43 (d, J = 15.6 Hz, 1H, H-3). 13C NMR (150 MHz, CDCl3): δ 48.2 (CH2), 51.5 (CH2CO2CH3), 52.7 (=CHCO2CH3), 110.4 (C-4′), 112.3 (C-3′), 113.5 (C-2), 126.8 (C-5′), 129.4 (C-2′), 131.5 (C-3), 167.9 (=CHCO2CH3), 168.4 (CH2CO2CH3). HRMS (EI): m/z [M+] calcd. for C11H13NO4: 223.0845; found: 223.0845.
- Methyl (E)-3-(5-formyl-1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl)acrylate (8i). At 0 °C and under N2 atmosphere, POCl3 (0.220 g, 1.44 mmol) was added to DMF (0.105 g, 1.44 mmol), and the mixture was stirred for 10 min. Subsequently, 10a (0.200 g, 0.90 mmol) in anhydrous CH2Cl2 (6.0 mL) was added dropwise, and the solution was stirred at 0 °C for 3 h. The reaction mixture was quenched with a 2N aqueous solution of NaOH until pH 8.0, and then CH2Cl2 (21.0 mL) was added. The mixture was washed with brine (7.0 mL × 3), the organic layer was dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 9:1) to furnish 8i (0.142 g, 63%) as a pale brown solid. Rf 0.67 (hexane/EtOAc, 1:1); mp 108–110 °C. IR (film): ῡ 2960, 1741, 1704, 1663, 1198, 1168, 980, 778 cm−1. 1H NMR (500 MHz, CDCl3): δ 3.75 (s, 3H, CH2CO2CH3), 3.77 (s, 3H, =CHCO2CH3), 5.24 (s, 2H, CH2), 6.41 (d, J = 15.8 Hz, 1H, H-2), 6.70 (d, J = 4.0 Hz, 1H, H-3′), 6.97 (d, J = 4.0 Hz, 1H, H-4′), 7.41 (d, J = 15.8 Hz, 1H, H-3), 9.53 (CHO). 13C NMR (125 MHz, CDCl3) δ 46.3 (CH2), 52.0 (CO2CH3), 52.8 (CO2CH3), 111.4 (C-3′), 121.1 (C-2), 124.6 (C-4′), 129.7 (C-3), 133.7 (C-5′), 137.7 (C-2′), 166.7 (=CHCO2CH3), 168.3 (CH2CO2CH3), 180.2 (CHO). HRMS (EI): m/z [M+] calcd. for C12H13NO5: 251.0794; found: 251.0785.
- Methyl (Z)-3-(dimethylamino)-2-(2-formyl-5-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-1H-pyrrol-1-yl)acrylate (11). Following the method described for 1b, a mixture of 8i (0.090 g, 0.36 mmol) and DMFDMA (0.213 g, 1.79 mmol) in anhydrous DMF (1.0 mL) afforded 11 (0.031 g, 28%) as a pale violet oil. Rf 0.16 (hexane/EtOAc, 1:1). IR (film): ῡ 2957, 1619, 1435, 1164, 1103, 1037, 762 cm−1. 1H NMR (750 MHz, CDCl3): δ 2.46 (br, 6H, N(CH3)2), 3.63 (s, 3H, CO2CH3-1), 3.78 (s, 3H, =CHCO2CH3), 6.41 (d, J = 16.1 Hz, 1H, H-2″), 6.74 (d, J = 3.8 Hz, 1H, H-4′), 7.05 (d, J = 3.8 Hz, 1H, H-3′) 7.41 (d, J = 16.1 Hz, 1H, H-1″), 7.67 (s, 1H, H-3), 9.61 (s, 1H, CHO). 13C NMR (187.5 MHz, CDCl3): δ 36.4 (br, N(CH3)2), 51.6 (CO2CH3-1), 51.8 (=CHCO2CH3), 93.4 (C-2), 111.2 (C-4′), 119.5 (C-2″), 120.6 (C-3′), 131.6 (C-1″), 136.8 (C-2′), 139.0 (C-5′), 147.4 (C-3), 166.8 (CO2CH3-1), 167.0 (=CHCO2CH3), 180.0 (CHO). HRMS (EI): m/z [M+] calcd. for C15H18N2O5: 306.1216; found: 306.1214.
