Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane
Abstract
:1. Introduction
2. Results
2.1. Synthesis
2.2. Antimicrobial Activity In Vitro
2.3. The Preliminary Structure–Activity Relationships
2.4. Molecular Docking Studies
3. Materials and Methods
3.1. Chemistry
3.2. General Synthesis Procedure for Intermediate B
3.3. General Synthesis Procedure for Intermediate C
3.4. General Synthesis Procedure for Intermediate D
3.5. General Synthesis Procedure for Intermediate E
3.6. General Synthesis Procedure for F1–F53
- 2-(2-Bromophenyl)-N-cyclopropylcyclopropane-1-carboxamide (F1): White solid, Yield: 68.9%, m.p. 119.2–120.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 4.2 Hz, 1H, H-N), 7.59 (dd, J = 8.0, 1.3 Hz, 1H), 7.33–7.29 (m, 1H), 7.17–7.13 (m, 1H), 7.08 (dd, J = 7.8, 1.7 Hz, 1H, Ar-H), 2.68–2.64 (m, 1H), 2.42–2.39 (m, 1H, H-2), 1.74–1.65 (m, 1H, H-1), 1.35–1.32 (m, 1H, H-3), 1.26–1.23 (m, 1H, H-3), 0.64–0.59 (m, 2H), 0.48–0.35 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 172.33 (C=O), 139.75, 132.29, 128.23,127.91, 127.14, 125.11, 24.52, 24.47, 22.49, 13.97, 5.84, 5.78. HRMS (ESI) m/z [M + Na]+ calcd for C13H14BrNNaO: 302.0151, found: 302.0160.
- 2-(2-Bromophenyl)-N-cyclobutylcyclopropane-1-carboxamide (F2): White solid, Yield: 73.3%, m.p. 135.4–136.7 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 7.8 Hz, 1H, H-N), 7.60 (dd, J = 8.0, 1.3 Hz, 1H), 7.38–7.26 (m, 1H),7.19–7.10 (m, 1H), 7.08 (dd, J = 7.8, 1.7 Hz, 1H), 4.28–4.17 (m, 1H), 2.44–2.34 (m, 1H, H-2), 2.20–2.12 (m, 2H), 1.94–1.80 (m, 2H), 1.75–1.71 (m, 1H, H-1), 1.65–1.56 (m, 2H), 1.36–1.27 (m, 1H, H-3), 1.25–1.21 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.66 (C=O), 139.78, 132.29, 128.20, 127.92, 127.08, 125.06, 44.05, 30.49, 24.58, 24.35, 14.64, 14.05. HRMS (ESI) m/z [M + H]+ calcd for C14H17BrNO, 294.0488, found: 294.0499.
- 2-(2-Bromophenyl)-N-cyclopentylcyclopropane-1-carboxamide (F3): White solid, Yield: 70.7%, m.p. 164.0–165.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 7.3 Hz, 1H, H-N), 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.33–7.29 (m, 1H), 7.17–7.13 (m, 1H), 7.08 (dd, J = 7.7, 1.7 Hz, 1H), 4.08–3.99 (m, 1H), 2.41–2.36 (m, 1H, H-2), 1.86–1.73 (m, 3H), 1.67–1.58 (m, 2H), 1.55–1.44 (m, 2H), 1.43–1.30 (m, 3H), 1.24–1.20 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.10 (C=O), 139.89, 132.26, 128.14, 127.88, 127.05, 125.10, 50.44, 32.48, 32.36, 24.61, 24.31, 23.43, 23.40, 13.85. HRMS (ESI) m/z [M + H]+ calcd for C15H19BrNO: 308.0645, found: 308.0654.
- 2-(2-Bromophenyl)-N-cyclohexylcyclopropane-1-carboxamide (F4): White solid, Yield: 76.0%, m.p. 166.0–167.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.9 Hz, 1H, H-N), 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.33–7.29 (m, 1H), 7.17–7.13 (m, 1H), 7.08 (dd, J = 7.8, 1.7 Hz, 1H), 3.62–3.51 (m, 1H), 2.41–2.36 (m, 1H, H-2), 1.87–1.66 (m, 5H), 1.56–1.52 (m, 1H), 1.34–1.30 (m, 1H, H-3),1.28–1.20 (m, 3H), 1.19–1.08 (m, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.71 (C=O), 139.90, 132.25, 128.14, 127.87, 127.07, 125.16, 47.59, 32.63, 32.56, 25.26, 24.65, 24.54, 24.39, 13.82. HRMS (ESI) m/z [M + H]+ calcd for C16H21BrNO: 322.0801, found: 322.0810.
- 2-(2-Bromophenyl)-N-(p-tolyl)cyclopropane-1-carboxamide (F5): White solid, Yield: 61.5%, m.p. 160.8–162.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H, H-N), 7.88 (dd, J = 8.3, 1.2 Hz, 1H), 7.78–7.71 (m, 2H), 7.63–7.58 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.39–7.32 (m, 2H), 2.82–2.79 (m, 1H, H-2), 2.78–2.75 (m, 3H), 2.28–2.19 (m, 1H, H-1), 1.74–1.63 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ169.54 (C=O), 139.48, 136.79, 132.31, 131.98, 129.15, 128.37, 127.94, 127.30, 125.20, 118.37, 25.48, 25.31, 20.45, 14.36. HRMS (ESI) m/z [M + H]+ calcd for C17H17BrNO: 330.0488, found: 330.0498.
- 2-(2-Bromophenyl)-N-(m-tolyl)cyclopropane-1-carboxamide (F6): White solid, Yield: 68.1%, m.p. 190.4–191.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H, H-N), 7.64 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.21–7.14 (m, 4H), 7.07 (t, J = 7.4 Hz, 1H), 2.23 (s, 3H), 2.13–2.07 (m, 1H, H-1), 1.50–1.38 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.90 (C=O), 139.57, 136.40, 132.31, 131.31, 130.31, 128.40, 127.94, 127.46, 125.96, 125.39, 125.01, 124.79, 25.45, 24.91, 17.93, 13.98. HRMS (ESI) m/z [M + H]+ calcd for C17H17BrNO: 330.0488, found: 330.0497.
