Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane

Abstract

As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20–F26, F36, and F38–F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC₈₀ = 16 μg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.

1. Introduction

Infectious diseases caused by bacterial pathogens seriously affect human health and have been a main public health problem in recent years [1]. The use of antibiotics has significantly improved the ability of humans to fight bacterial infections, which prolongs human life and improves the quality of human life [2]. However, the continuous use of antibiotics leads to the emergence of bacterial resistance. At present, one of the major challenges of healthcare worldwide is bacterial resistance to antibiotics [3]. Therefore, it is urgent to develop new, effective, and safe bactericides.

As an important small organic molecule, cyclopropane is widely found in natural products and drugs [4,5,6]. Cyclopropane is a structurally stable bioisostere, which can be used to replace carbon–carbon double bonds. It has the effects of improving the efficacy of drugs, enhancing metabolic stability, reducing the off-target effect of drugs, improving the dissociation degree of drugs, and enhancing the affinity to receptors [7,8,9,10]. Therefore, it is widely used in drug design. Compounds containing cyclopropane have certain drug properties and biological activities, including antibacterial [11,12], antifungal [13,14,15], antiviral [16,17], antitumor [18], antioxidant [19], and antidepressant activities [20,21,22]. Therefore, compounds with cyclopropane structures have attracted extensive research due to their biological activity and low toxicity.

At present, drugs containing cyclopropane structure have been applied to treat respiratory diseases, infectious diseases, mental disorders, endocrine and metabolic diseases, nervous system diseases, and cardiovascular and cerebrovascular diseases [23]. These include tranylcypromine, levomilnacipran, arotinib hydrochloride, cypermethrin, and fenpropathrin (Figure 1).

Phenyl, as a scaffold that could be substituted with various groups, can enhance the stability and biological activity of drugs [24]. The amide structure, as an important component of proteins, is widely present in antibacterial and antioxidant agents, and it is an important functional group in drug synthesis [25]. Therefore, we speculate that the introduction of substituted phenyl and cyclopropane with amide structure is likely to lead to new lead compounds with excellent biological activity.

In this study, amide groups and aryl groups of benodanil [26] and cinnamate ester derivatives [27] with excellent antibacterial activity were introduced into the C₁ and C₂ positions of cyclopropane by the active splicing method, and fifty-three amide derivatives containing cyclopropane were synthesized (Figure 2). The antibacterial and antifungal activity of the target compounds in vitro was tested. Then, the mode of action and binding affinity of the ideal compounds with the highest antifungal activity and CYP51 protein were analyzed by molecular docking to preliminarily explore their antifungal mechanism.

2. Results

2.1. Synthesis

In order to explore the effect of different substituent groups on the activity and find more potent compounds, based on the consideration of molecular diversity, 2-phenylcyclopropane-1-carboxamide was used as a template to introduce different substituents into the benzene ring and the amide part, respectively.

The synthetic rout is outlined in Scheme 1. Intermediate B was obtained by Knoevenagel condensation of substituted benzaldehyde A and malonic acid. Intermediate B was amidated with N,O-dimethylhydroxylamine hydrochloride to form intermediate C. Intermediate D was obtained from intermediate C and trimethylsulfonyl iodide by Corey-Chaykovsky cyclopropanation. Intermediate D was hydrolyzed to obtain intermediate E. A series of amide compounds containing cyclopropane F1–F53 were obtained by amide reaction of intermediate E with aliphatic amine, methylaniline, ethyl N-piperazinecarboxylate, and 2-aminothiazole, respectively.

Among the fifty-three cyclopropane amide derivatives synthesized in this study, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20–F26, F36, F38–F44). All of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS. The ¹H and ¹³C NMR spectra and HRMS of the compounds above are shown in Supplementary Materials.

In ¹H-NMR spectra, fatty amides (F1–F4, F10–F13, F18–F21, F27–F30, F36–F39, F45–F48) showed one doublet signal in the ranges of δ_H 7.95–8.39 due to H-N. Benzamides (F5–F7, F14–F16, F22–F24, F31–F33, F40–F42, F49–F51) and thiazole amides (F9, F17, F26, F35, F44, F53) showed one single signals in the ranges of δ_H 9.52–10.43 andδ_H 12.34–12.43 due to H-N, respectively. The two hydrogens on C₁ and C₂ show two sets of multiple signals in the ranges of δ_H 2.70–1.65. The two hydrogens on C3 show two sets of multiple signals in the ranges of δ_H 1.75–1.21. In ¹³C-NMR spectra, the amides showed a signal of one carbonyl in the ranges of δ_C 169.43–172.48. In ¹⁹F-NMR spectra, the compounds (F36–F44) showed a signal of one F in the ranges of δ_F −116.54–−117.24.