- Methyl (E)-6-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolo[1,2-a]pyrazine-4-carboxylate (4l). Following method A described for 4a, a mixture of 11 (0.030 g, 0.10 mmol), NH4OAc (0.023 g, 0.30 mmol), and Li2CO3 (0.022 g, 0.30 mmol) was heated at 70 °C for 7 h to give 4l (0.015 g, 61%) as a yellow solid. Rf 0.25 (hexane/EtOAc, 1:1); mp 100–102 °C. IR (film): ῡ 2917, 2852, 1717, 1623, 1717, 1623, 1427, 1330, 1262, 1171, 1099, 1066 cm−1. 1H NMR (600 MHz, CDCl3): δ 3.82 (s, 3H, =CHCO2CH3), 4.04 (s, 3H, CO2CH3-4), 6.39 (d, J = 15.6 Hz, 1H, H-2′), 7.18 (d, J = 4.2 Hz, 1H, H-8), 7.35 (d, J = 4.2 Hz, 1H, H-7), 7.70 (d, J = 15.6 Hz, 1H, H-1′), 8.24 (s, 1H, H-3), 8.93 (br s, 1H, H-1). 13C NMR (187.5 MHz, CDCl3): δ 51.8 (=CHCO2CH3), 53.0 (CO2CH3-4), 108.5 (C-8), 115.9 (C-2′), 118.1 (C-7), 120.9 (C-4), 126.9 (C-6), 132.01 (C-8a), 133.3 (C-1′), 135.2 (C-3), 147.9 (C-1), 163.3 (CO2CH3-4), 167.1 (=CHCO2CH3). HRMS (EI): m/z [M+] calcd. for C13H12N2O4: 260.0797; found: 260.0795.
- Ethyl (E)-3-(1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl)acrylate (10c). Following the method described for 10a, a mixture of 9b (0.100 g, 0.60 mmol), NaH (60%, 0.029 g, 0.72 mmol), and 7a (0.110 g, 0.72 mmol) formed 10c (0.10 g, 70%) as a pale brown solid. Rf 0.67 (hexane/EtOAc, 1:1); mp 56–57 °C. IR (film): ῡ 2997, 2949, 1742, 1692, 1626, 1474, 1290, 1171, 1080, 983, 745 cm−1. 1H NMR (400 MHz, CDCl3): δ 1.31 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 3.77 (s, 3H, CO2CH3), 4.22 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.75 (s, 2H, CH2), 6.16 (d, J = 15.6 Hz, 1H, H-2), 6.26–6.26 (ddd, J = 4.0, 3.0, 0.8 Hz, 1H, H-4′), 6.71 (dd, J = 4.0, 1.4 Hz, 1H, H-3′), 6.78 (dd, J = 3.0, 1.4 Hz, 1H, H-5′), 7.44 (d, J = 15.6 Hz, 1H, H-3). 13C NMR (100 MHz, CDCl3): δ 14.3 (CO2CH2CH3), 48.2 (CH2), 52.7 (CO2CH3), 60.2 (CO2CH2CH3), 110.4 (C-4′), 112.1 (C-3′), 114.0 (C-2), 126.7 (C-5′), 129.4 (C-2′), 131.3 (C-3), 167.5 (CO2CH2CH3), 168.4 (CO2CH3). HRMS (EI): m/z [M+] calcd. for C12H15NO4: 237.1001; found: 237.1001.