- 2-(2-Bromophenyl)-N-(o-tolyl)cyclopropane-1-carboxamide (F7): Pale yellow solid, Yield: 66.7%, m.p. 188.9–190.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H, H-N), 7.63 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21–7.14 (m, 4H), 7.07 (t, J = 7.5 Hz, 1H), 2.23 (s, 3H), 2.16–2.04 (m, 1H, H-1), 1.49–1.41 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.94 (C=O), 139.59, 136.42, 132.32, 131.33, 130.33, 128.40, 127.95, 127.48, 125.98, 125.42, 125.02, 124.82, 25.49, 24.93, 17.96, 14.01. HRMS (ESI) m/z [M + H]+ calcd for C17H17BrNO: 330.0488, found: 330.0498.
- Ethyl 4-(2-(2-bromophenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate (F8): Pale yellow oil, Yield: 78.7%. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 7.9, 1.3 Hz, 1H), 7.34–7.30 (m, 1H), 7.22–7.14 (m, 2H), 4.08–4.03 (m, 2H), 3.66 (d, J = 5.5 Hz, 2H), 3.56–3.46 (m, 2H), 3.42–3.40 (m, 2H), 3.36 (d, J = 4.0 Hz, 2H), 2.48–2.43 (m, 1H, H-2),2.25–2.14 (m, 1H, H-1), 1.49–1.38 (m, 1H, H-3), 1.45–1.40 (m, 1H, H-3), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.70 (C=O), 154.62, 139.50, 132.23, 128.32, 127.83, 127.79, 125.34, 60.93, 44.78, 43.59, 43.25, 41.46, 25.86, 20.68, 15.01, 14.56. HRMS (ESI) m/z [M+Na]+ calcd for C17H21BrN2NaO3: 403.0628, found: 403.0636.
- 2-(2-bromophenyl)-N-(thiazol-2-yl)cyclopropane-1-carboxamide (F9): White solid, Yield: 71.3%, m.p. 161.7–163.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H, NH, H-N), 7.63 (d, J = 6.3 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.29–7.12 (m, 3H), 2.67–2.54 (m, 1H, H-2), 2.19–2.12 (m, 1H, H-1), 1.56–1.52 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.00 (C=O), 157.82, 138.87, 137.64, 132.33, 128.69, 127.96, 127.81, 125.45, 113.47, 26.64, 23.98, 14.99. HRMS (ESI) m/z [M + H]+ calcd for C13H12BrN2OS: 322.9848, found: 322.9857.
- N-cyclopropyl-2-(p-tolyl)cyclopropane-1-carboxamide (F10): White solid, Yield: 51.6%, m.p. 153.7–155.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 7.9 Hz, 1H, H-N), 7.06 (d, J = 7.7 Hz, 2H), 6.98 (d, J = 7.7 Hz, 2H), 2.67–2.60 (m, 1H, H-2), 2.24 (s, 3H), 2.19–2.17 (m, 1H, H-1), 1.75–1.64 (m, 1H, H-3), 1.34–1.21 (m, 1H, H-3), 1.17–1.05 (m, 1H), 0.64–0.55 (m, 2H), 0.42–0.35 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 172.48 (C=O), 138.47, 135.36, 129.33, 126.15, 25.91, 24.00, 22.89, 21.04, 15.54, 6.18, 6.14. HRMS (ESI) m/z [M + H]+ calcd for C14H18NO: 216.1383, found: 216.1384.
- N-cyclobutyl-2-(p-tolyl)cyclopropane-1-carboxamide (F11): White solid, Yield: 58.8%, m.p. 165.2–165.7 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.8 Hz, 1H, H-N), 7.06 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 7.7 Hz, 2H), 4.26–4.16 (m, 1H), 2.24 (s, 3H), 2.16–2.10 (m, 3H), 1.90–1.80 (m, 2H), 1.75–1.71 (m, 1H), 1.65–1.50 (m, 2H), 1.30–1.22 (m, 1H, H-3), 1.12 (t, J = 7.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.26 (C=O), 138.49, 135.35, 129.33, 126.15, 44.39, 31.00, 30.92, 25.97, 23.94, 21.04, 15.50, 15.04. HRMS (ESI) m/z [M+Na]+ calcd for C15H19NNaO: 252.1359, found: 252.1367.
- N-cyclopentyl-2-(p-tolyl)cyclopropane-1-carboxamide (F12): Yellow solid, Yield: 50.6%, m.p. 176.1–176.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.3 Hz, 1H, H-N), 7.06 (d, J = 7.2 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 4.05–3.94 (m, 1H), 2.24 (s, 3H), 2.18–2.13 (m, 1H, H-1), 1.85–1.71 (m, 3H), 1.66–1.55 (m, 2H), 1.48 (s, 2H), 1.39–1.24 (m, 3H), 1.14–1.04 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.38 (C=O), 138.19, 134.90, 128.91, 125.71, 50.44, 32.54, 32.36, 25.57, 23.42, 20.63, 15.18. HRMS (ESI) m/z [M+Na]+ calcd for C16H21NNaO: 266.1515, found: 266.1523.
- N-cyclohexyl-2-(p-tolyl)cyclopropane-1-carboxamide (F13): White solid, Yield: 63.4%, m.p. 186.7–188.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 7.6 Hz, 1H, H-N), 7.07 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 3.62–3.45 (m, 1H), 2.24 (s, 3H), 2.17–2.09 (m, 1H, H-1), 1.90–1.59 (m, 5H), 1.53 (d, J = 11.3 Hz, 1H), 1.33–1.19 (m, 3H), 1.17–0.96 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.88 (C=O), 138.17, 134.85, 128.86, 125.67, 47.57, 32.64, 32.54, 25.53, 25.24, 24.55, 23.36, 20.59, 15.18. HRMS (ESI) m/z [M + H]+ calcd for C17H24NO: 258.1852, found: 258.1860.
- N,2-di-p-tolylcyclopropane-1-carboxamide (F14): White solid, Yield: 55.1%, m.p. 174.1–176.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, H-N), 7.47 (d, J = 7.9 Hz, 2H), 7.08 (dd, J = 11.0, 6.6 Hz, 6H), 2.35–2.28 (m, 1H, H-2), 2.26 (s, 3H), 2.24 (s, 3H), 2.04–1.97 (m, 1H, H-1), 1.46–1.43 (m, 1H, H-3), 1.31–1.26 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.71 (C=O), 137.75, 136.82, 135.10, 131.87, 129.11, 128.92, 125.82, 118.89, 26.47, 24.48, 20.61, 20.44, 15.47. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO: 266.1539, found: 266.1546.
