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Article

Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety

by
Shiyuan Li
1 and
Hong Jin
2,*
1
Key Laboratory of Drug-Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
2
Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(12), 2575; https://doi.org/10.3390/molecules30122575
Submission received: 14 May 2025 / Revised: 11 June 2025 / Accepted: 12 June 2025 / Published: 13 June 2025
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Abstract

:
Twenty-one novel chalcone derivatives, 5a-5u, incorporating a diphenyl ether moiety, were designed, prepared, and subsequently characterized using NMR and HR-MS and FR-IR techniques. Antibacterial evaluation of the target compounds was carried out against Staphylococcus aureus, Escherichia coli, Salmonella, and Pseudomonas aeruginosa. The in vitro results demonstrated that most compounds exhibited considerable potency in inhibiting bacterial growth, with MIC values ranging from 25.23 to 83.50 μM for S. aureus, 27.53 to 76.25 μM for E. coli, 29.73 to 71.73 μM for Salmonella, and 27.53 to 71.73 μM for P. aeruginosa. Notably, all synthesized compounds exhibited superior antibacterial activity compared to the lead chalcone. In particular, compound 5u, which features two diphenyl ether moieties, displayed outstanding antibacterial performance, with MIC values of 25.23 μM for S. aureus and 33.63 μM for E. coli, Salmonella, and P. aeruginosa. Moreover, compound 5u outperformed both ciprofloxacin and gentamicin against Salmonella and P. aeruginosa, and time-kill curve assays further revealed that concentrations of compound 5u at or above 33.63 μM provided potent and sustained inhibition of both Salmonella and P. aeruginosa. Additionally, molecular modeling of the P. aeruginosa LpxC-compound 5u complex suggested that compound 5u could strongly bind to and interact with the binding site of the LpxC. Based on these findings, compound 5u represents a promising lead for future antimicrobial development.

1. Introduction

Bacterial infections have represented a major global health threat for several centuries [1,2,3]. Pathogens such as Staphylococcus aureus, Escherichia coli, Salmonella, and Pseudomonas aeruginosa continue to pose significant challenges to healthcare systems [4,5,6]. Alarmingly, antimicrobial resistance (AMR) is projected to cause 10 million deaths annually by 2050 if no effective intervention is implemented [7]. This impending crisis necessitates the development of innovative, broad-spectrum agents capable of overcoming drug resistance. Despite vigorous antibacterial research efforts [8,9,10,11], the current antibiotic pipeline remains critically limited due to protracted development cycles of 10–15 years. The World Health Organization (WHO) has identified AMR as one of the top 10 global health threats, underscoring the urgent need for next-generation therapeutic strategies [12].
Chalcones, also known as α, β-unsaturated ketones, constitute an important class of natural drug scaffolds [13]. These compounds are widely distributed in vegetables, fruits, teas, and other plants, where they serve as precursors for the biosynthesis of flavonoids and isoflavonoids [14]. The chalcone family has attracted considerable attention due to its diverse biological activities, as exemplified by compounds 1, 2, and 3 (Figure 1) [14,15,16,17,18,19]. Several chalcone-based compounds have received clinical approval, including compound 4 (Metochalcone) and compound 5 (Sofalcone) (Figure 1) [20,21]. Numerous reviews have comprehensively discussed chalcone synthesis, biological activities, and molecular targets [13,14,15,16,17,18,19,20,21].
In our previous studies, we synthesized various substituted diphenyl ether derivatives that exhibited significant antimicrobial activity [22,23,24,25]. Natural diphenyl ether derivatives have been reported to possess potent pharmacological activities, including antifungal, antibacterial, antimitotic, and immunosuppressive effects [26,27,28]. To extend our research in developing novel chalcone-based antibacterial agents [29,30,31], we have designed and synthesized a series of new chalcone derivatives, 5a-5u, that incorporate a diphenyl ether moiety, based on the principle of integrating bioactive substructures (Figure 2). Herein, we report the synthesis of these novel chalcone derivatives (Scheme 1), after evaluating their antibacterial activities against S. aureus, E. coli, Salmonella, and P. aeruginosa. Furthermore, molecular modeling of the target compound was used to verify their potential mechanism.

2. Results and Discussion

2.1. Chemistry

The synthetic pathways and general structures of the target compounds 5a-5u are shown in Scheme 1. Initially, compound 3 was obtained via a condensation reaction between compounds 1 and 2 in the presence of CsCO3 [32]. Subsequently, compound 3 was reacted with substituted aromatic aldehydes 4 through a classical Aldol condensation, affording a series of novel target compounds 5a-5u [33,34].
Lipinski’s rule of five predicts whether a compound possesses the chemical and physical properties likely to confer oral bioavailability in drugs [35]. In accordance with this principle, we calculated the molecular weight (MW), partition coefficient (logP), number of hydrogen bond acceptors (HBA), and number of hydrogen bond donors (HBD) for all synthesized target compounds (Table 1). Several compounds exhibited parameters consistent with the rule of five, suggesting their potential as orally active drug candidates.

2.2. Antibacterial Activity

2.2.1. Minimum Inhibitory Concentration of the Target Compounds 5a-5u

In this study, the target compounds 5a-5u were evaluated for their ability to inhibit bacterial growth using a standard broth minimal inhibitory concentration (MIC) determination (Table 2) [34,36]. The bacterial strains used were S. aureus, E. coli, Salmonella, and P. aeruginosa, with ciprofloxacin and gentamicin serving as positive controls. Among the compounds 5a-5t, possessing a single diphenyl ether moiety, most exhibited notable inhibitory effects against the four bacterial species; however, variations in the nature and position of substituents significantly influenced their antibacterial activity. Specifically, our results indicated that both substituent type and position were critical determinants of antibacterial efficacy. For example, compound 5h, featuring a 3-chloro substituent, demonstrated an MIC of 44.60 µM against S. aureus, which is substantially lower than that of its 2-chloro analog, compound 5b (MIC = 58.65 µM). Additionally, compound 5c, with a 2-bromo substituent, exhibited broad-spectrum activity against all tested pathogens with a uniform MIC value of 33.48 µM. Notably, compound 5t, bearing a 4-nitro substituent, showed exceptional inhibition of P. aeruginosa (MIC = 32.20 µM), outperforming the analogous compound 5s with a 3-nitro group (MIC = 40.23 µM).
Furthermore, the compounds demonstrated high efficacy against Gram-negative bacteria, although challenges with Salmonella resistance were observed. Several compounds exhibited potent inhibition of Gram-negative bacteria, such as E. coli. For example, compound 5c (2-Br) achieved an MIC value of 33.48 µM against E. coli, which is comparable to its activity against S. aureus, thereby highlighting its broad-spectrum potential. In contrast, Salmonella displayed pronounced resistance; ciprofloxacin, a standard antibiotic, recorded an MIC of 259.17 µM against Salmonella, substantially exceeding its efficacy against E. coli (MIC = 0.78 µM). Moreover, gentamicin demonstrated a significant increase in MIC against P. aeruginosa (MIC = 521.1 µM) relative to E. coli (MIC = 1.04 µM), underscoring species-specific sensitivity differences.
In addition, all synthesized compounds exhibited superior antibacterial activity against the four bacterial strains compared to the lead chalcone (Table 2). Incorporation of the diphenyl ether moiety into the chalcone structure substantially enhanced antibacterial properties. Consequently, compound 5u, which features two diphenyl ether moieties, was synthesized, and it demonstrated the most potent activity, with MIC values of 25.23, 33.63, 33.63, and 33.63 μM against S. aureus, E. coli, Salmonella, and P. aeruginosa, respectively. Notably, its activity against Salmonella and P. aeruginosa surpassed that of ciprofloxacin and gentamicin, thereby warranting further study as a lead compound. As a result, compound 5u was subjected to in vitro time-kill assays.