- Methyl (Z)-3-(dimethylamino)-2-(2-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-1H-pyrrol-1-yl)acrylate (12a). Following the method described for 1b, a mixture of 10a (0.119 g, 0.53 mmol) and DMFDMA (0.318 g, 2.67 mmol) in anhydrous DMF (1.0 mL) provided 12a (0.134 g, 90%) as a pale violet oil. Rf 0.33 (hexane/EtOAc, 7:3). IR (film): ῡ 2949, 1690, 1615, 1308, 1208, 1164, 1103, 1079, 1034 cm−1. 1H NMR (400 MHz, CDCl3): δ 2.70 (br, 6H, N(CH3)2), 3.62 (s, 3H, =CHCO2CH3), 3.73 (s, 3H, CO2CH3-1), 6.15 (d, J = 15.8 Hz, 1H, H-2″), 6.23 (ddd, J = 3.7, 2.4, 0.4 Hz, 1H, H-4′), 6.78 (dd, J = 3.7, 1.5 Hz, 1H, H-3′), 6.71 (dd, J = 2.4, 1.5 Hz, H-5′), 7.37 (d, J = 15.8 Hz, 1H, H-1″), 7.57 (s, 1H, H-3). 13C NMR (100 MHz, CDCl3): δ 35.2 (N(CH3)2), 46.7 (N(CH3)2), 51.3 (CO2CH3-1), 51.5 (=CHCO2CH3), 96.3 (C-2), 110.1 (C-4′), 111.7 (C-3′), 112.5 (C-2″), 130.1 (C-5′), 132.3 (C-2′), 133.6 (C-1″), 147.1 (C-3), 167.6 (CO2CH3-1), 168.2 (=CHCO2CH3). HRMS (EI): m/z [M+] calcd. for C14H18N2O4: 278.1267; found: 278.1263.
- Ethyl (Z)-3-(dimethylamino)-2-(2-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrol-1-yl)acrylate (12b). In a MW glass vial equipped with a magnetic stirring bar and sealed with a cap, a mixture of 10b (0.300 g, 1.20 mmol) and tert-butoxy bis(dimethylamino)methane (0.625 g, 3.60 mmol) was heated at 125 °C for 2.0 h under MW irradiation (200 W) and a N2 atmosphere. The crude mixture was suspended and stirred in CH2Cl2/toluene (10:1, 11 mL), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 7:3), resulting in 12b (0.150 g, 41%) as a pale brown oil. Rf 0.52 (hexane/EtOAc, 1:1). IR (film): ῡ 2977, 1690, 1615, 1301, 1212, 1161, 1079, 1034 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.16 (t, J = 7.0 Hz, 3H, CO2CH2CH3), 1.29 (t, J = 7.0 Hz, 3H, CO2CH2CH3), 2.29 (br, 3H, N(CH3)2), 3.01 (br, 3H, N(CH3)2), 4.05–4.17 (m, 2H, CO2CH2CH3), 4.17–4.23 (m, 2H, CO2CH2CH3), 6.15 (d, J = 15.5 Hz, 1H, H-2″), 6.23 (dd, J = 4.0, 2.5 Hz, 1H, H-4′), 6.67 (dd, J = 4.0, 1.5 Hz, 1H, H-3′), 6.71 (dd, J = 2.5, 1.5 Hz, 1H, H-5′), 7.37 (d, J = 15.5 Hz, 1H, H-1″), 7.56 (s, 1H, H-3). 13C NMR (125 MHz, CDCl3): δ 14.4 (CO2CH2CH3), 14.5 (CO2CH2CH3), 38.6 (N(CH3)2), 59.98 (CO2CH2CH3), 60.03 (CO2CH2CH3), 96.3 (C-2), 110.0 (C-4′), 111.6 (C-3′), 112.7 (C-2″), 130.1 (C-5′), 132.4 (C-2′), 133.4 (C-1″), 146.9 (C-3), 167.2 (CO2CH2CH3-1), 168.9 (=CHCO2CH3). HRMS (EI): m/z [M+] calcd. for C16H22N2O4: 306.1580; found: 306.1573.
- Methyl (Z)-3-(dimethylamino)-2-(2-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrol-1-yl)acrylate (12c). Following the method described for 1b, a mixture of 10c (0.060 g, 0.25 mmol) and DMFDMA (0.151 g, 1.25 mmol) in anhydrous DMF (2.0 mL) afforded 12c (0.068 g, 92%) as a pale violet oil. Rf 0.48 (hexane/EtOAc, 1:1). IR (film): ῡ 2923, 1697, 1618, 1308, 1212, 1158, 1079, 1308, 1034 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.29 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.26 (br, 3H, N(CH3)2), 3.05 (br, 3H, N(CH3)2), 3.63 (s, 3H, CO2CH3), 4.20 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 6.15 (d, J = 16.0 Hz, 1H, H-2″), 6.24 (br d, J = 3.3 Hz, 1H, H-4′), 6.68 (br d, J = 3.3 Hz, 1H, H-3′), 6.71 (br t, J = 1.7 Hz, 1H, H-5′), 7.38 (d, J = 16.0 Hz, 1H, H-1″), 7.57 (s, 1H, H-3). 13C NMR (125 MHz, CDCl3): δ 14.4 (CO2CH2CH3), 35.0 (N(CH3)2), 47.4 (N(CH3)2), 51.5 (CO2CH3), 60.1 (CO2CH2CH3), 96.3 (C-2), 110.1 (C-4′), 111.6 (C-3′), 113.0 (C-2″), 130.1 (C-5′), 132.4 (C-2′), 133.3 (C-1″), 147.1 (C-3), 167.7 (CO2CH3), 167.8 (CO2CH2CH3). HRMS (EI): m/z [M+] calcd. for C15H20N2O4: 292.1423; found: 292.1414.