- N-(m-tolyl)-2-(p-tolyl)cyclopropane-1-carboxamide (F15): White solid, Yield: 56.4%, m.p. 163.9–165.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, H-N), 7.48 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.14–7.03 (m, 6H), 2.31 (d, J = 3.5 Hz, 1H, H-2), 2.27 (s, 3H), 2.18–2.11 (m, 4H), 1.44–1.40 (m, 1H, H-3), 1.32–1.21 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.11 (C=O), 137.88, 136.47, 135.10, 131.02, 130.32, 128.95, 125.94, 125.86, 124.87, 124.59, 25.84, 24.37, 20.64, 17.92, 15.71. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO: 266.1539, found: 266.1548.
- N-(o-tolyl)-2-(p-tolyl)cyclopropane-1-carboxamide (F16): White solid, Yield: 58.8%, m.p. 165.1–166.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, H-N), 7.48 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.14–7.03 (m, 6H), 2.35–2.29 (m, 1H, H-2), 2.27 (s, 3H), 2.20 (s, 4H), 1.45–1.40 (m, 1H, H-3), 1.31–1.22 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.77 (C=O), 137.86, 136.86, 135.08, 131.00, 130.30, 128.93, 125.92, 125.84, 124.85, 124.56, 25.81, 24.36, 20.62, 17.90, 15.68. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO: 266.1539, found: 266.1548.
- N-(thiazol-2-yl)-2-(p-tolyl)cyclopropane-1-carboxamide (F17): Pale yellow solid, Yield: 55.3%, m.p. 188.9–190.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H, H-N), 7.45 (d, J = 3.5 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H), 7.11–7.01 (m, 4H), 2.45–2.40 (m, 1H, H-2), 2.26 (s, 3H), 2.21–2.16 (m, 1H), 1.54–1.49 (m, 1H, H-3), 1.46–1.38 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.12 (C=O), 158.00, 137.64, 137.08, 135.44, 129.02, 126.03, 113.41, 25.72, 25.11, 20.64, 16.23. HRMS (ESI) m/z [M + H]+ calcd for C14H15N2OS: 259.0900, found: 259.0908.
- N-cyclopropyl-2-(4-methoxyphenyl)cyclopropane-1-carboxamide (F18): White solid, Yield: 54.8%, m.p. 158.1–160.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 4.2 Hz, 1H, H-N), 7.08–6.94 (m, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.70 (s, 3H), 2.68–2.54 (m, 1H, H-2), 2.23–2.15 (m, 1H, H-1), 1.69–1.65 (m, 1H, H-3), 1.30–1.20 (m, 1H, H-3), 1.15–0.98 (m, 1H), 0.62–0.53 (m, 2H), 0.43–0.25 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 172.11 (C=O), 157.64, 132.87, 126.90, 113.78, 55.06, 25.31, 23.22, 22.44, 14.88, 5.74, 5.69. HRMS (ESI) m/z [M + H]+ calcd for C14H18NO2: 232.1332, found: 232.1339.
- N-cyclobutyl-2-(4-methoxyphenyl)cyclopropane-1-carboxamide (F19): White solid, Yield: 72.2%, m.p. 188.3–189.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.9 Hz, 1H, H-N), 7.03 (d, J = 8.4 Hz, 2H), 6.92–6.74 (m, 2H), 4.26–4.12 (m, 1H), 3.71 (s, 3H), 2.21–2.06 (m, 3H), 1.90–1.80 (m, 2H), 1.71–1.65 (m, 1H), 1.63–1.54 (m, 2H), 1.28–1.24 (m, 1H, H-3), 1.11–1.07 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 169.89 (C=O), 157.64, 132.89, 126.89, 113.78, 55.06, 43.94, 30.56, 30.48, 25.36, 23.16, 14.84, 14.58. HRMS (ESI) m/z [M + H]+ calcd for C15H20NO2): 246.1489, found: 246.1495.
- N-cyclopentyl-2-(4-methoxyphenyl)cyclopropane-1-carboxamide (F20): White solid, Yield: 69.6%, m.p. 194.6–196.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.10–7.93 (m, 1H, H-N), 7.16–7.01 (m, 2H), 6.85–6.81 (m, 2H), 4.08–3.93 (m, 1H), 3.78–3.65 (m, 3H), 2.17–2.12 (m, 1H, H-2), 1.86–1.69 (m, 3H), 1.67–1.56 (m, 2H), 1.54–1.42 (m, 2H), 1.38–1.32 (m, 2H), 1.26 (dd, J = 9.2, 3.8 Hz, 1H), 1.09–1.04 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.39 (C=O), 157.62, 133.02, 126.86, 113.78, 55.06, 50.39, 32.52, 32.33, 25.37, 23.39, 23.02, 14.92. HRMS (ESI) m/z [M+Na]+ calcd for C16H21NNaO2: 282.1465, found: 282.1474.
- N-cyclohexyl-2-(4-methoxyphenyl)cyclopropane-1-carboxamide (F21): White solid, Yield: 68.3%, m.p. 142.8–144.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.9 Hz, 1H, H-N), 7.02 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 3.70 (s, 3H), 3.58–3.47 (m, 1H), 2.22–2.08 (m, 1H, H-2), 1.81–1.60 (m, 5H), 1.58–1.48 (m,1H, H-3), 1.31–1.18 (m,3H), 1.18–1.02 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 170.00 (C=O), 157.63, 133.03, 126.87, 113.79, 55.08, 47.59, 32.66, 32.56, 25.38, 25.26, 24.57, 23.05, 14.99. HRMS (ESI) m/z [M + H]+ calcd for C17H24NO2: 274.1802, found: 274.1809.
- 2-(4-Methoxyphenyl)-N-(p-tolyl)cyclopropane-1-carboxamide (F22): White solid, Yield: 74.4%, m.p. 171.4–173.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H, H-N), 7.47 (d, J = 8.4 Hz, 2H), 7.16–7.01 (m, 4H), 6.85 (d, J = 8.7 Hz, 2H), 3.72 (s, 3H), 2.33–2.26 (m, 1H, H-2), 2.23 (s, 3H), 2.02–1.91 (m,1H, H-1), 1.43–1.39 (m, 1H, H-3), 1.28–1.23 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.80 (C=O), 157.77, 136.84, 132.61, 131.86, 129.12, 127.04, 118.89, 113.84, 55.09, 26.34, 24.18, 20.45, 15.29. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO2: 282.1489, found: 282.1496.
