Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture

Abstract

A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [³H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC₅₀ values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.

1. Introduction

Chalcones (1,3-diaryl-2-propen-1-ones), or α,β-unsaturated carbonyl compounds, the bioprecursors of flavonoids, are an interesting class of compounds that engross medicinal [1,2], synthetic [3], and material chemists [4,5,6] with their diverse applications. Considerable evidence has shown that chalcones have immense chemotherapeutic importance, such as anti-inflammatory [7,8], antimicrobial [9,10], antileishmanial [11], anticancer [12,13], antimalarial [14,15,16] activities. Moreover, radiolabeled chalcones have been used as PET imaging agents for in vivo imaging of the β-amyloid plaques of Alzheimer’s disease [17,18]. After the advent of licochalcone A with its antiplasmodial activity [19], a large number ofnovel synthetic chalcone derivatives and chalcone hybrids have been designed, synthesized and evaluated for their antiplasmodial activity [20,21,22,23,24]. Several reports suggest that chalcones’ antiplasmodial potential is due the ability to inhibit both the plasmodial aspartate protease and cysteine protease targets [24,25].

Malaria is a parasitic disease caused by Plasmodium, which is transmitted to human by female anopheline mosquitoes and continues to be a major cause of the death, killing an estimated 1.5 to 2.7 million people per year [14,26,27]. The high mortality rate caused by P. falciparum strains is compounded by the fact the parasite has shown clinical resistance to currently used first-line antimalarial drugs like chloroquine and vaccines have proven ineffective. Even though Artemisinin is currently considered to be an effective drug for treating chloroquine-resistant P. falciparum infections the WHO has recommended artemisinin-based combination therapies (ACTs) due to the slow development of clinical resistance to this compound. This averts or slows down the resistance developed by P. falciparum to this compound. ACTs also mitigate the increasing demand for artemisinin, which is isolated from the plant Artemisia annua, due to the unavailability of commercially viable synthesis. Therefore, there is a state of emergency to develop new antimalarial agents or drug combinations which are effective and cost-effective [15,16,28].

The use of fluorine or fluorine-containing functional groups in organic compounds has shown spectacular growth in all branches of chemistry, such as medicinal chemistry [29,30,31], agrochemistry [32], material sciences [33], etc. Substitution of fluorine or fluorine-containing functional group in organic molecules exerts large electronic effects on neighboring carbon centers and greatly affects the physico-chemical properties of the resulting molecules. Lipophilicity is an important criterion for the molecules that increases fat solubility and bioavailability, and can be increased by a strategic transformation of organic molecules into fluoroorganic molecules [29,30]. Fluorine substitution at an appropriate site of the molecule can increase their biological half-life, extended activity, and potency by altering the rate of drug metabolism [30,34]. Interestingly, 2,2,2-trifluoroethoxy group-containing molecules appear to be one of the most attractive fluoro functionalities in pharmaceuticals, found in blockbuster drugs such as flecainide, lansoprazole, MF-310, etc. [35,36].

Fluoroorganic compounds and chalcones alone exhibit broad ranges of applications [1,2,3,4,5,6,29,30,31,32,33,37]. Therefore, incorporation of fluorine or fluorine containing groups into chalcones would be expected to have a strong effect on their physico-chemical properties which, in turn, could augment their biological activities. Moreover, biological evaluations of fluorochalcones have not been fully explored, except for some fluorochalcone derivatives, which have been reported for their anti-inflammatory [38,39], or anti-proliferative activity [40], or as inhibitors of monoamine oxidase-B [41,42]. Recently, we have reported a novel methodology for the coupling of bromochalcones with alcohols and fluoroalcohols by Pd/tBuXPhos catalyst systems [43,44,45,46,47]. Taking into consideration of the importance of fluoroethoxy groups and chalcones in biological activity, we pleased to synthesize fluoroethoxy chalcones and assess their antiplasmodial activity. Herein, we report the synthesis and antiplasmodial evaluation of 2,2,2-trifluoroethoxychalcones and 2-fluoroethoxychalcones on the growth of P. falciparum in culture. The most active compounds, 3a and 3f, were further tested for hemolytic activity, cytotoxicity on Vero cells and in combination with artemisinin as a partner antimalarial agent.

2. Results and Discussion

2.1. Chemistry

A series of 2,2,2-trifluoroethoxychalcones 1a–n, 2a–h, 2k, 2m, and 3a–j were synthesized in poor to excellent yields (40–94%) by base catalyzed Claisen−Schmidt condensation of 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (1), 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanone (2), and 1-(2-(2,2,2-trifluoroethoxy)phenyl)ethanone (3), with substituted benzaldehydes as shown in Scheme 1. All the reactions were carried out at room temperature for 30 min, except in the case of indole-2-carboxaldehyde which was the only aldehyde that required refluxing for 2 h as the reaction did not proceed at room temperature and gave the product 1n in poor yield (40%).