- Dimethyl indolizine-5,7-dicarboxylate (5a). At rt and under N2 atmosphere, a solution of AlCl3 (0.043 g, 0.321 mmol) in nitrobenzene (1.0 M) was added to a solution of 12a (0.030 g, 0.17 mmol) in anhydrous CH2Cl2 (5.0 mL). The mixture was stirred at rt for 2 h before adding CH2Cl2 (15 mL). It was then washed with brine (5.0 mL × 3) and dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (hexane/EtOAc, 9:1) to give 5a (0.024 g, 66%) as a yellow solid. Rf 0.80 (hexane/EtOAc, 1:1); mp 110–112 °C. IR (film): ῡ 2919, 1707, 1625, 1434, 1232, 1195, 1161, 1082, 758, 730 cm−1. 1H NMR (750 MHz, CDCl3): δ 3.94 (s, 3H, CO2CH3-5), 4.00 (s, 3H, CO2CH3-7), 6.95 (dd, J = 3.8, 0.9 Hz, 1H, H-1), 7.02 (dd, J = 3.8, 1.9 Hz, 1H, H-2), 8.17 (br d, J = 1.5 Hz, 1H, H-6), 8.41 (br d, J = 1.5 Hz, 1H, H-8), 8.84 (br s, 1H, H-3). 13C NMR (187.5 MHz, CDCl3): δ 52.2 (CO2CH3-7), 52.4 (CO2CH3-5), 107.6 (C-1), 116.0 (C-5), 116.7 (C-2), 118.0 (C-6), 119.4 (C-3), 123.0 (C-7), 127.2 (C-8), 133.5 (C-8a), 163.1 (CO2CH3-5), 165.9 (CO2CH3-7). HRMS (EI): m/z [M+] calcd. for C12H11NO4: 233.0688; found: 233.0687.
- Diethyl indolizine-5,7-dicarboxylate (5b). Following the method described for 5a, a mixture of 12b (0.060 g, 0.20 mmol) and AlCl3 (0.078 g, 0.39 mmol) in anhydrous CH2Cl2 (2.0 mL) was stirred at rt for 2h. After the further addition of AlCl3 (0.078 g, 0.39 mmol), the mixture was stirred for 2 h to obtain 5b (0.016 g, 31%) as a yellow solid. Rf 0.81 (hexane/EtOAc, 7:3); mp 55–57 °C. IR (film): ῡ 2923, 2851, 1707, 1226, 1198, 1182, 1024 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.42 (t, J = 7.0 Hz, 3H, CO2CH2CH3), 1.45 (t, J = 7.0 Hz, 3H, CO2CH2CH3), 4.39 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 4.46 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 6.94 (br d, J = 4.0 Hz, 1H, H-1), 7.02 (dd, J = 4.0, 3.0 Hz, 1H, H-2), 8.17 (d, J = 1.5 Hz, 1H, H-6), 8.41 (d, J = 1.5 Hz, 1H, H-8), 8.85 (br s, 1H, H-3). 13C NMR (125 MHz, CDCl3): δ 14.33 (CO2CH2CH3), 14.41 (CO2CH2CH3), 61.1 (CO2CH2CH3), 61.6 (CO2CH2CH3), 107.4 (C-1), 116.4 (C-5), 116.6 (C-2), 117.8 (C-6), 119.4 (C-3), 123.2 (C-7), 127.0 (C-8), 133.5 (C-8a), 162.7 (CO2Et), 165.6 (CO2Et). HRMS (EI): m/z [M+] calcd. for C12H11NO4: 233.0688; found: 233.0687.