- 2-(4-Methoxyphenyl)-N-(m-tolyl)cyclopropane-1-carboxamide (F23): White solid, Yield: 80.5%, m.p. 134.4–135.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, H-N), 7.47 (d, J = 7.7 Hz, 1H), 7.22–7.17 (m, 1H), 7.15 (dd, J = 7.6, 1.7 Hz, 1H), 7.13–7.08 (m, 2H), 7.08–7.01 (m, 1H), 6.90–6.83 (m, 2H), 3.72 (s, 3H), 2.33–2.28 (m, 1H, H-2), 2.20 (s, 3H), 2.17–2.12 (m, 1H, H-1), 1.44–1.35 (m, 1H, H-3), 1.28–1.20 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.16 (C=O), 157.76, 136.48, 132.71, 131.00, 130.30, 127.05, 125.92, 124.83, 124.57, 113.85, 55.10, 25.68, 24.05, 17.90, 15.48. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO2: 282.1489, found: 282.1499.
- 2-(4-Methoxyphenyl)-N-(o-tolyl)cyclopropane-1-carboxamide (F24): White solid, Yield: 75.4%, m.p. 135.1–136.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H, H-N), 7.49 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 8.7 Hz, 3H), 7.05 (s, 1H), 6.87 (d, J = 8.2 Hz, 2H), 3.72 (s, 3H), 2.36–2.29 (m, 1H, H-2), 2.3 (s, 3H), 2.18–2.12 (m, 1H, H-1), 1.43–1.38 (m, 1H, H-3), 1.28–1.23 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.16 (C=O), 157.77, 136.49, 132.73, 131.00, 130.30, 127.05, 125.93, 124.84, 124.57, 113.85, 55.10, 25.67, 24.05, 17.91, 15.49. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO2: 282.1489, found: 282.1498.
- Ethyl 4-(2-(4-methoxyphenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate (F25): Yellow oil, Yield: 54.9%. 1H NMR (400 MHz, DMSO-d6) δ 7.16–7.02 (m, 2H), 6.89–6.76 (m, 2H), 4.08 –4.01 (m, 2H), 3.72 (s, 3H), 3.63 (d, J = 16.3 Hz, 2H), 3.50 (s, 2H), 3.37 (d, J = 10.1 Hz, 4H), 2.34–2.12 (m, 2H), 1.39 –1.32 (m, 1H, H-3), 1.25–1.11 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.95 (C=O), 157.74, 154.63, 132.59, 127.17, 113.79, 60.92, 55.06, 44.65, 43.64, 43.12, 41.37, 24.18, 22.29, 15.96, 14.56. HRMS (ESI) m/z [M + H]+ calcd for C18H24N2NaO4: 355.1628, found: 355.1638.
- 2-(4-Methoxyphenyl)-N-(thiazol-2-yl)cyclopropane-1-carboxamide (F26): White solid, Yield: 74.7%, m.p. 172.9–174.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H, H-N), 7.45 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H), 7.14–7.08 (m, 2H), 6.90–6.82 (m, 2H), 3.72 (s, 3H), 2.47–2.39 (m, 1H, H-2), 2.17–2.13 (m, 1H, H-1), 1.51–1.47 (m, 1H, H-3), 1.43–1.38 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.17 (C=O), 158.99, 158.01, 157.95, 137.63, 131.92, 127.29, 113.89, 113.37, 55.11, 25.44, 24.98, 16.04. HRMS (ESI) m/z [M + H]+ calcd for C14H15N2O2S: 275.0849, found: 275.0857.
- N-cyclopropyl-2-(m-tolyl)cyclopropane-1-carboxamide (F27): Yellow oil, Yield: 66.0%. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 3.9 Hz, 1H, H-N), 7.13 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.92–6.84 (m, 2H), 2.70–2.61 (m, 1H, H-2), 2.25 (s, 3H), 2.20–2.13 (m, 1H, H-1), 1.76–1.71 (m, 1H, H-3), 1.37–1.27 (m, 1H, H-3), 1.19–1.10 (m, 1H), 0.64–0.55 (m, 2H), 0.41–0.34 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 172.00 (C=O), 141.04, 137.41, 128.22, 126.60, 126.40, 122.94, 25.58, 23.81, 22.45, 20.99, 15.10, 5.72. HRMS (ESI) m/z [M + H]+ calcd for C14H18NO: 216.1383, found: 216.1391.
- N-cyclobutyl-2-(m-tolyl)cyclopropane-1-carboxamide (F28): White solid, Yield: 56.9%, m.p. 146.6–148.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.9 Hz, 1H, H-N), 7.14 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.93–6.84 (m, 2H), 4.26–4.16 (m, 1H), 2.25 (s, 3H), 2.20–2.07 (m, 3H), 1.91–1.79 (m, 2H), 1.79–1.72 (m, 1H, H-1), 1.63–1.54 (m, 2H), 1.33–1.25 (m, 1H), 1.19–1.09 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 169.77 (C=O), 141.06, 137.41, 128.22, 126.59, 126.38, 122.94, 43.95, 30.54, 30.48, 25.64, 23.75, 20.99, 15.05, 14.59. HRMS (ESI) m/z [M + H]+ calcd for C15H20NO: 230.1539, found: 230.1548.
- N-cyclopentyl-2-(m-tolyl)cyclopropane-1-carboxamide (F29): White solid, Yield: 58.7%, m.p. 140.9–142.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.3 Hz, 1H, H-N), 7.14 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 4.05–3.93 (m, 1H), 2.25 (s, 3H), 2.18–2.13 (m, 1H, H-2), 1.86–1.71 (m, 3H), 1.67–1.57 (m, 2H), 1.55–1.44 (m, 2H), 1.39–1.24 (m, 3H), 1.15–1.10 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.27 (C=O), 141.21, 137.41, 128.22, 126.56, 126.34, 122.93, 50.41, 32.51, 32.35, 25.68, 23.62, 23.39, 21.01, 15.17. HRMS (ESI) m/z [M + H]+ calcd for C16H22NO: 244.1696, found: 244.1711.