2.2. Antimicrobial Activity In Vitro

Three strains of bacteria, including Gram-positive bacteria (Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli)) and Gram-negative bacteria (Pseudomonas aeruginosa (P. aeruginosa)), and one strain of fungu (Candida albicans (C. albicans)), which causes great harm to human health, were selected to test the biological activity of the compounds in vitro. The antibacterial activity and antifungal activity against all synthesized amide derivatives containing cyclopropane (F1–F53) were evaluated in vitro. The in vitro antibacterial and antifungal activities of the prepared compounds were determined by the MIC₈₀ value (minimum 80% inhibition concentration) using microdilution method with ciprofloxacin or fluconazole as positive controls, respectively. The results are listed in Table 1. Five compounds (F7, F30, F36, F49, and F51) showed some antibacterial activity against Staphylococcus aureus with the MIC₈₀ of 128 μg/mL, and four compounds (F5, F9, F29, and F53) showed moderate inhibitory activity against Staphylococcus aureus with the MIC₈₀ of 32 and 64 μg/mL. Two compounds (F5 and F53) show antibacterial activity against Escherichia coli with the MIC₈₀ of 128 μg/mL. Escherichia coli were relatively sensitive to three compounds (F9, F31, and F45) with the MIC₈₀ of 32 and 64 μg/mL, respectively, but far lower than the antibacterial activity of the positive control ciprofloxacin (MIC₈₀ = 2 μg/mL). Pseudomonas aeruginosa was not sensitive to all compounds with high MIC₈₀ values (>128 μg/mL).

Six compounds (F4, F10, F14, F33, F34, and F36) showed some antifungal activity against Candida albicans with the MIC₈₀ of 128 μg/mL, but the activity was far lower than that of fluconazole (MIC₈₀ = 2 μg/mL). Candida albicans were more sensitive to nine compounds (F5, F7, F9, F22, F23, F32, F49, F50, and F51) which showed moderate activity (MIC₈₀ = 32, 64 μg/mL). Three compounds (F8, F24, and F42) showed promising antifungal activity with the MIC₈₀ of 16 μg/mL.

Although the activity of the synthesized compounds is inferior to ciprofloxacin and fluconazole, this class of compounds showed some attractive advantages, such as simple structure, easy synthesis, and low cost.

2.3. The Preliminary Structure–Activity Relationships

The comparison of the antimicrobial activity and structure of the compounds in Table 1 showed that the types and substitution sites of benzene ring and amide substituents significantly influence the antimicrobial activity of the compounds. The antibacterial activity of the target compounds showed that aryl amides showed higher activity than fatty amides (F1–F4, F8 vs. F5–F7, F9 (S. aureus, E. coli))). The cyclopropane derivatives substituted by piperazine amide did not show antibacterial activity (F8, F25, F34, F43, F52 (S. aureus, E. coli)). Thiazole amide (F9) showed the best antibacterial activity (MIC₈₀ = 32 μg/mL (E. coli)). The introduction of halogen at the 2-position of the benzene ring showed better antibacterial activity than the 4-position (F9 vs. F52, F44 (S. aureus, E. coli)). The introduction of halogens (F, Cl, Br) in the benzene ring was beneficial to the improvement of antibacterial activity compared with methoxy groups as an electron-donating (F5, F49 vs. F22; F7, F51 vs. F24; F9, F53 vs. F26 (S. aureus, E. coli)). Similar to the antibacterial activity, the presence of fatty amides cannot improve antifungal activity (F1–F4, F10–F13, F18–F21, F27–F30, F36–F39, F45–F48 (C. albicans)) and the introduction of halogens in the benzene ring was beneficial to the improvement of antifungal activity (F5, F49 vs. F14, F31; F7, F42, F51 vs. F16, F33 (C. albicans)). This is consistent with the performance of cinnamic acid ester derivatives with similar structures [28]. Unlike antibacterial activity, the introduction of methoxy groups in the benzene ring also contributed to the improvement of antifungal activity (F22–F24 vs. F14–F16, F31–F33 (C. albicans)). The introduction of benzamide was more conducive to the improvement of antifungal activity, and o-tolyl amide showed better antifungal activity than m-tolyl amide and p-tolyl amide. (F7 vs. F5–F6; F24 vs. F22–F23; F42 vs. F40–F41; F51 vs. F49–F50 (C. albicans)).