- 7-Ethyl 5-methyl indolizine-5,7-dicarboxylate (5c). Following the method described for 5a, a mixture of 12c (0.030 g, 0.10 mmol) and AlCl3 (0.028 g, 0.20 mmol) in anhydrous CH2Cl2 (2.0 mL) furnished 5c (0.013 g, 52%) as a yellow solid. Rf 0.87 (hexane/EtOAc, 1:1); mp 133–135 °C. IR (film): ῡ 2987, 1704, 1256, 1232, 1198, 1168, 1018, 751 cm−1. 1H NMR (600 MHz, CDCl3): δ 1.42 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 4.00 (s, 3H, CO2CH3), 4.40 (q, J = 7.2 Hz, 2H, CO2CH2CH3), 6.94 (br d, J = 4.2 Hz, 1H, H-1), 7.02 (dd, J = 4.2, 2.0 Hz, 1H, H-2), 8.16 (br d, J = 1.8 Hz, H-6), 8.41 (s, 1H, H-8), 8.84 (br s, 1H, H-3). 13C NMR (150 MHz, CDCl3): δ 14.4 (CO2CH2CH3), 52.4 (CO2CH3), 61.1 (CO2CH2CH3), 107.5 (C-1), 116.4 (C-5), 116.6 (C-2), 118.1 (C-6), 119.4 (C-3), 123.0 (C-7), 127.1 (C-8), 133.5 (C-8a), 163.1 (CO2CH3), 165.5 (CO2CH2CH3). HRMS (EI): m/z [M+] calcd. for C13H13NO4: 247.0845; found: 247.0840.
3.3. Evaluation of Antifungal Activity
3.4. Docking Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Entry | 1–3 | Z | T (°C) | t (h) | 4 (%) b |
---|---|---|---|---|---|
1 | 1a | CO2Me | 70 | 4 | 4a (90) |
2 | 1b | CO2Et | 80 | 3 | 4b (66) |
3 | 2a | COPh | 80 | 3 | 4c (87) |
4 | 2b | COC6H4-3-OMe | 70 | 4 | 4d (83) |
5 | 2c | COC6H4-4-OMe | 70 | 4 | 4e (84) |
6 | 2d | COC6H3-3,4-(OMe)2 | 70 | 4 | 4f (60) |
7 | 3a | CN | 70 | 4 | 4g (53) |
Compound | C. albicans | C. glabrata | C. dubliniensis | C. krusei | C. auris | C. haemulonii | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
MIC50 | MIC70 | MIC50 | MIC70 | MIC50 | MIC70 | MIC50 | MIC70 | MIC50 | MIC70 | MIC50 | MIC70 | |
µg/mL | µg/mL | µg/mL | µg/mL | µg/mL | µg/mL | |||||||
fluconazole | 1.40 | 1.80 | 5.60 | 7.20 | 1.40 | 1.80 | 5.60 | 7.20 | >44.8 | >57.6 | >44.8 | >57.6 |
simvastatin | 1.25 | 1.75 | 15.00 | 21.00 | 1.25 | 1.75 | 40.00 | 56.00 | 10.00 | 14.00 | 20.00 | 28.00 |
atorvastatin | 3.77 | 5.27 | 1.71 | 2.39 | 2.77 | 3.87 | 4.80 | 6.72 | 15.3 | 21.42 | 8.00 | 11.20 |
1a | 0.11 | 0.15 | 0.09 | 0.12 | 0.07 | 0.09 | 0.05 | 0.07 | 4.17 | 5.83 | 4.45 | 6.23 |
1c | 4.20 | 5.88 | 0.65 | 0.91 | 4.00 | 5.60 | 0.36 | 0.50 | 2.59 | 3.62 | 2.00 | 2.80 |
2a | 0.13 | 0.18 | 0.09 | 0.12 | 0.06 | 0.08 | 0.03 | 0.04 | 5.57 | 7.79 | 3.74 | 5.23 |
2b | 0.13 | 0.18 | 0.11 | 0.15 | 0.07 | 0.09 | 0.05 | 0.07 | 5.31 | 7.43 | 5.20 | 7.28 |
2c | 0.10 | 0.14 | 0.07 | 0.09 | 0.06 | 0.08 | 0.06 | 0.08 | 4.50 | 6.30 | 4.45 | 6.23 |