Scheme 1.

Synthesis of 2,2,2-trifluoroethoxychalcones.

Similarly, 2-fluoroethoxychalcones, in which 2-fluoroethoxy group is substituted on both the 1-phenyl and 3-phenyl rings, were also synthesized in moderate to excellent yields (66–90%) by the same method from the corresponding 1-(4-(2-fluoroethoxy)phenyl)ethanone (4), 1-(3-(2-fluoroethoxy)phenyl)ethanone (5), and 1-(2-(2-trifluoroethoxy)phenyl)ethanone (6), with substituted benzaldehydes and 4-(2-fluoroethoxy)benzaldehyde (7), 3-(2-fluoroethoxy)benzaldehyde (8), and 2-(2-fluoroethoxy)benzaldehyde (9) with substituted acetophenones i–ix as shown in Scheme 2. Of the 59 chalcones synthesized, 12 chalcones (compounds 1a, 1e–g, 4a, 4e, 4g, 7i–ii, 7iv, 7vii, and 8ii) have already been reported [43,44] and the rest of the chalcones reported here are novel. All the chalcones were characterized by ¹H-, ¹³C- and ¹⁹F-NMR (NMR spectra of all the compounds can be found in the supplementary materials), IR and HRMS analysis and the data were consistent with the structure of the chalcones. The starting materials viz., ((2,2,2-trifluoroethoxy)phenyl)ethanones, ((2-fluoroethoxy)phenyl)ethanones, and 2-fluoroethoxy- benzaldehydes were synthesized by nucleophilic displacement reactions of 2,2,2-trifluoroethyl-4-methylbenzenesulphonate and 2-fluoroethyl-4-methylbenzenesulphonate with the corresponding hydroxyacetophenones and hydroxybenzaldehydes using sodium hydride base in dry DMF at 120 °C. The 2,2,2-trifluoroethyl-4-methylbenzenesulphonate and 2-fluoroethyl-4-methylbenzene- sulphonate were synthesized from the reaction of the corresponding fluoroalcohols with p-toluene-sulfonyl chloride in the presence of potassium hydroxide solution in water at room temperature.

Scheme 2.

Synthesis of 2-fluoroethoxychalcones.

2.2. Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones

Initially, we intended to investigate the effect of the position of the 2,2,2-trifluoroethoxy group on the 1-phenyl ring of chalcones (Scheme 1) on the growth inhibition of P. falciparum (3D7) in culture. The 50% inhibitory concentration (IC₅₀) values on parasite growth for all compound series are given in Table 1. The standard antimalarial drugs chloroquine (CQ) and artemisinin (ART) were used as positive controls. In the first series of fourteen chalcone derivatives 1a–n, in which the 2,2,2-trifluoroethoxy group has been incorporated at the p-position of the 1-phenyl ring of chalcones (Scheme 1 and Table 1), showed very weak inhibitory effects on parasite growth, having IC₅₀ values in the range of 32 to >50 µg/mL, except for the chalcone 1m which showed good activity with an IC₅₀ value of 10 µg/mL (27.3 µM). In the second series of ten chalcone derivatives 2a–h, 2k, and 2m, in which 2,2,2-trifluoroethoxy group has been incorporated at the m-position of the 1-phenyl ring of chalcones (Scheme 1 and Table 1), six chalcones 2a–c, 2h, 2k, and 2m showed weak inhibitory effects with IC₅₀ values of >46 µg/mL on parasite growth and other three chalcones 2d–f showed moderate activity towards the parasite with IC₅₀ values of 23–11 µg/mL. However, the chalcone 2g, was found to be active against P. falciparum (3D7) parasite with an IC₅₀ value of 6 μg/mL (20 µM). In the third series of ten chalcone derivatives 3a–j, in which the 2,2,2-trifluoroethoxy group has been incorporated at the o-position of the 1-phenyl ring (Scheme 1 and Table 1), only two chalcones, 3e and 3h, showed weak activity and the other chalcones were found to display moderate (compounds 3b, 3g, and 3j) and good activities (compounds 3a, 3c, 3d, 3f, and 3i), with IC₅₀ values less than 20 µg/mL and 10 µg/mL, respectively.

Table 1.

In vitro antiplasmodial activity of 2,2,2-trifluoroethoxychalcones against P. falciparum (3D7).