- N-cyclohexyl-2-(m-tolyl)cyclopropane-1-carboxamide (F30): White solid, Yield: 63.7%, m.p. 159.8–162.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.9 Hz, 1H, H-N), 7.14 (s, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 9.2 Hz, 2H), 3.60–3.49 (m, 1H), 2.25 (s, 3H), 2.18–2.13 (m, 1H, H-2), 1.87–1.78 (m, 1H, H-1), 1.76–1.59 (m, 4H), 1.58–1.48 (m, 1H, H-3), 1.33–1.18 (m, 3H), 1.17–1.03 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.86 (C=O), 141.21, 137.41, 128.23, 126.56, 126.36, 122.92, 47.59, 32.65, 32.55, 25.69, 25.26, 24.56, 23.64, 21.02, 15.24. HRMS (ESI) m/z [M + H]+ calcd for C17H24NO: 258.1852, found: 258.1858.
- 2-(m-Tolyl)-N-(p-tolyl)cyclopropane-1-carboxamide (F31): White solid, Yield: 57.1%, m.p. 132.0–133.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H, H-N), 7.52–7.43 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.01–6.90 (m, 3H), 2.33–2.28 (m, 1H, H-2), 2.27 (s, 3H), 2.24 (s, 3H), 2.07–1.99 (m, 1H, H-1), 1.48–1.44 (m, 1H, H-3), 1.44–1.27 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.69 (C=O), 140.80, 137.50, 136.83, 131.91, 129.15, 128.29, 126.78, 126.46, 123.10, 118.90, 26.63, 24.75, 21.02, 20.47, 15.52. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO: 266.1539, found: 266.1547.
- N,2-Di-m-tolylcyclopropane-1-carboxamide (F32): White solid, Yield: 59.8%, m.p. 150.8–151.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, H-N), 7.48 (d, J = 7.7 Hz, 1H), 7.17 (dd, J = 16.1, 7.5 Hz, 3H), 7.05 (s, 1H), 7.02–6.92 (m, 3H), 2.36–2.28 (m, 4H), 2.25–2.20 (m, 4H), 1.46–1.41 (m, 1H, H-3), 1.36–1.23 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.07 (C=O), 140.91, 137.50, 136.46, 130.98, 130.32, 128.30, 126.76, 126.47, 125.95, 124.87, 124.55, 123.11, 25.96, 24.61, 21.05, 17.93, 15.78. HRMS (ESI) m/z [M + H]+ calcd for C18H20NO: 266.1539, found: 266.1546.
- 2-(m-Tolyl)-N-(o-tolyl)cyclopropane-1-carboxamide (F33): White solid, Yield: 60.5%, m.p. 150.5–151.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H, H-N), 7.48 (d, J = 8.0 Hz, 1H), 7.21–7.12 (m, 3H), 7.02 (d, J = 28.5 Hz, 4H), 2.29 (d, J = 9.4 Hz, 4H), 2.20 (s, 4H), 1.48–1.39 (m, 1H, H-3), 1.35–1.24 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.07 (C=O), 140.92, 137.50, 136.48, 130.99, 130.33, 128.30, 126.76, 126.48, 125.95, 124.87, 124.55, 123.11, 25.97, 24.62, 21.05, 17.93, 15.79. HRMS (ESI) m/z [M+Na]+ calcd for C18H19NNaO: 288.1359, found: 288.1367.
- Ethyl 4-(2-(m-tolyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate (F34): Yellow oil, Yield: 67.2%. 1H NMR (400 MHz, DMSO-d6) δ 7.17–7.12 (m, 1H), 7.02–6.92 (m, 3H), 4.10–3.98 (m, 2H), 3.72–3.57 (m, 2H), 3.56–3.40 (m, 4H), 2.29–2.24 (m, 5H), 1.45–1.33 (m, 1H, H-3), 1.27–1.12 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.85 (C=O), 154.63, 140.76, 137.45, 128.21, 126.72, 126.59, 123.23, 60.94, 44.67, 43.59, 43.05, 41.39, 24.74, 22.09, 21.03, 14.57. HRMS (ESI) m/z [M+Na]+ calcd for C18H24N2NaO3: 339.1679, found: 339.1688.
- N-(thiazol-2-yl)-2-(m-tolyl)cyclopropane-1-carboxamide (F35): White solid, Yield: 50.8%, m.p. 152.8–154.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H, H-N), 7.45 (d, J = 3.6 Hz, 1H), 7.22–7.10 (m, 2H), 7.01 (d, J = 9.0 Hz, 2H), 6.97 (s, 1H), 2.45–2.37 (m, 1H, H-2), 2.27 (s, 3H), 2.24–2.17 (m, 1H, H-1), 1.55–1.50 (m, 1H, H-3), 1.48–1.43 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 170.07 (C=O), 157.98, 140.07, 137.65, 137.27, 128.37, 127.05, 126.79, 123.22, 113.43, 25.94, 25.17, 21.02, 16.19. HRMS (ESI) m/z [M + H]+ calcd for C14H15N2OS: 259.0900, found: 259.0909.
- N-cyclopropyl-2-(4-fluorophenyl)cyclopropane-1-carboxamide (F36): White solid, Yield: 51.4%, m.p. 152.5–153.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.9 Hz, 1H, H-N), 7.15 (dd, J = 8.7, 5.6 Hz, 2H), 7.11–7.04 (m, 2H), 2.67–2.60 (m, 1H, H-2), 2.247–2.22 (m, 1H, H-1), 1.76–1.67 (m, 1H, H-3), 1.37–1.28 (m, 1H, H-3), 1.18–1.13 (m, 1H), 0.62–0.55 (m, 2H), 0.41–0.35 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 171.89 (C=O), 160.71 (J C-F= 241.5 Hz), 137.26, 127.63 (J C-F = 8.0 Hz, 2C), 115.06 (J C-F = 21.2 Hz, 2C), 25.68, 23.13, 22.47, 15.16, 5.75, 5.72. 19F NMR (376 MHz, DMSO-d6) δ-117.09. HRMS (ESI) m/z [M+Na]+ calcd for C13H14FNNaO: 242.0952, found: 242.0960.