2.2.2. Concentration Time-Kill Curves of Compound 5u

Initially, the inhibitory effect of compound 5u on Salmonella was analyzed, revealing significant concentration- and time-dependent characteristics (Figure 3a) [36]. At concentrations equal to or greater than 1 MIC, the antibacterial efficacy was markedly enhanced and sustained. Specifically, after 4 h of treatment, the optical density (OD) values for the 1 MIC and 2 MIC groups decreased to 0.062 and 0.058, respectively, compared to 0.302 for the control, corresponding to approximately 79.5% and 80.8% inhibition. At 24 h, the OD values remained low (1 MIC: 0.124; 2 MIC: 0.073), with the 2 MIC group achieving a 92.6% inhibition rate (control OD at 24 h: 0.987), thereby demonstrating long-term suppression of bacterial growth at higher concentrations. In contrast, the 0.5 MIC concentration exhibited only transient efficacy with rebound tendencies, while the OD value increased from 0.135 at 6 h to 0.278 at 8 h, and further to 0.614 at 24 h, suggesting that this lower concentration is insufficient for complete bacterial control.
Similarly, the inhibitory effect of compound 5u on P. aeruginosa was evaluated and was found to be significantly concentration- and time-dependent (Figure 3b). At concentrations equal to or exceeding 1 MIC, the OD values for the 1 MIC and 2 MIC groups decreased to 0.064 and 0.057, respectively, from a control value of 0.301 (approximately 79% inhibition), and remained low at 24 h (1 MIC: 0.117; 2 MIC: 0.062). In contrast, the 0.5 MIC group showed limited efficacy with rebound tendencies; its OD value increased to 0.626 at 12 h, approaching the control value of 0.741, and remained elevated at 0.638 by 24 h, which may indicate bacterial adaptation. High concentrations (>1 MIC) demonstrated rapid and stable inhibition: the 1 MIC group achieved an OD value of 0.064 within 4 h, with only a modest increase to 0.117 by 24 h, while the 2 MIC group’s OD value at 24 h (0.062) even fell below the initial baseline, suggesting complete bacterial eradication or metabolic suppression. In brief, compound 5u at concentrations of ≥1 MIC provided potent and durable inhibition against both Salmonella and P. aeruginosa, whereas a 0.5 MIC concentration only temporarily delayed growth without fully controlling bacterial proliferation.

2.3. Molecular Docking Comparison of Compound 5u and Chalcone

LpxC is a key and essential enzyme in the biosynthesis pathway of lipid A in Gram-negative bacteria [37]. In order to further verify the antibacterial activity of compound 5u, the theoretical binding mode between 5u and P. aeruginosa LpxC was investigated (Figure 4) [38,39,40]. The evaluated binding energy between 5u and LpxC was −8.2 kcal mol−1. Compound 5u adopted a W-shaped conformation in the pocket of the LpxC. Compound 5u stretched into the hydrophobic pocket that consisted of the residues Leu-18, Met-62, Phe-191, Ile-197, Leu-200, Ala-206, Ala-214, and Val-216, forming strong hydrophobic bindings. Detailed analysis showed that the 2,4-dichlorophenyl group of 5u formed a Cl-π interaction with the residue Phe-191, while the 4-chlorophenyl group of 5u formed a cation-π interaction with the residue Arg-201. Importantly, one hydrogen bond interaction was observed between the residue Thr-190 and 5u (bond length: 2.6 Å), which was the main interactions between 5u and LpxC. All these interactions helped 5u to anchor in the binding site of LpxC.
To further clarify the activity order between 5u and chalcone, chalcone was docked to the binding pocket of the LpxC, and the theoretical binding mode between chalcone and LpxC was investigated (Figure 5). The evaluated binding energy between chalcone and LpxC was −7.2 kcal mol−1. Chalcone adopted a compact conformation in the pocket of the LpxC. Chalcone stretched into the hydrophobic pocket that consisted of the residues Leu-18, Ile-197, Leu-200, Ala-206, Ala-214, and Val-216, forming stable hydrophobic bindings. Detailed analysis showed that one of the phenyl groups of chalcone formed cation-π interaction with the residue Arg-201, which was the main interactions between chalcone and LpxC. All these interactions helped chalcone to anchor in the binding site of LpxC.
Chalcone overlapped the half conformation of 5u in the pocket of the LpxC (Figure 6). Regardless of hydrophobic interactions, π interactions, and hydrogen bond interactions, chalcone was weaker than compound 5u, which made 5u more active than chalcone against LpxC. This result is consistent with the antibacterial activity observed in the experiment.

2.4. Molecular Modeling of Compound 5u

To further explore the potential binding mode between 5u and LpxC, molecular dynamics simulations were performed using the AutoDock vina 1.1.2 and Amber14 software package [41,42,43,44,45,46,47]. The preferential binding mechanism of LpxC with 5u was determined by 40 ns molecular dynamics simulations based on the docking results. To explore the dynamic stability of the models and to ensure the rationality of the sampling strategy, the root mean square deviation (RMSD) values of the protein backbone based on the starting structure along the simulation time were calculated and plotted in Figure 7 and the protein structures of the two systems were stabilized during the simulation.
The root mean square fluctuations (RMSF) of the residues of the whole protein in the LpxC-5u complex and in the free LpxC were calculated to reveal the flexibility of these residues. The RMSF of these residues are shown in Figure 8, clearly depicting different flexibilities in the binding site of LpxC in the presence and absence of 5u. All of the residues in the LpxC binding site that bound with 5u showed a small degree of flexibility with an RMSF of less than 2 Å when compared with free LpxC, indicating that these residues seemed to be more rigid as a result of binding to 5u.
To gain more information about the residues surrounding the binding site and their contribution to the whole system, the electrostatic, Van der Waals, solvation, and total contribution values of the residues to the binding free energy were calculated with the MMGBSA method. The summations of the per residue interaction free energies were separated into Van der Waals (∆Evdw), solvation (∆Esol), electrostatic (∆Eele), and total contribution (∆Etotal). In the LpxC-5u complex, the residue Ser-210 had a strong electrostatic (∆Eele) contribution, with an ∆Eele of <−10.0 kcal/mol (Figure 9). Detailed analysis showed that the residue Ser-210 formed a hydrogen bond interaction with 5u, with a bond length of 3.5 Å (Figure 10). Moreover, the residues Arg-201 and Lys-238 had moderate electrostatic (∆Eele) contributions, with an ∆Eele of <−7.5 kcal/mol (Figure 9). Detailed analysis showed that the residues Arg-201 and Lys-238 formed cation-π interactions with phenyl groups of 5u (Figure 10). In addition, residues Met-62 and Ile-197, with ∆Evdw values of <−2.0 kcal/mol, had strong Van der Waals interaction with the ligand because of the close proximity between the residue and the 5u. Overall, the majority of the decomposed energy interaction originated from Van der Waals interactions, mainly through hydrophobic interactions, such as Leu-18, Phe-191, Leu-200, Ala-206, Val-211, Ala-214, and Val-216. In addition, the total binding free energy for the LpxC-5u complex calculated according to the MMGBSA approach, and an estimated ∆Gbind value of −38.0 kcal/mol was obtained for 5u, suggesting that 5u can bind to the binding site of the LpxC.