2d | 0.12 | 0.16 | 0.12 | 0.16 | 0.09 | 0.12 | 0.04 | 0.06 | 4.68 | 6.55 | 12.48 | 17.47 |
4a | 0.18 | 0.25 | 1.56 | 2.18 | 0.73 | 1.02 | 0.20 | 0.28 | 5.85 | 8.19 | 11.70 | 16.30 |
4b | 0.15 | 0.21 | 0.11 | 0.15 | 0.07 | 0.09 | 0.09 | 0.12 | 3.07 | 4.29 | 3.90 | 5.46 |
4c | 0.33 | 0.46 | 0.15 | 0.21 | 0.09 | 0.12 | 0.01 | 0.02 | 1.46 | 2.04 | 18.72 | 26.20 |
4d | 0.45 | 0.63 | 0.12 | 0.16 | 0.16 | 0.22 | 0.18 | 0.36 | 1.62 | 2.25 | 11.70 | 16.38 |
4e | 0.33 | 0.46 | 0.13 | 0.18 | 0.36 | 0.50 | 0.18 | 0.36 | 1.46 | 2.04 | 7.80 | 10.92 |
4f | 0.18 | 0.25 | 0.16 | 0.22 | 0.09 | 0.12 | 0.36 | 0.50 | 10.63 | 14.88 | 11.70 | 16.38 |
4g | 0.07 | 0.09 | 0.18 | 0.25 | 0.09 | 0.12 | 0.14 | 0.19 | 6.15 | 8.61 | 6.88 | 9.63 |
4h | 0.23 | 0.32 | 0.12 | 0.16 | 0.09 | 0.12 | 0.12 | 0.16 | 2.20 | 3.08 | 4.92 | 6.88 |
4i | 0.08 | 0.11 | 0.15 | 0.21 | 0.01 | 0.02 | 0.28 | 0.39 | 11.68 | 16.35 | 11.68 | 16.35 |
4j | 0.22 | 0.30 | 0.11 | 0.15 | 0.22 | 0.04 | 0.05 | 0.07 | 11.68 | 16.35 | 11.68 | 16.35 |
4k | 0.10 | 0.14 | 0.08 | 0.11 | 0.07 | 0.09 | 0.18 | 0.36 | 3.90 | 5.46 | 18.72 | 26.20 |
4l | 0.04 | 0.05 | 0.11 | 0.15 | 0.06 | 0.08 | 0.04 | 0.06 | 5.57 | 7.79 | 4.92 | 6.88 |
5a | 0.25 | 0.17 | 0.12 | 0.16 | 0.12 | 0.16 | 0.12 | 0.16 | 4.00 | 5.60 | 3.12 | 4.36 |
5b | 0.50 | 0.70 | 1.82 | 2.54 | 1.58 | 2.21 | 4.00 | 5.60 | 3.10 | 4.34 | 2.55 | 3.57 |
5c | 0.50 | 0.70 | 2.00 | 2.80 | 2.45 | 3.43 | 0.45 | 0.63 | 2.60 | 3.64 | 3.24 | 4.53 |
8a | 0.10 | 0.14 | 0.24 | 0.33 | 0.03 | 0.04 | 0.06 | 0.08 | 1.46 | 2.04 | 7.20 | 10.08 |
8b | 0.19 | 0.26 | 0.12 | 0.16 | 0.14 | 0.19 | 0.06 | 0.08 | 2.96 | 4.14 | 18.72 | 26.20 |
8c | 0.07 | 0.09 | 0.10 | 0.14 | 0.07 | 0.09 | 0.04 | 0.06 | 8.35 | 11.69 | 11.70 | 16.38 |
8d | 0.20 | 0.28 | 0.03 | 0.04 | 0.05 | 0.07 | 0.05 | 0.07 | 6.15 | 8.61 | 11.70 | 16.38 |
8e | 0.28 | 0.39 | 0.09 | 0.12 | 0.06 | 0.08 | 0.04 | 0.06 | 9.00 | 12.60 | 10.63 | 14.88 |
8f | 0.20 | 0.28 | 0.05 | 0.07 | 0.05 | 0.07 | 0.05 | 0.07 | 4.68 | 6.55 | 10.63 | 14.88 |
8g | 0.12 | 0.16 | 0.08 | 0.11 | 0.16 | 0.22 | 0.04 | 0.06 | 5.57 | 7.79 | 16.71 | 23.39 |
8h | 4.00 | 5.60 | 0.82 | 1.14 | 2.43 | 3.40 | 1.00 | 1.40 | 2.38 | 3.33 | 2.27 | 3.17 |
8i | 0.14 | 0.19 | 0.45 | 0.63 | 0.32 | 0.44 | 0.20 | 0.28 | 6.88 | 9.63 | 10.63 | 14.88 |
10a | 0.50 | 0.70 | 0.50 | 0.70 | 0.55 | 0.77 | 0.88 | 1.23 | 3.57 | 4.99 | 4.00 | 5.60 |