- N-cyclobutyl-2-(4-fluorophenyl)cyclopropane-1-carboxamide (F37): White solid, Yield: 62.9%, m.p. 170.2–172.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 7.9 Hz, 1H, H-N), 7.15 (dd, J = 8.6, 5.6 Hz, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.26–4.16 (m, 1H), 2.25–2.20 (m, 1H, H-2), 2.17–2.11 (m, 2H), 1.90–1.80 (m, 2H), 1.76–1.72 (m, 1H, H-3), 1.67–1.51 (m, 2H), 1.32–1.28 (m, 1H, H-3), 1.22–1.12 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 169.67 (C=O), 160.71 (J C-F = 240.5 Hz), 137.31, 127.62 (J C-F = 8.1 Hz, 2C), 115.06 (J C-F = 21.3 Hz, 2C), 43.98, 30.56, 30.48, 25.74, 23.07, 15.12, 14.61. 19F NMR (376 MHz, DMSO-d6) δ-117.17. HRMS (ESI) m/z [M + H]+ calcd for C14H17FNO: 234.1289, found: 234.1296.
- N-cyclopentyl-2-(4-fluorophenyl)cyclopropane-1-carboxamide (F38): White solid, Yield: 51.8%, m.p. 166.1–167.6 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.3 Hz, 1H, H-N), 7.15 (dd, J = 8.6, 5.6 Hz, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.05–3.97 (m, 1H), 2.25–2.20 (m, 1H, H-2), 1.88–1.72 (m, 3H), 1.66–1.57 (m, 2H), 1.53–1.46 (m, 2H), 1.41–1.26 (m, 3H), 1.15–1.11 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.16 (C=O), 160.69 (J C-F = 241.4 Hz), 137.43, 127.58 (J C-F = 7.9 Hz, 2C), 115.04 (J C-F = 21.1 Hz, 2C), 50.44, 32.53, 32.33, 25.75, 23.41, 22.94, 15.20. 19F NMR (376 MHz, DMSO-d6) δ-117.21. HRMS (ESI) m/z [M + H]+ calcd for C15H19FNO: 248.1445, found: 248.1455.
- N-cyclohexyl-2-(4-fluorophenyl)cyclopropane-1-carboxamide (F39): White solid, Yield: 72.4%, m.p. 188.2–190.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.8 Hz, 1H, H-N), 7.14 (dd, J = 8.4, 5.5 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 3.54 (d, J = 7.6 Hz, 1H), 2.27–2.18 (m, 1H, H-2), 1.84–1.80 (m, 1H, H-2), 1.77–1.61 (m, 4H), 1.53 (d, J = 12.9 Hz, 1H), 1.36–1.19 (m, 3H), 1.17–1.07 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.75 (C=O), 160.70 (J C-F = 241.5 Hz), 137.43, 127.58 (J C-F = 8.0 Hz, 2C), 115.04 (J C-F = 21.1 Hz, 2C), 47.63, 32.66, 32.54, 25.74, 25.26, 24.58, 24.55, 22.95, 15.27. 19F NMR (376 MHz, DMSO-d6) δ-117.24. HRMS (ESI) m/z [M + H]+ calcd for C16H21FNO: 262.1602, found: 262.1611.
- 2-(4-Fluorophenyl)-N-(p-tolyl)cyclopropane-1-carboxamide (F40): White solid, Yield: 65.9%, m.p. 181.9–183.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H, H-N), 7.47 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 8.5, 5.4 Hz, 2H), 7.11 (q, J = 8.4 Hz, 4H), 2.41–2.32 (m, 1H, H-2), 2.24 (s, 3H), 2.04–1.98 (m, 1H, H-2), 1.48–1.43 (m, 1H, H-3), 1.34–1.30 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.57 (C=O), 160.82 (J C-F = 241.7 Hz), 137.04, 136.80, 131.97, 129.16 (2C), 127.79 (J C-F = 8.0 Hz, 2C), 118.94, 115.12 (J C-F = 21.3 Hz, 2C), 26.67, 24.04, 20.47, 15.54. 19F NMR (376 MHz, DMSO-d6) δ-116.92. HRMS (ESI) m/z [M + H]+ calcd for C17H17FNO: 270.1289, found: 270.1296.
- 2-(4-Fluorophenyl)-N-(m-tolyl)cyclopropane-1-carboxamide (F41): White solid, Yield: 73.2%, m.p. 157.4–159.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H, H-N), 7.48 (d, J = 7.9 Hz, 1H), 7.23–7.01 (m, 7H), 2.37 (s, 1H, H-2), 2.20 (s, 4H), 1.45–1.31 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.97 (C=O), 160.84 (J C-F = 242.7 Hz), 137.13, 136.44, 131.06, 130.35, 127.81 (J C-F = 8.0 Hz, 2C), 125.98, 124.94, 124.61, 115.14 (J C-F = 21.3 Hz, 2C), 25.99, 23.91, 17.93, 15.77. 19F NMR (376 MHz, DMSO-d6) δ-116.97. HRMS (ESI) m/z [M + H]+ calcd for C17H17FNO: 270.1289, found: 270.1297.
- 2-(4-Fluorophenyl)-N-(o-tolyl)cyclopropane-1-carboxamide (F42): White solid, Yield: 74.2%, m.p. 158.0–159.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H, H-N), 7.48 (d, J = 7.6 Hz, 1H), 7.34–6.83 (m, 7H), 2.40–2.36 (m, 1H, H-2), 2.20 (s, 4H), 1.47–1.23 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.94 (C=O), 160.82 (J C-F = 241.3 Hz), 137.13, 136.44, 131.03, 130.33, 127.80 (J C-F= 8.0 Hz, 2C), 125.96, 124.92, 124.58, 115.13 (J C-F = 21.2 Hz, 2C), 25.98, 23.90, 17.92, 15.75. 19F NMR (376 MHz, DMSO-d6) δ-116.97. HRMS (ESI) m/z [M+Na]+ calcd for C17H16FNNaO: 292.1108, found: 292.1118.
- Ethyl 4-(2-(4-fluorophenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate (F43): Yellow oil, Yield: 73.3%. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (dd, J = 8.6, 5.6 Hz, 2H), 7.09 (t, J = 8.8 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.67–3.56 (m, 2H), 3.52–3.43 (m, 4H), 3.35–3.27 (m, 2H), 2.38–2.24 (m, 2H), 1.41–1.35 (m, 1H, H-3), 1.22–1.16 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.77 (C=O), 160.81 (J C-F = 241.6 Hz), 154.66, 136.99, 127.94 (J C-F = 8.0 Hz, 2C), 115.05 (J C-F = 21.2 Hz, 2C), 60.96, 44.67, 43.56, 43.07, 41.42, 24.01, 22.07, 16.40, 14.59. 19F NMR (376 MHz, DMSO-d6) δ-117.08. HRMS (ESI) m/z [M+Na]+ calcd for C17H22FN2O3: 343.1428, found: 343.1438.