3. Materials and Methods

3.1. General Chemical Procedures

All starting materials and reagents were commercially available and were used without further purification. Merck silica gel GF254 plates (Darmstadt, Germany) were used for analytical TLC. 1H and 13C NMR spectra were obtained on a Bruker, AVAVNCE NEO 400 (Billerica, MA, USA, 400 MHz for 1H and 100 MHz for 13C) in DMSO-d6. Chemical shifts are expressed in δ (ppm) and coupling constants (J) in Hz. The high-resolution mass (HRMS) spectra were recorded on a Bruker maxis impact Q-TOF instrument (Bruker, Billerica, MA, USA) coupled with a Dionex Ultimate 3000 spectrometer (Dionex, Sunnyvale, CA, USA) and the melting points of the target compounds were determined on an X-4B melting point apparatus (Shanghai Precision Scientific Instrument Ltd., Shanghai, China). The FR-IR spectrum data were obtained on a Thermo Scientific Nicolet Summit X (Thermo Fisher Scientific, Waltham, MA, USA). The calculation of Lipinski’s rule of compounds’ five parameters was carried out using the XLOGP3+ software v1.0.0 [48].

3.2. Bacterial Strains

Bacterial strains of S. aureus, E. coli, Salmonella, and P. aeruginosa were provided by the Key Laboratory of Industrial Fermentation Microorganism of Chongqing University of Science and Technology.

3.3. General Procedure of for the Synthesis of Compounds 5a-5u

3.3.1. Synthesis of Intermediate Compound 3

Compound 1 (15 mmol) was dissolved in DMSO (10 mL), and then Cs2CO3 (10 mmol) was added, and finally compound 2 (10 mmol) was added into the solution. The reaction mixture was stirred at 150 °C, and monitored by TLC (petroleum ether/ethyl acetate 20:1). After the reaction was completed at 8 h, the solvent was removed under reduced pressure and the residue was purified by column chromatography with petroleum ether/ethyl acetate (40:1) as eluent to give intermediate compound 3 with 76% yield.