10b | 0.58 | 0.81 | 0.26 | 0.36 | 4.00 | 5.60 | 4.66 | 6.52 | 2.82 | 3.94 | 2.38 | 3.33 |
10c | 3.74 | 5.23 | 1.42 | 1.98 | 1.08 | 1.51 | 1.02 | 1.42 | 2.56 | 3.58 | 2.30 | 3.22 |
11 | 0.18 | 0.25 | 0.84 | 1.17 | 0.73 | 1.02 | 0.16 | 0.22 | 4.87 | 6.81 | 5.85 | 8.19 |
12a | 0.10 | 0.14 | 0.13 | 0.18 | 0.10 | 0.70 | 0.14 | 0.19 | 4.00 | 5.60 | 2.00 | 2.80 |
12b | 0.12 | 0.17 | 0.91 | 1.27 | 2.14 | 2.99 | 0.88 | 1.20 | 2.80 | 3.92 | 2.27 | 3.17 |
12c | 1.77 | 2.47 | 0.85 | 1.19 | 2.38 | 3.33 | 1.30 | 1.82 | 2.85 | 3.99 | 2.70 | 3.78 |
Compound | HMGR Enzymes of Candida spp. | |||||
---|---|---|---|---|---|---|
C. albicans | C. glabrata | C. dubliniensis | C. krusei | C. auris | C. haemulonii | |
simvastatin | −6.12 | −6.30 | −6.57 | −6.06 | −6.51 | −6.18 |
atorvastatin | −3.82 | −4.63 | −4.64 | −4.97 | −2.14 | −4.66 |
1a | −6.21 | −5.26 | −5.42 | −6.55 | −5.47 | −5.34 |
2a | −7.19 | −7.48 | −8.00 | −8.73 | −8.34 | −6.89 |
2c | −7.14 | −6.34 | −8.05 | −6.88 | −7.98 | −7.35 |
4b | −6.41 | −5.53 | −5.74 | −7.02 | −5.69 | −7.01 |
4g | −5.74 | −5.18 | −5.18 | −6.07 | −5.18 | −6.22 |
4l | −7.70 | −6.44 | −6.48 | −7.58 | −7.31 | −6.43 |
5a | −7.22 | −6.65 | −6.73 | −7.04 | −6.71 | −5.57 |
8a | −5.33 | −4.74 | −4.49 | −5.55 | −5.55 | −5.92 |
8c | −8.24 | −6.77 | −6.81 | −8.32 | −7.06 | −7.49 |
8g | −5.21 | −5.00 | −4.56 | −5.28 | −4.93 | −5.58 |
10a | −6.42 | −5.88 | −5.92 | −6.52 | −6.11 | −4.93 |
12a | −7.09 | −7.20 | −7.15 | −5.42 | −6.70 | −5.50 |
Compound | Residues of the Enzyme Interacting with the Ligand | Polar Interactions | Hydrophobic Interactions |
---|---|---|---|
simvastatin | Ala62, Thr95, Glu96, Gly97, Cys98, Arg127, Met192, Met194, Asn195, Asp227, Lys228, Gly302, Gln303, Asp304, Gln307, Gly343, Gly344 | Asp227, Lys228, Asp304 | - |
atorvastatin | Thr95, Glu96, Gly97, Met192, Met194, Asn195, Asp227, Lys228, Asn292, His289, Gly302, Gln303, Asp304, Gln307, Gly342, Gly343, Gly344, Leu389 | Asn195, Asp304 | Glu96, Met192, Met194, Lys228, Asp304 |
1a | Ala62, Cys63, Thr95, Glu96, Gly97, Met192, Gly302, Gln303, Asp304, Pro305, Gly343, Gly344 | Asp304 | Cys63, Glu96 |
2a | Glu96, Leu99, Arg127, Met194, Asn195, Ser221, Asp227, Lys228, Lys272, Ala288, His289, Ans292, Leu389 | Asp227, Lys228, Asn292 | Glu96, Met194, His289, Leu389 |
2c | Thr95, Glu96, Met192, Met194, Asn195, Asp227, Lys228, Gln303, Asp304, Pro305, Gly344 | Lys228 | Met192, Met194 |