No.	Chalcone	Yield (%) a	P. falciparum (3D7)
			IC50 (µg/mL) b	IC50 (µM)
1		87	>50	>156.1
2		77	>50	>143.1
3		90	41	120.3
4		77	43	111.6
5		94	43	122.4
6		78	37	101.0
7		61	>50	>168.8
8		93	38	97.1
9		81	32	83.1
10		74	>50	>129.8
11		72	40	118.9
12		91	36	107.0
13		70	10	27.3
14		40	>50	>144.8
15		80	>50	>156.1
16		71	>50	>143.1
17		73	49	143.8
18		75	23	59.7
19		73	22	62.6
20		77	11	30.0
21		65	6	20.3
22		85	>50	>127.8
23		73	48	142.7
24		64	46	125.6
25		82	3	9.4
26		72	12.5	35.8
27		73	9	26.4
28		73	10	26.0
29		75	46	130.9
30		62	2.2	6.0
31		59	14	47.3
32		87	30	76.7
33		74	7	18.2
34		74	19	49.3
	Chloroquine (CQ) c		0.010	0.031
	Artemisinin (ART) c		0.021	0.074

^a Isolated yield; ^b IC₅₀ (µg/mL): concentration corresponding to 50% growth inhibition of parasite; ^c Antimalarial control.

Among the third series of chalcones, the chalcones 3a–d, 3f, and 3i–j possessing diverse substituent(s) such as 4-methyl-, 4-dimethylamino-, 4-chloro-, 4-bromo-, 2,5-dimethoxy-, 2-bromo-, and 3-bromo- on the 3-phenyl ring and a 2,2,2-trifluoroethoxy group on the o-position of the 1-phenyl ring showed moderate to good antiplasmodial activities, whereas, the chalcones possessing the same substituents on the 3-phenyl ring, and a 2,2,2-trifluoroethoxy group on the p-(the first series) and m-positions (the second series) of the 1-phenyl ring (compounds 1a–d, 1f, 1i–j; 2a–d, and 2f) showed weak antiplasmodial activities. Evidently, the chalcones with 2,2,2-trifluoroethoxy groups substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity (compounds 3a–d, 3f, and 3i–j). Also, chalcone 2g, with 3-furyl ring and a 2,2,2-trifluoroethoxy group on the m-position of the 1-phenyl ring showed significant activity in comparison with those of 2,2,2-trifluoroethoxy group on the p-(compound 1g) and o-(compound 3g) positions. This result indicates that the position of 2,2,2-trifluoroethoxy group on the 1-phenyl ring of chalcones plays an important role in the increase of parasite killing i.e., a 2,2,2-trifluoroethoxy group on the o-position in the 1-phenyl ring of chalcones exhibited an enhanced killing effect on parasites whereas, those on the m- and p-positions have little-to-no influence on parasite killing. Therefore, the antiplasmodial activity of chalcones with 2,2,2-trifluoroethoxy groups substituted on the 1-phenyl ring is highly position-dependent, which is graphically represented in Figure 1.

Figure 1.

Results of in vitro antiplasmodial activity of some para-, meta-, and ortho-2,2,2-trifluoro ethoxychalcones with common substituent; NS: not synthesized.

We further evaluated the stage-specific inhibitory effect of the most active chalcones 3a and 3f on the progression of developmental blood stages and survival of parasites. Parasites treated with chalcones displayed altered phenotypes with distorted morphological appearance according to microscopy studies as shown in Figure 2. Moreover, compounds 3a and 3f arrested the growth of mature blood stages (trophozoite) of parasites, leading to cell death. The most active compounds, 3a and 3f were found to be non-hemolytic at their effective concentrations (<20 µg/mL) indicating the non-toxicity towards the normal (uninfected) red blood cells.

Figure 2.

Effect of 2,2,2-trifluoroethoxychalcones (3a and 3f) upon treatment causes developmental growth arrest of P. falciparum (3D7) on blood stages shown using Giemsa-stained light micrographs of highly synchronized ring-stage parasites in comparison to untreated parasites.

Most importantly, identification ofnew synthetic derivatives as drug partners for standard combination therapy with artemisinin is now recommended for the treatment of P. falciparum malaria due to improved efficacy, fast action, and delaying the resistance development [15,16]. Therefore, the effect of the most active molecules 3a and 3f in combination with artemisinin on the various blood stages of parasites in culture were studied.

It is observed that chalcones 3a and 3f exhibited enhanced antiplasmodial activity with reduced IC₅₀ values, as shown in Table 2. The drug combination study was carried out at a fixed concentration of artemisinin (5 ng/mL & 10 ng/mL) with varying concentrations of the chalcones 3a and 3f to find out the 50% inhibition concentration of parasite growth.