- 2-(4-Fluorophenyl)-N-(thiazol-2-yl)cyclopropane-1-carboxamide (F44): Pale yellow solid, Yield: 70.4%, m.p. 187.0–189.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H, H-N), 7.45 (s, 1H), 7.36–6.97 (m, 5H), 2.20 (s, 1H, H-1), 1.53–1.46 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.95 (C=O), 160.96 (J C-F = 242.4 Hz), 157.98, 137.66, 136.34, 128.05 (J C-F = 8.0 Hz, 2C), 115.20 (d, J = 21.2 Hz), 113.45, 25.20, 16.24. 19F NMR (376 MHz, DMSO-d6) δ-116.54. HRMS (ESI) m/z [M + H]+ calcd for C13H12FN2OS: 263.0649, found: 263.0657.
- 2-(4-Chlorophenyl)-N-cyclopropylcyclopropane-1-carboxamide (F45): White solid, Yield: 67.5%, m.p. 160.0–161.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 7.3 Hz, 1H, H-N), 7.18 (d, J = 7.7 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 2.37–2.23 (m, 1H, H-2), 2.14–2.07 (m, 1H, H-2), 1.61 (d, J = 4.2 Hz, 1H, H-3), 1.25–1.19 (m, 1H, H-3), 1.05 (d, J = 4.3 Hz, 1H), 0.50–0.42 (m, 2H), 0.30–0.24 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 171.75 (C=O), 140.32, 130.41, 128.24, 127.68, 25.84, 23.23, 22.47, 15.35, 5.75, 5.71. HRMS (ESI) m/z [M + H]+ calcd for C13H15ClNO: 236.0837, found: 236.0845.
- 2-(4-Chlorophenyl)-N-cyclobutylcyclopropane-1-carboxamide (F46): White solid, Yield: 72.8%, m.p. 194.5–195.7 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 7.8 Hz, 1H, H-N), 7.36–7.26 (m, 2H), 7.16–7.11 (m, 2H), 4.26–4.13 (m, 1H), 2.26–2.18 (m, 1H, H-2), 2.17–2.07 (m, 2H), 1.90–1.80 (m, 2H), 1.80–1.74 (m, 1H), 1.65–1.56 (m, 2H), 1.35–1.28 (m, 1H), 1.21–1.13 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 169.53 (C=O), 140.36, 130.42, 128.25, 127.68, 43.99, 30.54, 30.46, 25.90, 23.17, 15.31, 14.62. HRMS (ESI) m/z [M + H]+ calcd for C14H17ClNO: 250.0993, found: 250.1002.
- 2-(4-Chlorophenyl)-N-cyclopentylcyclopropane-1-carboxamide (F47): White solid, Yield: 74.6%, m.p. 197.9–199.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 7.2 Hz, 1H, H-N), 7.31 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 4.07–3.95 (m, 1H), 2.32–2.18 (m, 1H, H-2), 1.89–1.70 (m, 3H), 1.67–1.55 (m, 2H), 1.53–1.42 (m, 2H), 1.39–1.25 (m, 3H), 1.16 (d, J = 4.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 170.03 (C=O), 140.48, 130.37, 128.24, 127.65, 50.46, 32.53, 32.33, 25.92, 23.41, 23.05, 15.39. HRMS (ESI) m/z [M+Na]+ calcd for C15H18ClNNaO: 286.0969, found: 286.0980.
- 2-(4-Chlorophenyl)-N-cyclohexylcyclopropane-1-carboxamide (F48): White solid, Yield: 74.5%, m.p. 181.3–183.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.7 Hz, 1H, H-N), 7.31 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 3.57–3.50 (m, 1H), 2.26–2.16 (m, 1H, H-2), 1.88–1.80 (m, 1H, H-1), 1.77–1.60 (m, 4H), 1.52 (s, 1H), 1.36–1.29 (m, 1H), 1.27–1.19 (m, 2H), 1.18–1.05 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.61 (C=O), 140.48, 130.37, 128.24, 127.65, 47.65, 32.64, 32.52, 25.92, 25.25, 24.55, 23.06, 15.45. HRMS (ESI) m/z [M + H]+ calcd for C16H21ClNO: 278.1306, found: 278.1313.
- 2-(4-Chlorophenyl)-N-(p-tolyl)cyclopropane-1-carboxamide (F49): White solid, Yield: 62.5%, m.p. 192.3–194.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H, H-N), 7.47 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 2.41–2.34 (m, 1H, H-2), 2.23 (s, 3H), 2.07–2.03 (m, 1H, H-1), 1.55–1.44 (m, 1H, H-3), 1.36–1.31 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.43 (C=O), 140.07, 136.76, 132.01, 130.60, 129.17, 128.30, 127.82, 118.96, 26.82, 24.12, 20.47, 15.72. HRMS (ESI) m/z [M + H]+ calcd for C17H17ClNO: 286.0993, found: 286.0999.
- 2-(4-Chlorophenyl)-N-(m-tolyl)cyclopropane-1-carboxamide (F50): White solid, Yield: 69.4%, m.p. 163.5–165.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H, H-N), 7.49 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 8.9 Hz, 3H), 7.13 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 2.30–2.34 (m, 1H, H-2), 2.21 (s, 4H), 1.49–1.45 (m, 1H, H-3), 1.38–1.27 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.87 (C=O), 140.18, 136.44, 131.08, 130.63, 130.37, 128.34, 127.85, 126.00, 124.98, 124.63, 26.17, 24.04, 17.95, 15.98. HRMS (ESI) m/z [M + H]+ calcd for C17H17ClNO: 286.0993, found: 286.1000.