3.3.2. Synthesis of Target Compounds 5a-5u

Compound 4, (20 mmol), NaOH solution (10%, 4 mL), and intermediate compound 3 (20 mmol) were dissolved in anhydrous ethanol (10 mL). The mixture was stirred for 5–10 h at room temperature, and monitored by TLC (petroleum ether/ethyl acetate 30:1). Ice water (100 mL) was added and the mixture was neutralized with HCl (5%). The solid was precipitated out, filtered off, and washed with water. The pure target compounds 5a-5u were obtained by recrystallization in anhydrous ethanol. The chemical structures of the target compounds were accurately confirmed using 1H NMR, 13C NMR, HRMS, and FR-IR. The yields and spectral data of target compounds 5a-5u are given below.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(2-fluorophenyl)prop-2-en-1-one 5a, yellow powder, m.p. 110–112 °C, Yield: 83%. IR(KBr): ʋmax 3069, 1664, 1605, 1504, 1280, 1258, 975, 868, 822, 750, 697, 708 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.21 (dt, J = 9.2, 2.9 Hz, 2H), 8.16–8.08 (m, 1H), 8.04–7.94 (m, 1H), 7.86 (dt, J = 6.1, 2.7 Hz, 1H), 7.84–7.78 (m, 1H), 7.54 (dd, J = 6.3, 2.7 Hz, 1H), 7.52–7.44 (m, 1H), 7.38–7.35 (m, 1H), 7.35–7.29 (m, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.09 (t, J = 2.7 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.87 (s, 1C), 161.39 (d, 1C), 161.00 (s, 1C), 149.68 (s, 1C), 135.38 (d, 1C), 133.15 (d, 1C), 133.00 (s, 1C), 131.79 (s, 2C), 130.92 (s, 1C), 130.48 (s, 1C), 129.67 (d, 1C), 127.14 (s, 1C), 125.46 (d, 1C), 124.46 (d, 1C), 122.77 (d, 1C), 122.23 (s, 1C), 118.09 (s, 1C), 117.03 (s, 2C), 116.57 (d, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl2FO2 387.0355, found 387.0358.
  • (E)-3-(2-Chlorophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5b, yellow powder, m.p. 117–119 °C, Yield: 86%. IR (KBr): ʋmax 3063, 1681, 1594, 1502, 1308, 1254, 979, 867, 829, 749, 685, 705 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 2.0 Hz, 1H), 8.23 (q, J = 2.8 Hz, 2H), 8.10–7.96 (m, 2H), 7.86 (d, J = 2.5 Hz, 1H), 7.60–7.56 (m, 1H), 7.54 (dd, J = 8.7, 2.5 Hz, 1H), 7.50–7.47 (m, 1H), 7.48–7.44 (m, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.15–7.04 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.80 (s, 1C), 161.03 (s, 1C), 149.68 (s, 1C), 138.76 (s, 1C), 134.83 (s, 1C), 132.96 (s, 1C), 132.76 (s, 1C), 132.45 (s, 1C), 131.87 (s, 2C), 130.91 (s, 1C), 130.51 (s, 1C), 130.48 (s, 1C), 129.70 (s, 1C), 129.07 (s, 1C), 128.15 (s, 1C), 127.14 (s, 1C), 125.06 (s, 1C), 124.45 (s, 1C), 117.00 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl3O2 403.0059, found 403.0063.
  • (E)-3-(2-Bromophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5c, yellow powder, m.p. 119–121 °C, Yield: 87%. IR (KBr): ʋmax 3060, 1659, 1596, 1503, 1310, 1240, 973, 867, 828, 749, 702, 660 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.28–8.22 (m, 2H), 8.20 (dd, J = 7.9, 1.8 Hz, 1H), 7.99 (d, J = 4.5 Hz, 2H), 7.87 (d, J = 2.6 Hz, 1H), 7.75 (dd, J = 8.0, 1.3 Hz, 1H), 7.60–7.52 (m, 1H), 7.49 (dd, J = 7.6, 1.3 Hz, 1H), 7.41 (dd, J = 7.7, 1.7 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 187.80 (s, 1C), 161.04 (s, 1C), 149.67 (s, 1C), 141.51 (s, 1C), 134.43 (s, 1C), 133.78 (s, 1C), 132.96 (s, 1C), 132.65 (s, 1C), 131.89 (s, 2C), 130.92 (s, 1C), 130.48 (s, 1C), 129.72 (s, 1C), 129.25 (s, 1C), 128.71 (s, 1C), 127.14 (s, 1C), 125.86 (s, 1C), 125.23 (s, 1C), 124.48 (s, 1C), 117.01 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14BrCl2O2 446.9554, found 446.9556.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(o-tolyl)prop-2-en-1-one 5d, light yellow powder, m.p. 105–107 °C, Yield: 81%. IR (KBr): ʋmax 3060, 2971, 1656, 1592, 1482, 1379, 1318, 1253, 978, 867, 827, 755, 698, 669 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dq, J = 9.2, 2.4 Hz, 2H), 8.05–8.00 (m, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.89–7.84 (m, 1H), 7.83 (dq, J = 4.6, 2.1 Hz, 1H), 7.55–7.49 (m, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.30 (d, J = 6.6 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.14–7.04 (m, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 193.76 (s, 1C), 188.00 (s, 1C), 160.81 (s, 1C), 149.74 (s, 1C), 141.27 (s, 1C), 138.45 (s, 1C), 133.77 (s, 1C), 131.70 (s, 2C), 131.25 (s, 1C), 130.87 (s, 1C), 130.80 (s, 1C), 129.64 (s, 1C), 127.32 (s, 1C), 127.12 (s, 1C), 126.83 (s, 1C), 124.35 (s, 1C), 123.15 (s, 1C), 122.13 (s, 1C), 116.96 (s, 2C), 19.81 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O2 383.0606, found 383.0608.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(2-methoxyphenyl)prop-2-en-1-one 5e, orange powder, m.p. 107–109 °C, Yield: 84%. IR (KBr): ʋmax 3071, 2962, 1653, 1599, 1435, 1414, 1335, 1315, 1241, 970, 870, 825, 745, 702, 670 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.28–8.14 (m, 2H), 8.07 (d, J = 15.7 Hz, 1H), 8.01–7.94 (m, 1H), 7.90 (d, J = 15.7 Hz, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.53 (dt, J = 8.9, 2.7 Hz, 1H), 7.46 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.16–7.12 (m, 1H), 7.12–7.06 (m, 2H), 7.04 (d, J = 7.4 Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 188.14 (s, 1C), 160.73 (s, 1C), 158.72 (s, 1C), 149.76 (s, 1C), 138.80 (s, 1C), 132.76 (s, 1C), 131.59 (s, 2C), 130.88 (s, 1C), 130.40 (s, 1C), 129.66 (s, 1C), 129.02 (s, 1C), 127.12 (s, 1C), 124.38 (s, 1C), 123.40 (s, 1C), 122.10 (s, 1C), 121.15 (s, 1C), 118.04 (s, 1C), 116.97 (s, 2C), 112.23 (s, 1C), 56.16 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O3 399.0555, found 399.0557.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one 5f, light yellow powder, m.p. 120–122 °C, Yield: 82%. IR (KBr): ʋmax 2972, 1663, 1601, 1576, 1483, 1416, 1384, 1330, 1311, 1280, 974, 872, 829, 751, 703, 651 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 7.2 Hz, 1H), 8.31–8.16 (m, 2H), 8.13–8.03 (m, 1H), 7.98 (d, J = 14.5 Hz, 1H), 7.86 (dd, J = 9.9, 4.6 Hz, 1H), 7.81 (t, J = 6.8 Hz, 1H), 7.68 (t, J = 7.1 Hz, 1H), 7.54 (ddt, J = 9.1, 6.6, 3.3 Hz, 1H), 7.38 (dd, J = 8.9, 4.9 Hz, 1H), 7.18–7.07 (m, 2H), 7.08–6.99 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 187.67 (s, 1C), 161.13 (s, 1C), 149.64 (s, 1C), 138.02 (s, 1C), 133.43 (s, 1C), 132.77 (s, 1C), 131.95 (s, 2C), 130.96 (s, 1C), 130.91 (s, 1C), 130.69 (s, 1C), 130.51 (s, 1C), 129.70 (s, 1C), 129.26 (s, 1C), 127.15 (s, 1C), 126.64 (dd, J = 6 Hz, 1C), 126.51 (s, 1C), 124.47 (s, 1C), 122.22 (s, 1C), 118.05 (s, 1C), 117.00 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C22H14Cl2F3O2 437.0323, found 437.0325.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(3-fluorophenyl)prop-2-en-1-one 5g, light yellow powder, m.p. 114–116 °C, Yield: 80%. IR (KBr): ʋmax 2972, 1664, 1599, 1502, 1304, 1234, 979, 865, 805, 752, 691, 691 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.32–8.14 (m, 2H), 8.02 (dd, J = 15.7, 3.4 Hz, 1H), 7.89–7.85 (m, 1H), 7.85 (s, 1H), 7.76 (d, J = 3.4 Hz, 1H), 7.73–7.67 (m, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.35 (dd, J = 8.7, 3.5 Hz, 1H), 7.33–7.23 (m, 1H), 7.10 (dd, J = 8.6, 3.5 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.95 (s, 1C), 162.97 (d, J = 242 Hz, 1C), 160.94 (s, 1C), 149.72 (s, 1C), 142.78 (d, J = 3 Hz, 1C), 137.75 (d, J = 7 Hz, 1C), 133.11 (s, 1C), 131.83 (s, 2C), 131.32(d, J = 9 Hz, 1C), 130.90 (s, 1C), 130.44 (s, 1C), 129.69 (s, 1C), 127.11 (s, 1C), 126.07 (s, 1C), 124.41 (s, 1C), 123.79 (s, 1C), 117.72 (d, J = 22 Hz, 1C), 116.99 (s, 2C), 115.14 (d, J = 22 Hz, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl2FO2 387.0355, found 387.0357.