Table 2.

Effect on antiplasmodial activity of chalcones 3a and 3f with artemisinin against P. falciparum (3D7) at two different concentrations.

Drug Combination	P. falciparum 3D7 (CQ Sensitive) IC50 Values µg/mL
3a + Artemisinin 5 ng/mL	1.04
3a + Artemisinin 10 ng/mL	0.6
3f + Artemisinin 5 ng/mL	2.15
3f + Artemisinin 10 ng/mL	0.89

It is important to note that the IC₅₀ values of chalcones 3a and 3f alone were found to be 3.0 µg/mL and 2.2 µg/mL (Table 1) respectively, and the parasite killing effect of artemisinin at 5 ng/mL and 10 ng/mL concentration was found to be 10–15% only. However, the combination study of chalcones 3a and 3f at a fixed concentration of artemisinin showed enhanced antiplasmodial activity with reduced IC₅₀ values (Table 2). Therefore, the combined treatment of artemisinin with chalcones 3a and 3f exhibited positive interactions with synergetic effect on the parasites.

As a result, these active molecules may find an effective means as strong chemotherapeutic agent in combination with other antimalarial drugs in combating clinical resistance against malaria infections.

2.3. Antiplasmodial Activity of 2-fluoroethoxychalcones

Due to fluorine’s baffling nature, the effects of fluorine substitution on chemical reactivities and biological activities remains unpredictable [30,48]. Therefore, we attempted to explore the effect of the number of fluorine atoms in the fluoroethoxy group and its position in chalcones on antiplasmodial activity. Therefore, we synthesized a series of 2-fluoroethoxychalcone derivatives in which a 2-fluoroethoxy group substituted in both the 1-phenyl ring and 3-phenyl ring of chalcones (Scheme 2). The antiplasmodial activity results of these 2-fluoroethoxychalcones are given in Table 3. All the chalcones with 2-fluoroethoxy groups on the 1-phenyl ring (compounds 4a, 4e–g, 5d, 5k, and 6i) exhibited moderate to good antiplasmodial activity, with IC₅₀ values ranging from 20 µg/mL to 6.5 µg/mL.

Table 3.

In vitro antiplasmodial activity of 2-fluoroethoxychalcones against P. falciparum (3D7).

No.	Entry	Yield (%) a	P. falciparum (3D7)
			IC50 (µg/mL) b	IC50 (µM)
1		78	20	70.3
2		66	13	41.2
3		80	8	24.2
4		67	20	76.8
5		76	c	c
6		69	12	34.4
7		75	c	c
8		90	12	39.9
9		76	6.5	18.6
10		76	25	92.5
11		59	10	35.2
12		67	8	23.6
13		73	5	16.6
14		71	10	28.6
15		90	7	25.9
16		70	9	31.6
17		80	4.5	13.3
18		86	c	c
19		74	12.5	35.8
20		81	c	c
21		83	3.5	12.3
22		89	6	17.7
23		78	10	28.6
24		71	c	c
25		85	5	17.6
	Chloroquine (CQ)d		0.010	0.031
	Artemisinin (ART)d		0.021	0.074

^a Isolated yield; ^b IC₅₀ (µg/mL): concentration corresponding to 50% growth inhibition of parasite; ^c Not tested; ^d Antimalarial control.

Surprisingly, it is observed that 2-fluoroethoxychalcones 4a, 4e–g, 5d, 5k, and 6i showed enhanced parasite-killing activity, relative to their 2,2,2-trifluroethoxy analogues, irrespective of the position of the 2-fluoroethoxy group on the 1-phenyl ring (Figure 3).

Figure 3.

Graphical representation for the comparison of antiplasmodial activity of some 2,2,2-trifluoroethoxychalcones and 2-fluoroethoxychalcones with some common substituents; NE: not evaluated.

As a result, the number of fluorine atoms on the ethoxy group in chalcones plays an important role in their antiplasmodial activity. The chalcones, 4f, and 6i showed good antiplasmodial activity with IC₅₀ values of 8.0 µg/mL and 6.5 µg/mL, respectively. Similarly, chalcones 7i–iv, 7vii; 8i–v; 9i–iii, 9v, and 9vii–viii with 2-fluoroethoxy groups on the 3-phenyl ring showed moderate to good antiplasmodial activity. Among these chalcones, the chalcones 7iv, 8iii, 9ii, 9iii, and 9viii showed significant antiplasmodial activities, with IC₅₀ values of 3.5–6.0 µg/mL. Of all 2-fluoro-ethoxychalcones, only two, 8iii, and 9ii, were found to be most active towards P. falciparum parasite. Our result reveals that 2-fluoroethoxy substitution in chalcone derivatives are more effective than 2,2,2-trifluoroethoxy substitution, irrespective of the position, in inhibition of plasmodial growth.