2.4. Molecular Docking Studies

Sterol 14-α demethylase (CYP51), as a key enzyme in the synthesis of biosterols, is a potential target for antifungal drugs. It has the functions of regulating and distributing proteins and changing the fluidity and permeability of membranes, and it is an enzyme necessary for the growth and development of various eukaryotes [29,30]. In order to further explore the antifungal activity mechanism of the target compounds, molecular docking was used to predict the mode of action and binding affinity of excellent antifungal compounds (F8, F24, and F42) with CYP51 protein. The molecular docking results are shown in Figure 3. Compound F8 is able to bind with CYP51 by interaction with two amino residues of SER378 and HIE377. The binding modes involved one halogen bond and one π…π interaction. Compared with F8, F42 is mainly bound with CYP51 by interaction with TYR118 and HEM601 involved two π…π interaction. Compared with F42, F24 also forms two additional interactions with CYP51 including two hydrogen bond ((CO)N…TYR132, (CH₃)O…HEM601). The compounds F8, F24, and F42 have good binding affinity with CYP51 and gave −6.087, −6.526, and −6.874 kcal/mol of docking scores, respectively. Compared with the reported compounds with excellent antifungal activity, the binding energies were slightly lower [13]. This may be the reason why the antibacterial activity of the above compounds was lower than that of fluconazole. The results further verified the potential bacteriostatic effect of derivatives F8, F24 and F42.

3. Materials and Methods

3.1. Chemistry

All reactions were monitored by thin-layer silica chromatography (TLC) with GF₂₅₄ under 254 nm UV light (Beijing Innochem Science&Technology Co.,Ltd, Beijing, China). The melting points (m.p.) of all synthesized chemicals were determined on an XT-4 micro-melting point apparatus (Hanon Technologies, Jinan, China). Compounds were purified by column chromatography with silica gel (200–300 mesh) (Qingdao Haiwan Chemical, Qingdao, China) using a mixture of ethyl acetate and petroleum ether as eluent. ¹H nuclear magnetic resonance (¹H NMR) and ¹³C NMR spectra were recorded on a Bruker AVANCE III operating at 400 and 100 MHz (Bruker, Karlsruhe, Germany) instrument in DMSO-d₆ and using tetramethyl silane (TMS) as an internal standard. All chemical shifts (δ values) are given in ppm, and coupling constants (J values) are given in Hz. High-resolution mass spectra (HRMS) were obtained using a Bruker micrOTOF-Q II focus spectrometer (ESI) (AB SCIEX, Framingham, MA, USA). All starting materials were purchased from commercial suppliers and used without further purification unless otherwise stated.

3.2. General Synthesis Procedure for Intermediate B

Substituted benzaldehyde (A1–A6, 100 mmol), malonic acid (300 mmol), and pyridine (100 mmol) were added to a 500 mL flask containing N,N-dimethylformamide (100 mL) solution. The solution was reacted at 90 °C for 6 h. The reaction process was monitored by TLC. To the mixture was added water (60 mL) and concentrated HCl to pH = 1. Then, the solution was cooled to 0 °C. Filtrate and wash solid with ice water. The solid was collected and dried to give the intermediate B in 80–82% yield [31].

3.3. General Synthesis Procedure for Intermediate C

The intermediates B (70 mmol), N,O-dimethylhydroxylamine hydrochloride (105 mmol), 4-dimethylaminopyridine (DMAP, 14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 105 mmol) were added to a 500 mL flask containing 100 mL dichloromethane at 0 °C. Triethylamine (105 mmol) was added slowly, and the reaction mixture was warmed slowly to room temperature and stirred for 2 h. The mixture was quenched with 1 mol/L HCl (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with aqueous saturated NaHCO₃ (100 mL × 3) and brine, dried over anhydrous Na₂SO₄, and concentrated to give the intermediate C in 60–70% yield [32].

3.4. General Synthesis Procedure for Intermediate D

To a solution of NaH (174 mmol) in anhydrous tetrahydrofuran (THF) (350 mL) was added intermediate C (60 mmol) dropwise under argon at 0 °C. The reaction mixture was allowed to be stirred at 0 °C for 0.5 h. Then trimethylsulfonyl iodide (79.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, quenched with water, and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give the intermediate D in 76–82% yield [33].