  • (E)-3-(3-Chlorophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5h, light yellow powder, m.p. 120–122 °C, Yield: 80%. IR (KBr): ʋmax 3097, 1663, 1594, 1503, 1311, 1262, 976, 869, 814, 750, 685, 685 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.29–8.20 (m, 2H), 8.09 (d, J = 2.0 Hz, 1H), 8.08–8.00 (m, 1H), 7.87 (dd, J = 2.5, 0.9 Hz, 1H), 7.83 (dt, J = 6.6, 1.9 Hz, 1H), 7.72 (d, J = 15.6 Hz, 1H), 7.57–7.52 (m, 1H), 7.51 (q, J = 1.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.14–7.03 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.93 (s, 1C), 160.96 (s, 1C), 149.72 (s, 1C), 142.54 (s, 1C), 137.44 (s, 1C), 134.27 (s, 1C), 133.10 (s, 1C), 131.87 (s, 2C), 131.17 (s, 1C), 130.92 (s, 1C), 130.61 (s, 1C), 130.45 (s, 1C), 129.71 (s, 1C), 128.43 (s, 1C), 128.40 (s, 1C), 127.12 (s, 1C), 124.44 (s, 1C), 123.89 (s, 1C), 116.99 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl3O2 403.0059, found 403.0063.
  • (E)-3-(3-Bromophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5i, yellow powder, m.p. 124–126 °C, Yield: 84%. IR (KBr): ʋmax 3403, 1652, 1601, 1557, 1307, 1241, 943, 867, 817, 752, 690, 662 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (t, J = 2.8 Hz, 1H), 8.23 (dd, J = 6.1, 3.1 Hz, 2H), 8.04 (d, J = 15.6 Hz, 1H), 7.87 (d, J = 3.3 Hz, 1H), 7.86–7.80 (m, 1H), 7.71 (dt, J = 15.6, 2.9 Hz, 1H), 7.64 (dt, J = 8.2, 2.6 Hz, 1H), 7.53 (dt, J = 8.8, 3.1 Hz, 1H), 7.45–7.30 (m, 2H), 7.10 (q, J = 3.1 Hz, 1H), 7.09–7.02 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 187.90 (s, 1C), 160.95 (s, 1C), 149.72 (s, 1C), 142.49 (s, 1C), 137.69 (s, 1C), 133.49 (s, 1C), 133.10 (s, 1C), 131.87 (s, 2C), 131.42 (s, 1C), 131.28 (s, 1C), 130.91 (s, 1C), 130.44 (s, 1C), 129.70 (s, 1C), 128.77 (s, 1C), 127.12 (s, 1C), 124.43 (s, 1C), 123.85 (s, 1C), 122.88 (s, 1C), 116.98 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14BrCl2O2 446.9554, found 446.9556.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(m-tolyl)prop-2-en-1-one 5j, yellow powder, m.p. 108–110 °C, Yield: 80%. IR (KBr): ʋmax 3680, 2920, 1660, 1595, 1470, 1379, 1314, 1255, 978, 861, 817, 751, 692, 666 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.26–8.18 (m, 2H), 7.98–7.88 (m, 1H), 7.75–7.71 (m, 1H), 7.69–7.64 (m, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.36 (ddd, J = 9.4, 6.7, 2.0 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.20 (q, J = 2.0 Hz, 1H), 7.19 (t, J = 2.0 Hz, 1H), 7.16–7.10 (m, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 188.06 (s, 1C), 161.27 (s, 1C), 154.53 (s, 1C), 144.40 (s, 1C), 138.64 (s, 1C), 135.08 (s, 1C), 133.22 (s, 1C), 131.81 (s, 1C),131.70 (s, 1C), 131.67 (s, 1C), 130.91 (s, 1C), 130.69 (s, 2C), 129.62 (s, 1C), 129.29 (s, 1C), 129.03 (s, 1C), 126.80 (s, 1C), 122.16 (s, 1C), 122.12 (s, 1C), 118.07 (s, 2C), 21.35 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O2 383.0606, found 383.0608.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(3-methoxyphenyl)prop-2-en-1-one 5k, light yellow powder, m.p. 110–112 °C, Yield: 85%. IR (KBr): ʋmax 3065, 2937, 1660, 1598, 1470, 1432, 1415, 1291, 1235, 979, 870, 828, 733, 693, 670 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.28–8.17 (m, 2H), 7.95 (ddt, J = 15.5, 6.3, 3.1 Hz, 1H), 7.86 (p, J = 3.5 Hz, 1H), 7.72 (dd, J = 15.5, 2.6 Hz, 1H), 7.50–7.47 (m, 1H), 7.46–7.41 (m, 1H), 7.40–7.36 (m, 1H), 7.36–7.31 (m, 1H), 7.22–7.13 (m, 1H), 7.08 (ddt, J = 12.9, 8.9, 3.1 Hz, 2H), 7.03 (dd, J = 5.6, 2.8 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 188.10 (s, 1C), 160.84 (s, 1C), 160.11 (s, 1C), 149.75 (s, 1C), 144.28 (s, 1C), 136.56 (s, 1C), 133.27 (s, 1C), 131.76 (s, 1C), 130.90 (s, 1C), 130.69 (s, 1C), 130.42 (s, 2C), 129.70 (s, 1C), 127.11 (s, 1C), 124.41 (s, 1C), 122.63 (s, 1C), 122.15 (s, 1C), 117.14 (s, 1C), 116.98 (s, 2C), 113.87 (s, 1C), 55.77 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O3 399.0555, found 399.0557.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one 5l, light yellow powder, m.p. 124–126 °C, Yield: 83%. IR (KBr): ʋmax 3068, 1665, 1601, 1578, 1483, 1417, 1327, 1237, 1214, 984, 869, 830, 751, 702, 658 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.47–8.23 (m, 1H), 8.14 (d, J = 29.0 Hz, 1H), 8.01–7.85 (m, 1H), 7.85–7.74 (m, 1H), 7.75–7.61 (m, 1H), 7.60–7.44 (m, 2H), 7.43–7.25 (m, 2H), 7.18 (d, J = 21.3 Hz, 1H), 7.15–7.06 (m, 1H), 7.06–6.96 (m, 1H), 6.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 187.98 (s, 1C), 160.98 (s, 1C), 149.72 (s, 1C), 142.41 (s, 1C), 136.35 (s, 1C), 133.34 (s, 1C), 131.91 (s, 1C), 130.90 (s, 1C), 130.68 (s, 1C), 130.45 (s, 1C), 130.40 (s, 2C), 129.69 (s, 1C), 127.12 (s, 1C), 125.58 (s, 1C), 124.90 (s, 1C), 124.41 (s, 1C), 123.24 (d, J = 215 Hz, 1C), 118.25 (s, 1C), 118.05 (s, 1C), 116.98 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C22H14Cl2F3O2 437.0323, found 437.0326.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(4-fluorophenyl)prop-2-en-1-one 5m, light yellow powder, m.p. 120–122 °C, Yield: 85%. IR (KBr): ʋmax 3066, 1655, 1597, 1504, 1301, 1234, 991, 870, 813, 757, 699, 659 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.29–8.14 (m, 2H), 7.97 (qd, J = 7.4, 3.3 Hz, 2H), 7.92–7.81 (m, 1H), 7.75 (dd, J = 15.6, 3.9 Hz, 1H), 7.52 (dp, J = 10.0, 3.3 Hz, 1H), 7.36–7.28 (m, 2H), 7.18 (dt, J = 10.3, 3.7 Hz, 1H), 7.09 (ddq, J = 10.2, 6.5, 3.4 Hz, 2H), 7.03 (dt, J = 7.7, 4.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 187.97 (s, 1C), 163.92 (d, 1C), 160.83 (s, 1C), 149.73 (s, 1C), 143.04 (s, 1C), 131.85 (d, 1C), 131.76 (s, 1C), 131.72 (s, 2C), 131.68 (s, 2C), 130.89 (s, 1C), 130.68 (s, 1C), 129.69 (s, 1C), 124.41 (s, 1C), 122.16 (s, 1C), 118.04 (s, 1C), 116.97 (s, 2C), 116.52 (s, 1C), 116.30 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl2FO2 387.0355, found 387.0353.