Finally, the most active molecules 3a, 3f, 8iii, and 9ii were studied for their cytotoxic effect in Vero cell lines (kidney cells of African green monkey) and the results are given in Table 4. The selectivity index (SI) values for the most active molecules, 3a, 3f, 8iii, and 9ii were calculated using the formula of IC₅₀ value fnormal cell line (Vero)/IC₅₀ value P. falciparum (3D7), are 8.6, 8.2, 3.3 and 6.9, respectively. The most active molecules showed minimal cytotoxic effect towards Vero cells at therapeutic dosages with selective killing of parasites. Therefore, the active molecules are considered to be selective towards the inhibition of parasites.

Table 4.

Cytotoxic effect on Vero cells and selectivity index of most active molecules (3a, 3f, 8iii, and 9ii) in vitro.

Chalcone	Cytotoxicity (Vero Cell)		Selectivity Index (SI)
	µg/mL	µM
3a	26	81.2	8.6
3f	18	49.1	8.2
8iii	15	44.2	3.3
9ii	24	84.4	6.9

3. Experimental

3.1. General Information

All substituted benzaldehydes, substituted acetophenones, p-toluenesulphonyl chloride and dry DMF were purchased from Spectrochem Pvt. Ltd. (Mumbai, India). 2′-Hydroxy-, 3′-hydroxy-, and 4′-hydroxyacetophenones, 2-hydroxy-, 3-hydroxy-, and 4-hydroxybenzaldehydes were purchased from Sigma Aldrich Chemicals pvt. Ltd. (Bangalore, India). Sodium hydride 60% dispersion in mineral oil was purchased from Thermo Fisher Scientific India Pvt. Ltd. (Mumbai, India) and purged withnitrogen after every use. Other common solvents & reagent were purchased from other common suppliers. Other starting materials such as 2,2,2-trifluoroethyl-4-methylbenzenesulphonate, 2-fluoroethyl-4-methylbenzenesulphonate, 4′-(2,2,2-trifluoroethoxy)-, 3′-(2,2,2-trifluoroethoxy)-, and 2′-(2,2,2-trifluoroethoxy)acetophenones, 4′-(2-fluoroethoxy)-, 3′-(2-fluoroethoxy)-, and 2′-(2-fluoroethoxy)acetophenones, 4-(2-fluoroethoxy)benzaldehyde, 3-(2-fluoroethoxy)benzaldehyde, and 2-(2-fluoroethoxy)benzaldehyde were synthesized in house and used for the preparation of chalcones. The chalcones were prepared by a Claisen-Schmidt condensation reported elsewhere in the literature. Reactions were monitored by thin layer chromatography (TLC) on pre-coated silica gel plates (silica gel 60, F_254, Merck, Darmstadt, Germany) and visualized under UV light.

3.2. Analytical Methods

NMR data were obtained on a Jeol 400 MHz spectrometers (Jeol USA, Inc., Peabody, MA, USA). All compounds were characterized by ¹H-, ¹³C-, ¹⁹F-NMR (at 399.78 MHz, 100.5 MHz, 376.17 MHz respectively), IR and HRMS. All ¹H- and ¹³C-NMR chemical shifts were reported in parts per million (ppm) and were measured relative to TMS or residual deuterated CDCl₃ as solvent. ¹⁹F-NMR signals are reported in ppm units and were referenced to CFCl₃ as external reference. FTIR spectra were recorded on a model RXI (Perkin-Elmer, Waltham, MA, USA) or model alphaT (Bruker, Billerica, MA, USA, untry) spectrometer, using KBr pellets and KBr films (DCM solvent) methods. HRMS (ESI) measurements were performed on an 1969A TOF (MS ES+) mass spectrometer (Agilent, Santa Clara, CA, USA) and an Orbitrap Elite Hybrid Ion Trap-Orbitrap Mass Spectrometer (Thermo Scientific, Waltham, MA, USA). Yields refer to isolated compounds.

3.3. Biological Evaluation

3.3.1. In Vitro Culture of Plasmodium falciparum

We have tested a series of fluoroethoxychalcone derivatives against drug-susceptible P. falciparum (3D7) obtained from National Institute of Malaria Research (NIMR, New Delhi, India). The strain of P. falciparum was maintained by serial passages in human red blood cells (RBCs) cultured at 4–5% hematocrit in RPMI-1640 medium supplemented with 0.5% AlbuMAX II (complete RPMI) and incubated at 37 °C under the atmosphere of mixed gases (5% CO₂, 5% O₂, and 90% N₂). The whole blood was collected from the Rotary Blood Bank (New Delhi, India). RBCs were separated under sterile conditions by centrifugation to remove plasma and peripheral blood mononuclear cells (PBCs) using Histopaque 1077 solution. The levels of parasitemia were routinely monitored by thin blood smear and staining with 5% Giemsa solution.