3.5. General Synthesis Procedure for Intermediate E

The intermediate D (50 mmol) and sodium hydroxide (NaOH, 100 mmol) were dissolved in a mixed solution of methanol (75 mL) and water (10 mL) and stirred overnight at 25 °C. To the mixture was added diluted hydrochloric acid HCl to Ph = 3–4. The mixture was extracted with dichloromethane (DCM, 50 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give the intermediate E in 76–82% yield [34].

3.6. General Synthesis Procedure for F1–F53

The intermediate E (2 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 2.4 mmol) and 1-Hydroxybenzotriazole (HOBT, 2.4 mmol) were dissolved in anhydrous tetrahydrofuran (THF, 10 mL). Then, the reaction mixture was stirred for 5 min at room temperature. The corresponding amine (3 mmol) was added and stired at 37 °C overnight. Water (20 mL) was added and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate as eluent to give F1–F53 in 50–80% yield [35].

• 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

Three strains of bacteria (S. aureus, E. coli, and P. aeruginosa) and one strain of fungal (C. albicans) were selected to determine the antimicrobial activity in vitro by the broth microdilution method. The fungal and bacterial strains were obtained from China General Microbiological Culture Collection Center. The bacteria and fungi were cultured to 1–5 × 10³ CFU/mL in Mueller Hinton Broth medium and RPMI1640 medium, respectively, before use. The commercial ciprofloxacin or fluconazole was selected as the positive control. All compounds were dissolved in DMSO and serially diluted, and the concentrations of all tested compounds were 1, 2, 4, 8, 16, 32, 64, and 128 μg/mL. Then, the plates were continuously incubated at 37 °C for 24 h. The OD values were read on a Microplate reader at a wavelength of 600 nm. The plates without drugs acted as the growth control, while the plates without cells and drugs acted as blank control. The MIC₈₀ value was the lowest concentration; the inhibition rate was ≥80%. The test was performed in triplicates.

$\mathrm{I}\mathrm{n}\mathrm{h}\mathrm{i}\mathrm{b}\mathrm{i}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n} \mathrm{r}\mathrm{a}\mathrm{t}\mathrm{e}\left(\mathrm{\%}\right)={\displaystyle \frac{{\mathrm{O}\mathrm{D}}_{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{l}}-{\mathrm{O}\mathrm{D}}_{\mathrm{s}\mathrm{a}\mathrm{m}\mathrm{p}\mathrm{l}\mathrm{e}}}{{\mathrm{O}\mathrm{D}}_{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{l}}-{\mathrm{O}\mathrm{D}}_{\mathrm{b}\mathrm{l}\mathrm{a}\mathrm{n}\mathrm{k}}}}\times 100\mathrm{\%}$

3.8. Molecular Docking Analysis

The 3D crystal structure of CYP51 (PDB code: 6AY6) was acquired from the RCSB Protein Date Bank (https://www.rcsb.org/structure/6AY6 (accessed on 7 September 2017)). The molecular docking process was conducted for the investigation of the binding mode of compounds F8, F24, and F42 with CYP51 using Discovery Studio 2016 software (Accelrys, San Diego, CA, USA) [32]. ChemBio 3D Ultra 14.0 software was used to generate the 3D structure of the above compounds and treated with energy minimization [36]. Water molecules and the co-crystallized ligand of the 3D crystal structure of CYP51 were removed, and the crystal structure was hydrotreated before molecular docking. The parameters of docking were in accordance with the previously reported method [13].

4. Conclusions

In summary, a series of amide derivatives containing cyclopropane were designed and synthesized, and their antimicrobial activity in vitro was evaluated. The results showed that the four and three of the compounds exhibited moderate activity against Staphylococcus aureus and Escherichia coli, respectively. Three compounds were sensitive to Candida albicans and exhibited excellent antifungal activity, with great potential for further development. SAR analysis showed that introducing halogens into the benzene ring was beneficial for improving antibacterial and antifungal activity. The presence of thiazolamide contributed to the improvement of antibacterial activity, while benzamides were beneficial to the improvement of antifungal activity. Compounds F8, F24, and F42 showed the highest activity against C. albicans (MIC₈₀ = 16 μg/mL). The molecular docking results showed that the above compounds had a good binding affinity with the CYP51 protein. Thus, amide compounds containing cyclopropane can be considered promising antimicrobial lead compounds. It is necessary to further study the in vivo activity and mechanism of action of these compounds.