  • (E)-3-(4-Chlorophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5n, light yellow powder, m.p. 125–127 °C, Yield: 80%. IR (KBr): ʋmax 3066, 1678, 1599, 1502, 1317, 1255, 978, 867, 867, 752, 705, 658 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 8.9, 3.4 Hz, 2H), 7.99 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 7.55–7.52 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.22–7.12 (m, 1H), 7.12–7.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.97 (s, 1C), 160.91 (s, 1C), 149.72 (s, 1C), 142.80 (s, 1C), 135.55 (s, 1C), 134.14 (s, 1C), 133.16 (s, 1C), 131.78 (s, 2C), 131.06 (s, 2C), 130.91 (s, 1C), 129.71 (s, 1C), 129.44 (s, 2C), 127.13 (s, 1C), 124.45 (s, 1C), 123.09 (s, 1C), 118.06 (s, 1C), 116.98 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl3O2 403.0059, found 403.0058.
  • (E)-3-(4-Bromophenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5o, light yellow powder, m.p. 130–132 °C, Yield: 86%. 1H NMR (400 MHz, DMSO-d6) δ 8.26–8.18 (m, 1H), 8.04–7.95 (m, 2H), 7.85 (tt, J = 5.4, 2.6 Hz, 2H), 7.76–7.68 (m, 1H), 7.67 (dd, J = 8.5, 2.8 Hz, 1H), 7.51 (ddt, J = 8.3, 5.4, 2.5 Hz, 1H), 7.33 (ddd, J = 11.7, 8.7, 2.8 Hz, 1H), 7.13 (qd, J = 25.2, 11.5, 7.2, 2.7 Hz, 2H), 7.07–6.95 (m, 2H). ESI-HRMS: m/z [M + H]+ calcd. for C21H14BrCl2O2 446.9554, found 446.9555.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(p-tolyl)prop-2-en-1-one 5p, orange powder, m.p. 108–110 °C, Yield: 84%. IR (KBr): ʋmax 3062, 2916, 1654, 1593, 1469, 1380, 1303, 1253, 982, 857, 838, 749, 696, 670 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dt, J = 9.5, 3.0 Hz, 2H), 7.89–7.83 (m, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 15.7 Hz, 1H), 7.56–7.47 (m, 1H), 7.34 (dd, J = 8.8, 3.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.21–7.11 (m, 1H), 7.11–6.99 (m, 2H), 3.40 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 188.02 (s, 1C), 160.74 (s, 1C), 149.78 (s, 1C), 144.35 (s, 1C), 141.15 (s, 1C), 133.39 (s, 1C), 132.44 (s, 1C), 131.65 (s, 2C), 130.89 (s, 1C), 130.67 (s, 1C), 130.02 (s, 2C), 129.68 (s, 1C), 129.39 (s, 1C), 127.10 (s, 1C), 124.38 (s, 1C), 122.14 (s, 1C), 121.27 (s, 1C), 116.98 (s, 2C), 21.57 (s, 1C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O2 383.0606, found 383.0608.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one 5q, yellow powder, m.p. 114–116 °C, Yield: 85%. IR (KBr): ʋmax 3085, 2910, 1675, 1598, 1470, 1413, 1386, 1293, 1232, 959, 881, 832, 751, 697, 670 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.25–8.14 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.85–7.82 (m, 2H), 7.80 (d, J = 15.5 Hz, 1H), 7.72 (d, J = 15.5 Hz, 1H), 7.52 (dd, J = 8.7, 2.6 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.12–7.06 (m, 2H), 7.04–6.98 (m, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 187.92 (s, 1C), 161.83 (s, 1C), 160.64 (s, 1C), 149.82 (s, 1C), 144.28 (s, 1C), 133.58 (s, 1C), 131.56 (s, 2C), 131.27 (s, 2C), 130.90 (s, 1C), 130.35 (s, 1C), 129.68 (s, 1C), 127.79 (s, 1C), 127.08 (s, 1C), 124.35 (s, 1C), 119.81 (s, 1C), 116.98 (s, 2C), 116.78 (s, 1C), 114.88 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C22H17Cl2O3 399.0555, found 399.0554.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one 5r, light yellow powder, m.p. 132–134 °C, Yield: 81%. IR (KBr): ʋmax 3070, 1677, 1601, 1578, 1483, 1416, 1323, 1234, 1161, 989, 870, 830, 750, 673, 622 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (ddd, J = 9.1, 4.9, 2.6 Hz, 2H), 7.84 (t, J = 2.5 Hz, 1H), 7.58 (d, J = 3.5 Hz, 1H), 7.54–7.48 (m, 2H), 7.31 (dd, J = 8.8, 5.7 Hz, 2H), 7.18–7.13 (m, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.05–7.01 (m, 2H), 7.00–6.97 (m, 1H). ESI-HRMS: m/z [M + H]+ calcd. for C22H13Cl2F3NaO2 459.0142, found 459.0149.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one 5s, yellow powder, m.p. 125–127 °C, Yield: 87%. IR (KBr): ʋmax 3071, 1652, 1599, 1570, 1484, 1418, 1348, 1221, 1169, 984, 874, 837, 745, 677, 640 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 8.28 (d, J = 3.0 Hz, 1H), 8.26 (q, J = 3.2 Hz, 2H), 8.17 (dt, J = 15.6, 3.0 Hz, 1H), 7.86 (ddd, J = 12.3, 6.9, 3.4 Hz, 1H), 7.75 (td, J = 8.0, 3.5 Hz, 1H), 7.53 (dq, J = 10.2, 3.3 Hz, 1H), 7.36 (dt, J = 8.8, 3.4 Hz, 1H), 7.22–7.14 (m, 1H), 7.11 (dt, J = 6.5, 4.7 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.93 (s, 1C), 161.03 (s, 1C), 149.69 (s, 1C), 148.88 (s, 1C), 141.71 (s, 1C), 137.07 (s, 1C), 135.58 (s, 1C), 131.93 (s, 2C),130.91 (s, 1C), 130.83 (s, 1C), 130.69 (s, 1C), 129.70 (s, 1C), 127.13 (s, 1C), 125.12 (s, 1C), 124.44 (s, 1C), 123.47 (s, 1C), 122.19 (s, 1C), 118.04 (s, 1C), 116.98 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl2NO4 414.0300, found 414.0295.
  • (E)-1-(4-(2,4-Dichlorophenoxy)phenyl)-3-(4-nitrophenyl)prop-2-en-1-one 5t, orange powder, m.p. 148–150 °C, Yield: 82%. IR (KBr): ʋmax 3075, 1658, 1599, 1577, 1484, 1415, 1415, 1219, 1168, 983, 875, 830, 747, 660, 626 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.31–8.27 (m, 1H), 8.24 (dt, J = 9.1, 2.6 Hz, 2H), 8.16 (dd, J = 9.1, 2.3 Hz, 2H), 8.10 (d, J = 2.1 Hz, 1H), 7.87–7.76 (m, 2H), 7.53 (ddd, J = 8.9, 4.6, 2.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.3 Hz, 1H), 7.22–7.12 (m, 1H), 7.10 (dd, J = 8.9, 2.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 187.94 (s, 1C), 161.13 (s, 1C), 149.61 (s, 1C), 148.52 (s, 1C), 141.62 (s, 1C), 141.41 (s, 1C), 132.84 (s, 1C), 131.94 (s, 2C), 130.91 (s, 1C), 130.52 (s, 1C), 130.32 (s, 2C), 129.73 (s, 1C), 127.16 (s, 1C), 126.37 (s, 1C), 124.52 (s, 1C), 124.42 (s, 2C), 116.99 (s, 2C). ESI-HRMS: m/z [M + H]+ calcd. for C21H14Cl2NO4 414.0300, found 414.0299.
  • (E)-3-(4-(4-Chlorophenoxy)phenyl)-1-(4-(2,4-dichlorophenoxy)phenyl)prop-2-en-1-one 5u, yellow powder, m.p. 129–131 °C, Yield: 82%. IR (KBr): ʋmax 2980, 1657, 1600, 1580, 1481, 1419, 1293, 1155, 980, 870, 746, 666, 623 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.19–8.10 (m, 2H), 7.99–7.92 (m, 1H), 7.89 (dp, J = 5.9, 2.9 Hz, 2H), 7.76 (dd, J = 15.6, 2.4 Hz, 1H), 7.71–7.64 (m, 1H), 7.62–7.55 (m, 2H), 7.46 (dt, J = 6.4, 3.9 Hz, 3H), 7.43–7.35 (m, 1H), 7.32–7.21 (m, 1H), 7.21–7.12 (m, 1H), 7.12–7.02 (m, 1H), 6.84 (dd, J = 26.0, 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 188.02 (s, 1C), 160.78 (s, 1C), 158.96 (s, 1C), 155.15 (s, 1C), 143.55 (s, 1C), 133.33 (s, 1C), 131.65 (s, 2C), 131.49 (s, 2C), 130.88 (s, 1C), 130.69 (s, 1C), 130.55 (s, 2C), 129.70 (s, 1C), 128.46 (s, 1C), 127.11 (s, 1C), 124.42 (s, 1C), 122.16 (s, 1C), 121.52 (s, 2C), 121.41 (s, 1C), 118.99 (s, 2C), 118.06 (s, 1C), 116.97 (s, 2C). HRMS (ESI) m/z calcd for C27H18Cl3O3 (M + H)+ 495.0322, found 495.0320.