3.3.2. Evaluation of In Vitro Antiplasmodial Activity

In vitro antiplasmodial activity was determined based on the [³H]-hypoxanthine incorporation inhibition assay. The level of radiolabelled precursor [³H]-hypoxanthine incorporation in the nucleic acid of parasites was used as direct measurement for determining the inhibitory growth concentration of parasites. Stock solutions of test compounds (chalcones) and artemisinin were dissolved in 100% DMSO and chloroquine diphosphate in sterile distilled water. The final concentration of DMSO is 0.4% (vehicle control) was found to be non-toxic to parasites. Briefly, different concentrations of test compounds ranging from 50 µg/mL to 0.1 µg/mL were serially diluted (2-fold dilution) and added to P. falciparum infected asynchronous erythrocyte suspension (4% final hematocrit and 2% parasitemia) in a 96-well micro dilution plate along with an untreated control. In another set, different concentration of standard antimalarial drugs chloroquine diphosphate (CQ) and artemisinin (ART) were added to infected erythrocyte suspension as positive control. After 30 h of incubation period at 37 °C, 20 µL of 0.2 µCi/well of [³H]-hypoxanthine (American Radiolabeled Chemicals, Inc., ST. Louis, MO, USA specific activity 25 Ci/mmol) was added to each well containing infected erythrocytes. After additional 18 h of incubation, the cells were harvested onto a glass-fiber filter mat (Whatman GF/A) using a semi-automated 96 well cell harvester (Skatron, Norway, MI, USA). The dried paper discs were placed in 5 mL toluene based scintillation cocktail and radioactive count was measured in a TriCarb 2900TR liquid scintillation analyzer beta-counter (PerkinElmer, Waltham, MA, USA). The 50% inhibitory concentration (IC₅₀) values were determined by plotting the drug concentration versus the percent cell viability of the parasite after 48 h of incubation of growth assay period. All data points were collected in triplicate for each experiment conducted independently.

3.3.3. Assessment of In Vitro Hemolytic Activity

The hemolytic activity was measured at different concentrations for highly potent 2,2,2-trifluoroethoxychalcones, 3a, and 3f, and 2-fluroethoxychalcones, 6i, 7iv, 8iii, 9ii, 9iii, and 9viii, in normal and infected erythrocytes by measuring the lysis of RBCs in culture medium at absorbance of 405 nm. Briefly, a series of concentrations 50 µg/mL−0.1 µg/mL were added to normal erythrocytes at 4% hematocrit in a 96-well plate for 48 h incubation period at 37 °C. After incubation, the plate was spun down and absorbance of supernatant was measured using spectrophotometric microplate reader (infinite 200 pro, Tecan trading AG, Switzerland). By mixing the erythrocytes with sterile distilled water (for 100% hemolysis) and PBS alone (for baseline values) served as positive and negative controls, respectively.

3.3.4. Assessment of In Vitro Cytotoxicity on Vero Cells

The cytotoxic effect of most potent molecules (3a, 3f, 8iii, and 9ii) was evaluated against Vero cells using MTT assay. In Brief, exponentially growing Vero cells were seeded in 96 well plates at a cell density of 1 × 10⁴ cells/well in 200 μL DMEM medium, 24 h prior to the experiment. Cells were incubated with different concentrations of compounds (100 µg/mL to 0.78 µg/mL) two-fold dilution and incubated further for 48 h at 37 °C, followed by incubating with 10 µL of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) MTT reagent (5 mg/mL) for additional 3 h at 37 °C. The presence of formazan crystals were solubilized using 100 µL DMSO and the absorbance of each well optical density was measured using a microplate reader (BioRad, CA, USA) at 570 nm. The 50% inhibitory concentration (IC₅₀ value) was determined by plotting the drug concentration versus the percentage cell viability of 48 h of a growth assay period. The relative cell viability (%) compared with control cells were calculated as follows:

$$\mathrm{Cell}\mathrm{viability}(\%)=\frac{\mathrm{Abs}\left(\mathrm{sample}\right)-\left(\mathrm{Abs}\mathrm{blank}\right)}{\mathrm{Abs}\left(\mathrm{control}\right)-\left(\mathrm{Abs}\mathrm{blank}\right)}\times 100,$$ (1)

3.4. General Procedure for Fluoroethoxylation of Hydroxyacetophenones and Benzaldehydes

A round bottom flask was charged with sodium hydride (1.2 eq.). The appropriate hydroxyacetophenone or hydroxybenzaldehyde (1 eq.) in DMF (100 mL) was added dropwise over 10 min at rt. Then 2,2,2-trifluoroethyl-4-methylbenzenesulphonate (1.2 eq.) in DMF (50 mL) was added dropwise. The reaction mixture was then allowed to reflux at 130 °C for 15 h. After completion of reaction, monitored by TLC, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine solution and finally dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by column chromatography (silica gel 60–200 mesh) to afford desired compounds.