Author Contributions

D.C. and Z.D. designed the experiments and wrote the main manuscript text; Y.C., D.C., L.S., X.G. and Y.H. performed the experiments; D.C. and Z.D. took part in data analysis and discussion. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data are contained within the article.

Acknowledgments

We thank the Chemical Experiment Teaching and Research Center for providing us with nuclear magnetic resonance analysis and thank the core service of Life Science Research for providing us with HRMS.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures, Scheme and Table

Figure 1. Structure of commercial drugs of cyclopropane.

Figure 2. Design strategy of title compounds.

Scheme 1. Synthetic reaction and structures of target compounds. Reagents and conditions: (i) Malonic acid, DMF, 90 °C, 6 h, yield: 80–82%; (ii) DMAP, N,O-dimethylhydroxylamine hydrochloride, EDCI, DCM, rt, 2 h, yield: 60–70%; (iii) NaH, Trimethylsulfonyl iodide, THF, 25 °C, yield: 76–82%; (iv) MeOH, NaOH, 25 °C, yield: 80–90%; (v) THF, EDCI, HOBT, amine, 37 °C, yield: 50–80%.

Figure 3. Binding interactions of compounds (F8, F24, and F42) with CYP51 protein (PDB code: 6AY6).

Table 1

The results of antimicrobial and antifungal activity of tested compounds (MIC₈₀, μg/mL).

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
[Image omitted. Please see PDF.]  (F1–F9)						[Image omitted. Please see PDF.]  (F27–F35)
F1	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F27	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F2	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F28	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F3	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F29	[Image omitted. Please see PDF.]	64	>128	>128	>128
F4	[Image omitted. Please see PDF.]	>128	>128	>128	128	F30	[Image omitted. Please see PDF.]	128	>128	>128	>128
F5	[Image omitted. Please see PDF.]	64	128	>128	64	F31	[Image omitted. Please see PDF.]	>128	64	>128	>128
F6	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F32	[Image omitted. Please see PDF.]	>128	>128	>128	64
F7	[Image omitted. Please see PDF.]	128	>128	>128	32	F33	[Image omitted. Please see PDF.]	>128	>128	>128	128
F8	[Image omitted. Please see PDF.]	>128	>128	>128	16	F34	[Image omitted. Please see PDF.]	>128	>128	>128	128
F9	[Image omitted. Please see PDF.]	64	32	>128	64	F35	[Image omitted. Please see PDF.]	>128	>128	>128	>128
[Image omitted. Please see PDF.]  (F10–F17)						[Image omitted. Please see PDF.]  (F36–F44)
F10	[Image omitted. Please see PDF.]	>128	>128	>128	128	F36	[Image omitted. Please see PDF.]	128	>128	>128	128
F11	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F37	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F12	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F38	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F13	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F39	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F14	[Image omitted. Please see PDF.]	>128	>128	>128	128	F40	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F15	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F41	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F16	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F42	[Image omitted. Please see PDF.]	>128	>128	>128	16
F17	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F43	[Image omitted. Please see PDF.]	>128	>128	>128	>128
[Image omitted. Please see PDF.]  (F18–F26)						F44	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F18	[Image omitted. Please see PDF.]	>128	>128	>128	>128	[Image omitted. Please see PDF.]  (F45–F53)
F19	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F45	[Image omitted. Please see PDF.]	>128	64	>128	>128
F20	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F46	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F21	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F47	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F22	[Image omitted. Please see PDF.]	>128	>128	>128	32	F48	[Image omitted. Please see PDF.]	>128	>128	>128	>128
F23	[Image omitted. Please see PDF.]	>128	>128	>128	64	F49	[Image omitted. Please see PDF.]	128	>128	>128	64
F24	[Image omitted. Please see PDF.]	>128	>128	>128	16	F50	[Image omitted. Please see PDF.]	>128	>128	>128	64
F25	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F51	[Image omitted. Please see PDF.]	128	>128	>128	32
F26	[Image omitted. Please see PDF.]	>128	>128	>128	>128	F52	[Image omitted. Please see PDF.]	>128	>128	>128	>128
						F53	[Image omitted. Please see PDF.]	64	128	>128	>128
Ciprofloxacin		2	2	2	-	Ciprofloxacin		2	2	2	-
Fluconazole		-	-	-	2	Fluconazole		-	-	-	2

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29174124/s1, Compounds characterization—Pages S2–S86: ¹H NMR, ¹³C NMR and HRMS spectrum of all the target compounds.

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