3.4. Compounds MIC Testing

The MIC testing of the target compounds was conducted on the following four bacteria stains: Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Salmonella (ATCC 12022), and Pseudomonas aeruginosa (ATCC 27853) by microdilution in a 96-well cell culture plate. The 5 μL of suspension was transferred to 5 mL of fresh medium and incubated for a few hours to reach the log phase stage. After that, the bacteria were diluted to reach 2 × 106 colony-forming units per milliliter (CFU mL−1). Each well contained 100 μL of the bacterial cell suspension and various concentrations of the target compounds in 100 μL for a final volume of 200 μL wells. The optical density was determined using an enzyme plate analyzer. The experimental results were expressed as OD600, and the experiment was repeated in triplicate.

3.5. Constant Concentration Time-Kill Curves

P. aeruginosa and Salmonella were cultured in an LB liquid medium broth at 37 °C using a shaking incubator at 180 rpm with shaking and then diluted to approximately 6 × 105 CFU mL−1. Test compound samples of 3b with final concentrations of 0.5 × MIC, 1 × MIC, 2 × MIC, and 4 × MIC were inoculated with aliquots of bacteria resuspended in fresh media. A small quantity (0.1 mL) was taken from each sample 2, 4, 6, 8, 10, 12, and 24 h following inoculation, and the optical density was determined using an enzyme plate analyzer. The experimental results were expressed as OD600, and the experiment was repeated in triplicate.

3.6. Molecular Docking of Compound 5u and Chalcone

Molecular docking studies were performed to investigate the binding mode between the compounds and P. aeruginosa LpxC using Autodock vina 1.1.2 [34]. The three-dimensional (3D) structure of the LpxC (PDB ID: 3P3E) was downloaded from RCSB Protein Data Bank (www.rcsb.org). The 3D structures of the compounds were obtained using ChemBioDraw Ultra 14.0 and ChemBio3D Ultra 14.0 software. The AutoDockTools 1.5.6 package was employed to generate the docking input files [36,37]. The search grid of LpxC was identified as center_x: −25.363, center_y: 15.669, and center_z: −5.177 with dimensions size_x: 15, size_y: 15.75, and size_z: 15. The value of exhaustiveness was set to 16. For Vina docking, the default parameters were used if it was not mentioned. The best-scoring pose as judged by the Vina docking score was chosen and visually analyzed using PyMOL 1.7.6 software (www.pymol.org).

3.7. Molecular Modeling of Compound 5u

3.7.1. Molecular Docking

Molecular docking studies were performed to investigate the binding mode between the compounds and P. aeruginosa LpxC using Autodock vina 1.1.2 [34]. The three-dimensional (3D) structure of the LpxC (PDB ID: 3P3E) was downloaded from RCSB Protein Data Bank (www.rcsb.org). The 3D structure of the compounds was obtained using ChemBioDraw Ultra 14.0 and ChemBio3D Ultra 14.0 software. The AutoDockTools 1.5.6 package was employed to generate the docking input files [36,37]. The search grid of LpxC was identified as center_x: −25.363, center_y: 15.669, and center_z: −5.177 with dimensions size_x: 15, size_y: 15.75, and size_z: 15. The value of exhaustiveness was set to 16. For Vina docking, the default parameters were used if it was not mentioned. Then, an MD study was performed to revise the docking result.

3.7.2. Molecular Dynamics

The Amber 14 and AmberTools 15 programs were used for MD simulations of the selected docked pose. The compound was first prepared by ACPYPE, a tool based on ANTECHAMBER for generating automatic topologies and parameters in different formats for different molecular mechanics programs, including calculation of partial charges. Then, the forcefield “leaprc.gaff” (generalized amber forcefield) was used to prepare the ligand, while “leaprc.ff14SB” was used for the receptor. The system was placed in a rectangular box (with a 10.0 Å boundary) of TIP3P water using the “SolvateOct” command with the minimum distance between any solute atoms. Equilibration of the solvated complex was achieved by carrying out a short minimization (5000 steps of each steepest descent and conjugate gradient method), 500 ps of heating, and 50 ps of density equilibration with weak restraints using the GPU (NVIDIA® Tesla K20c, NVIDA, Santa Clara, CA, USA) accelerated PMEMD (Particle Mesh Ewald Molecular Dynamics) module. Finally, 40 ns of MD simulations were carried out. All the molecular dynamics were performed on a Dell Precision T5500 workstation (Dell, Austin, TX, USA).

3.7.3. Binding Free Energy and Energy Decomposition per Residue Calculations

The binding free energies (ΔGbind in kcal/mol) were calculated using the molecular mechanics/generalized born surface area (MM/GBSA) method, implemented in AmberTools 15. Moreover, to identify the key protein residues responsible for the ligands binding process, the binding free energy was decomposed on a per-residue basis. For each complex, the binding free energy of MM/GBSA was estimated as follows:
ΔGbind= Gcomplex − Gprotein − Gligand
where ΔGbind is the binding free energy and Gcomplex, Gprotein, and Gligand are the free energies of complex, protein, and ligand, respectively.