1-(4-(2,2,2-Trifluoroethoxy)phenyl)ethanone (1) [49]. White solid, Yield: 75%, m.p. 67–68 °C (lit. 67–68 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.57 (s, 3H), 4.42 (q, 2H, ³J = 8.0 Hz), 6.98–7.00 (m, 2H), 7.97 (d, 2H, ³J = 8.8 Hz).

1-(3-(2,2,2-Trifluoroethoxy)phenyl)ethanone (2) [49]. White solid, Yield: 71%, m.p. 66–68 °C (lit. 67–68 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 4.41 (q, 2H, ³J = 8.0 Hz), 7.17–7.19 (m, 1H), 7.41–7.45 (m, 1H), 7.51–7.52 (m, 1H), 7.63–7.65 (m, 1H)

1-(2-(2,2,2-Trifluoroethoxy)phenyl)ethanone (3) [50]. Yellow liquid, Yield: 68%, ¹H-NMR (CDCl₃) δ (ppm): 2.63 (s, 3H), 4.45 (q, 2H, ³J = 7.9 Hz), 6.88–6.90 (m, 1H), 7.10–7.14 (m, 1H), 7.47–7.52 (m, 1H), 7.79–7.81 (m, 1H)

1-(4-(2-Fluoroethoxy)phenyl)ethanone (4) [46]. Yellow solid, Yield: 75%, m.p. 52–54 °C (lit. 51–55 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.56 (s, 3H), 4.28 (dt, 2H, ³J_H-H = 3.9 Hz, ³J_H-F = 27.5 Hz), 4.78 (dt, 2H, ³J_H-H = 4.2 Hz, ²J_H-F = 47.5 Hz), 6.95–6.97 (m, 2H), 7.93–7.95 (m, 2H)

1-(3-(2-Fluoroethoxy)phenyl)ethanone (5). White solid, Yield: 69%, m.p. 66–68 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.60 (s, 3H), 4.27 (dt, 2H, ³J_H-H = 3.90 Hz, ³J_H-F = 27.90 Hz), 4.78 (dt, 2H, ³J_H-H = 4.1 Hz, ²J_H-F = 47.9 Hz), 7.14–7.17 (m, 1H), 7.37–7.41 (m, 1H), 7.50 (s, 1H), 7.56–7.58 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 26.86, 67.38 (d, ²J_C-F = 20.2 Hz), 81.91 (d, ¹J_C-F = 171.1 Hz), 113.04, 120.41, 121.85, 129.86, 138.61, 158.76, 198.00; HRMS (ESI) calcd. for C₁₀H₁₁FO₂: [M + H]⁺ 183.0821; Found: 183.0818.

1-(2-(2-Fluoroethoxy)phenyl)ethanone) (6). Yellow liquid, Yield: 64%, ¹H-NMR (CDCl₃) δ (ppm): 2.66 (s, 3H), 4.32 (dt, 2H, ³J_H-H = 4.1 Hz, ³J_H-F = 27.8 Hz), 4.81 (dt, 2H, ³J_H-H = 4.7 Hz, ²J_H-F = 46.5 Hz), 6.92–6.94 (m, 1H), 7.02–7.06 (m, 1H), 7.44–7.48 (m, 1H), 7.75–7.78 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 32.14, 67.73 (d, ²J_C-F = 20.1 Hz), 81.66 (d, ¹J_C-F = 171.6 Hz), 112.49, 121.42, 128.73, 130.75, 133.79, 157.77, 199.94; HRMS(ESI) calcd. for C₁₀H₁₁FO₂: [M + H]⁺ 183.08213 and [M + Na]⁺ 205.06408; Found: 183.0813 and 205.0634.