4b | Thr95, Glu96, Met192, Gly302, Gln303, Asp304, Gln307, Glu337, Val338, Gly339, Ile341, Gly342, Gly343, Gly344, Thr345 | Gly339, Ile341, Gly344 | Met192, Asp304, Gly342, Gly343 |
4g | Leu73, Ala93, Thr94, Thr95, Glu96, Thr295, Ala 296, Leu299, Gln303, Asp304, Pro305 | Thr95 | Ala296, Pro305 |
4l | Leu73, Ala93, Thr94, Thr95, Glu96, Leu99, Asn292, Thr295, Ala296, Leu299, Gly302, Gln303, Asp304, pro305, Gly344 | Ala93, Thr94 | Leu73, Thr94, Ala296, Leu299, Pro305 |
5a | Thr95, Glu96, Met192, Met194, Asn195, Gly302, Gln303, Asp304, Gly339, Ile341, Gly342, Gly343, Gly344, Thr345 | Thr95, Asn195, Gly302, Gly343, Gly344 | Met192, Gly339, Gly342, Thr345 |
8a | Thr95, Glu96, Met192, Gly302, Gln303, Asp304, Gln307, Glu337, Val338, Gly339, Ile341 Gly342, Gly343, Gly344, Thr345 | Asp304, Thr95, Val338, Gly344 | Met192 |
8c | Thr95, Glu96, Met192, Met194, Asn195, Lys228, Gly302, Gln303, Asp304, Gly339, Ile341 Gly342, Gly343, Gly344, Thr345 | Thr95, Gly344 | Glu96, Met192 |
8g | Thr94, Thr95, Ala93, Glu96, Leu99, Asn292, Thr295, Ala296, Gln303, Pro305 | Thr94, Thr95, Thr295 | Ala296, Pro305 |
10a | Leu73, Ala93, Thr94, Thr95, Glu96, Leu99, Asn292, Thr295, Ala296, Leu299, Gln303, Asp304, Pro305, Ala306 | Asn292, Thr295, Asp304 | Leu73, Thr94, Ala296, Leu299, Pro305 |
12a | Ala62, Thr95, Glu96, Gly97, Met192, Gly193, Met194, Asn195, Gly302, Gln303, Asp304, Ile341, Gly342, Gly343, Gly344 | Ala62, Gly97, Ile341 | Met192, Met194 |
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Miranda-Sánchez, D.; Escalante, C.H.; Andrade-Pavón, D.; Gómez-García, O.; Barrera, E.; Villa-Tanaca, L.; Delgado, F.; Tamariz, J. Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity. Molecules 2023, 28, 7223. https://doi.org/10.3390/molecules28207223
Miranda-Sánchez D, Escalante CH, Andrade-Pavón D, Gómez-García O, Barrera E, Villa-Tanaca L, Delgado F, Tamariz J. Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity. Molecules. 2023; 28(20):7223. https://doi.org/10.3390/molecules28207223
Chicago/Turabian StyleMiranda-Sánchez, Diter, Carlos H. Escalante, Dulce Andrade-Pavón, Omar Gómez-García, Edson Barrera, Lourdes Villa-Tanaca, Francisco Delgado, and Joaquín Tamariz. 2023. "Pyrrole-Based Enaminones as Building Blocks for the Synthesis of Indolizines and Pyrrolo[1,2-a]pyrazines Showing Potent Antifungal Activity" Molecules 28, no. 20: 7223. https://doi.org/10.3390/molecules28207223