4. Conclusions

In conclusion, a novel series of chalcone derivatives, 5a-5u, incorporating a diphenyl ether moiety, was designed in pursuit of innovative antibacterial agents. The newly synthesized molecules were prepared and characterized by NMR, HR-MS, and FR-IR techniques. The biological evaluation of these compounds was conducted against both Gram-negative and Gram-positive bacteria. In vitro results demonstrated that most of the target compounds exhibited significant potency in inhibiting bacterial growth. In particular, compound 5u with two diphenyl ether moieties displayed exceptional antibacterial activity. Molecular modeling of the P. aeruginosa LpxC-compound 5u complex suggested that compound 5u could strongly bind to and interact with the binding site of the LpxC. Based on these findings, compound 5u represents a promising lead for further optimization and development.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30122575/s1, Compound spectra.

Author Contributions

Conceptualization, H.J.; methodology, S.L. and H.J.; formal analysis, S.L.; investigation, S.L.; writing—original draft preparation, S.L. and H.J.; writing—review and editing, S.L. and H.J.; supervision, H.J.; funding acquisition, H.J.; project administration, H.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Natural Science Foundation of Sichuan, China (2022NSFSC0169), for financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 02575 g001
Figure 1. Natural antibacterial chalcones 1-3 and chalcone drugs 4, 5.
Figure 1. Natural antibacterial chalcones 1-3 and chalcone drugs 4, 5.
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Molecules 30 02575 g002
Figure 2. The strategy for design of novel chalcone derivatives 5a-5u with the diphenyl ether moiety.
Figure 2. The strategy for design of novel chalcone derivatives 5a-5u with the diphenyl ether moiety.
Molecules 30 02575 g002
Molecules 30 02575 sch001
Scheme 1. Synthesis of the target compounds. Reagents and conditions: (i) CsCO3, 150 °C, 8 h; (ii) NaOH, EtOH, r.t., 5–10 h.
Scheme 1. Synthesis of the target compounds. Reagents and conditions: (i) CsCO3, 150 °C, 8 h; (ii) NaOH, EtOH, r.t., 5–10 h.
Molecules 30 02575 sch001
Molecules 30 02575 g003
Figure 3. Time-kill analysis of compound 5u against Salmonella (a) and P. aeruginosa (b).
Figure 3. Time-kill analysis of compound 5u against Salmonella (a) and P. aeruginosa (b).
Molecules 30 02575 g003
Molecules 30 02575 g004
Figure 4. Compound 5u was docked to the binding pocket of the LpxC (detailed view).
Figure 4. Compound 5u was docked to the binding pocket of the LpxC (detailed view).
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Molecules 30 02575 g005
Figure 5. Chalcone was docked to the binding pocket of the LpxC (total view).
Figure 5. Chalcone was docked to the binding pocket of the LpxC (total view).
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Molecules 30 02575 g006
Figure 6. Chalcone and 5u were docked to the binding pocket of the LpxC (overlapped).
Figure 6. Chalcone and 5u were docked to the binding pocket of the LpxC (overlapped).
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Molecules 30 02575 g007
Figure 7. The root mean square deviations (RMSDs) of all the atoms of LpxC-5u complex with respect to its initial structure as function of time.
Figure 7. The root mean square deviations (RMSDs) of all the atoms of LpxC-5u complex with respect to its initial structure as function of time.
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Molecules 30 02575 g008
Figure 8. RMSF of residues of the whole protein in LpxC-5u complex and free LpxC during the 40 ns simulation.
Figure 8. RMSF of residues of the whole protein in LpxC-5u complex and free LpxC during the 40 ns simulation.
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Molecules 30 02575 g009
Figure 9. Decomposition of the binding energy on a per-residue basis in the LpxC-5u complex.
Figure 9. Decomposition of the binding energy on a per-residue basis in the LpxC-5u complex.
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Molecules 30 02575 g010
Figure 10. The predicted binding mode of 5u in the LpxC binding pocket obtained from MD simulation.
Figure 10. The predicted binding mode of 5u in the LpxC binding pocket obtained from MD simulation.
Molecules 30 02575 g010
Table 1. Lipinski’s rule of five parameters of the synthesized chalcone derivatives 5a-5u.
Table 1. Lipinski’s rule of five parameters of the synthesized chalcone derivatives 5a-5u.
CompdRMWlogPHBAHBD
5a2-F387.234.8230
5b2-Cl403.685.6620
5c2-Br448.145.6020
5d2-CH3383.274.7320
5e2-CH3O399.274.4030
5f2-CF3437.245.3220
5g3-F387.234.8230
5h3-Cl403.685.6620
5i3-Br448.145.6020
5j3-CH3383.275.0120
5k3-CH3O399.274.4030
5l3-CF3437.245.3220
5m4-F387.234.8230
5n4-Cl403.685.6620
5o4-Br448.145.6020
5p4-CH3383.274.7320
5q4-CH3O399.274.4030
5r4-CF3437.245.3220
5s3-NO2414.244.2040
5t4-NO2414.244.1860
5u4-(4-ClPh)O495.786.8230
MW: Molecular weight; logP: logarithm of octanol–water partition coefficient; HBA: number of hydrogen bond acceptors; HBD: number of hydrogen bond donors.
Table 2. Antibacterial activity of the synthesized chalcone derivatives 5a-5u.
Table 2. Antibacterial activity of the synthesized chalcone derivatives 5a-5u.
CompdMIC (μM)
S. aureusE. coliSalmonellaP. aeruginosa
5a68.8545.0945.0945.09
5b58.6539.1039.1039.10
5c33.4833.4833.4833.48
5d34.8034.8034.8034.80
5e66.8033.4033.4033.40
5f76.2550.8350.8350.83
5g68.8545.9045.9045.90
5h44.6029.7329.7329.73
5i55.0527.5336.7027.53
5j66.1044.0744.0744.07
5k83.5033.4033.4033.40
5l76.2538.1338.1338.13
5m71.7371.7371.7371.73
5n71.0047.3347.3347.33
5o67.2544.8344.8344.83
5p77.4051.6051.6051.60
5q66.8044.5344.5344.53
5r50.8376.2550.8350.83
5s60.3540.2340.2340.23
5t64.4042.9342.9332.20
5u25.2333.6333.6333.63
chalcone80.03106.70106.70106.70
ciprofloxacin9.720.78259.17388.75
gentamycin6.511.0452.11521.10
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Li, S.; Jin, H. Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety. Molecules 2025, 30, 2575. https://doi.org/10.3390/molecules30122575

AMA Style

Li S, Jin H. Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety. Molecules. 2025; 30(12):2575. https://doi.org/10.3390/molecules30122575

Chicago/Turabian Style

Li, Shiyuan, and Hong Jin. 2025. "Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety" Molecules 30, no. 12: 2575. https://doi.org/10.3390/molecules30122575

APA Style

Li, S., & Jin, H. (2025). Synthesis, Antibacterial Evaluation and Molecular Modeling of Novel Chalcone Derivatives Incorporating the Diphenyl Ether Moiety. Molecules, 30(12), 2575. https://doi.org/10.3390/molecules30122575

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