- 2-(4-Chlorophenyl)-N-(o-tolyl)cyclopropane-1-carboxamide (F51): White solid, Yield: 67.7%, m.p. 157.9–159.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H, H-N), 7.48 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.24–7.18 (m, 3H), 7.14 (d, J = 1.7 Hz, 1H), 7.08–7.03 (m, 1H), 2.40–2.36 (m, 1H, H-2), 2.26–2.22 (m, 1H, H-2), 2.20 (s, 3H), 1.49–1.43 (m, 1H, H-3), 1.36–1.29 (m, 1H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.80 (C=O), 140.17, 136.42, 131.02, 130.59, 130.33, 128.30, 127.82, 125.96, 124.92, 124.57, 26.16, 24.00, 17.93, 15.93. HRMS (ESI) m/z [M + Na]+ calcd for C17H16ClNNaO: 308.0813, found: 308.0821.
- Ethyl 4-(2-(4-Chlorophenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate (F52): Yellow oil, Yield: 76.0%. 1H NMR (400 MHz, DMSO-d6) δ 7.33–7.25 (m, 2H), 7.23–7.15 (m, 2H), 4.09–4.00 (m, 2H), 3.73–3.56 (m, 2H), 3.55–3.44 (m, 2H), 3.35 (d, J = 5.5 Hz, 2H), 2.38–2.24 (m, 2H), 1.50–1.38 (m, 1H, H-3), 1.18 (t, J = 7.1 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ 169.58 (C=O), 154.60, 139.98, 130.60, 128.17, 127.87, 60.92, 44.67, 43.55, 43.07, 41.41, 24.11, 22.31, 16.48, 14.50. HRMS (ESI) m/z [M + H]+ calcd for C17H22ClN2O3: 337.1313, found: 337.1317.
- 2-(4-Chlorophenyl)-N-(thiazol-2-yl)cyclopropane-1-carboxamide (F53): White solid, Yield: 59.0%, m.p. 218.3–221.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H, H-N), 7.45 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.28–7.15 (m, 3H), 2.30–2.16 (m, 1H, H-1), 1.63–1.41 (m, 2H, H-3). 13C NMR (100 MHz, DMSO-d6) δ 169.81 (C=O), 157.99, 139.35, 137.66, 130.91, 128.36, 127.99, 113.44, 25.38, 25.26, 16.38. HRMS (ESI) m/z [M + H]+ calcd for C13H12ClN2OS: 279.0353, found: 279.0363.
3.7. The Antimicrobial Activity In Vitro
3.8. Molecular Docking Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Gram-Negative Bacteria | Gram-Positive Bacteria | Fungus | Compound | Gram-Negative Bacteria | Gram-Positive Bacteria | Fungus | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
No. | R | S. aureus | E. coli | P. aeruginosa | C. albicans | No. | R | S. aureus | E. coli | P. aeruginosa | C. albicans |
F1 | >128 | >128 | >128 | >128 | F27 | >128 | >128 | >128 | >128 | ||
F2 | >128 | >128 | >128 | >128 | F28 | >128 | >128 | >128 | >128 | ||
F3 | >128 | >128 | >128 | >128 | F29 | 64 | >128 | >128 | >128 | ||
F4 | >128 | >128 | >128 | 128 | F30 | 128 | >128 | >128 | >128 | ||
F5 | 64 | 128 | >128 | 64 | F31 | >128 | 64 | >128 | >128 | ||
F6 | >128 | >128 | >128 | >128 | F32 | >128 | >128 | >128 | 64 | ||
F7 | 128 | >128 | >128 | 32 | F33 | >128 | >128 | >128 | 128 | ||
F8 | >128 | >128 | >128 | 16 | F34 | >128 | >128 | >128 | 128 | ||
F9 | 64 | 32 | >128 | 64 | F35 | >128 | >128 | >128 | >128 | ||
F10 | >128 | >128 | >128 | 128 | F36 | 128 | >128 | >128 | 128 | ||
F11 | >128 | >128 | >128 | >128 | F37 | >128 | >128 | >128 | >128 | ||
F12 | >128 | >128 | >128 | >128 | F38 | >128 | >128 | >128 | >128 | ||
F13 | >128 | >128 | >128 | >128 | F39 | >128 | >128 | >128 | >128 | ||
F14 | >128 | >128 | >128 | 128 | F40 | >128 | >128 | >128 | >128 | ||
F15 | >128 | >128 | >128 | >128 | F41 | >128 | >128 | >128 | >128 | ||
F16 | >128 | >128 | >128 | >128 | F42 | >128 | >128 | >128 | 16 | ||
F17 | >128 | >128 | >128 | >128 | F43 | >128 | >128 | >128 | >128 | ||
F44 | >128 | >128 | >128 | >128 | |||||||
F18 | >128 | >128 | >128 | >128 | |||||||
F19 | >128 | >128 | >128 | >128 | F45 | >128 | 64 | >128 | >128 | ||
F20 | >128 | >128 | >128 | >128 | F46 | >128 | >128 | >128 | >128 | ||
F21 | >128 | >128 | >128 | >128 | F47 | >128 | >128 | >128 | >128 | ||
F22 | >128 | >128 | >128 | 32 | F48 | >128 | >128 | >128 | >128 | ||
F23 | >128 | >128 | >128 | 64 | F49 | 128 | >128 | >128 | 64 | ||
F24 | >128 | >128 | >128 | 16 | F50 | >128 | >128 | >128 | 64 | ||
F25 | >128 | >128 | >128 | >128 | F51 | 128 | >128 | >128 | 32 | ||
F26 | >128 | >128 | >128 | >128 | F52 | >128 | >128 | >128 | >128 | ||
F53 | 64 | 128 | >128 | >128 | |||||||
Ciprofloxacin | 2 | 2 | 2 | - | Ciprofloxacin | 2 | 2 | 2 | - | ||
Fluconazole | - | - | - | 2 | Fluconazole | - | - | - | 2 |
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Chen, D.; Cheng, Y.; Shi, L.; Gao, X.; Huang, Y.; Du, Z. Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane. Molecules 2024, 29, 4124. https://doi.org/10.3390/molecules29174124
Chen D, Cheng Y, Shi L, Gao X, Huang Y, Du Z. Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane. Molecules. 2024; 29(17):4124. https://doi.org/10.3390/molecules29174124
Chicago/Turabian StyleChen, Dongdong, Yu Cheng, Lele Shi, Xueting Gao, Yuhang Huang, and Zhenting Du. 2024. "Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane" Molecules 29, no. 17: 4124. https://doi.org/10.3390/molecules29174124