4-(2-Fluoroethoxy)benzaldehyde (7) [46]. Yellow liquid, Yield: 77%, ¹H-NMR (CDCl₃) δ (ppm): 4.30 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 28.3 Hz), 4.79 (dt, 2H, ³J_H-H = 3.9 Hz, ²J_H-F = 47.5 Hz), 7.02–7.05 (m, 2H), 7.84–7.86 (m, 2H), 9.90 (s, 1H)

3-(2-Fluoroethoxy)benzaldehyde (8). Yellow oil, Yield: 71%, ¹H-NMR (CDCl₃) δ (ppm): 4.28 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 28 Hz), 4.78 (dt, 2H, ³J_H-H = 4.0 Hz, ²J_H-F = 47.5 Hz), 7.22–7.24 (m, 1H), 7.40–7.41 (m, 1H), 7.45–7.51 (m, 2H), 9.98 (s, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.43 (d, ²J_C-F = 20.7 Hz), 81.83 (d, ¹J_C-F = 170.9 Hz), 112.60, 122.32, 124.34, 130.36, 137.92, 159.11, 192.14; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.44 to −223.84 (m, 1F).

2-(2-Fluoroethoxy)benzaldehyde (9) [51]. Yellow solid, Yield: 69%, m.p. 37–38 °C (lit. 37.5–38 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.35 (dt, 2H, ³J_H-H = 3.9 Hz, ³J_H-F = 27.9 Hz), 4.82 (dt, 2H, ³J_H-H = 3.7 Hz, ²J_H-F = 47.8 Hz), 6.97–6.99 (m, 1H), 7.05–7.09 (m, 1H), 7.55 (t, 1H, ³J = 8.0 Hz), 7.86 (d, 1H, ³J = 7.8 Hz), 10.54 (s, 1H).

3.5. General Procedure for the Preparation of Fluoroethoxychalcones

An aqueous solution of KOH (1.2 eq.) was added at room temperature to a solution of the appropriate acetophenone (1.0 eq.), and benzaldehyde (1.2 eq.) in ethanol (10 mL). The reaction mixture was then stirred for 30 min. After completion of reaction, the reaction was judged by TLC. The reaction mixture was filtered through a Buckner funnel under vacuum. The solid was washed several times with a 1:1 ethanol-water mixture. The solid was finally dried under vacuum. The crude product was further purified by column chromatography or recrystallization.

(E)-3-(4-Methylphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1a) [43]. Yellow crystalline solid, Yield: 87%, m.p. 148–150 °C (lit. 148–151 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.40 (s, 3H), 4.44 (q, 2H, ³J = 8.0 Hz), 7.03 (d, 2H, ³J = 8.7 Hz), 7.23 (d, 2H, ³J = 8.8 Hz) 7.48 (d, 1H, ³J = 15.2 Hz), 7.55 (d, 2H, ³J = 8.4 Hz), 7.80 (d, 1H, ³J = 15.6 Hz), 8.06 (d, 2H, ³J = 8.8 Hz).

(E)-3-(4-(Dimethylamino)phenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1b). Yellow solid, Yield: 77%, m.p. 130–135 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.05 (s, 6H), 4.43 (q, 2H, ³J = 8.0 Hz), 6.70 (d, 2H, ³J = 8.4 Hz), 7.02 (d, 2H, ³J = 9.1 Hz), 7.33 (d, 1H, ³J = 15.2 Hz), 7.55 (d, 2H, ³J = 8.4 Hz), 7.79 (d, 1H, ³J = 15.2 Hz), 8.04 (d, 2H, ³J = 9.1 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 40.26, 65.65 (q, ²J_C-F = 36.2 Hz), 111.92, 114.53, 116.43, 122.71, 130.54, 130.75, 133.63, 145.75, 152.14, 160.36, 188.95; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.7(t, 3F,³J = 8.7 Hz); IR (KBr) ν: 3070, 2909, 1650, 1585, 1528, 1371, 1343, 1287, 1231, 1162, 1069, 1027, 969, 808, 676; HRMS (ESI) calcd. for C₁₉H₁₈F₃NO₂: [M + H]⁺ 350.1368 and [M + Na]⁺ 372.1187; Found: 350.1366 and 372.1163.

(E)-3-(4-Chlorophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1c). Pale yellow solid, Yield: 90%, m.p. 139–140 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.0 Hz), 7.04 (d, 2H, ³J = 8.8 Hz), 7.40 (d, 2H, ³J = 8.4 Hz), 7.49 (d, 1H, ³J = 15.4 Hz), 7.58 (d, 2H, ³J = 8.4 Hz), 7.76 (d, 1H, ³J = 15.4 Hz), 8.05 (d, 2H, ³J = 8.8 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.70 (q, ²J_C-F = 36.7 Hz), 114.79, 122.16, 129.41, 129.72, 131.06, 132.70, 133.54, 136.57, 143.23, 160.95, 188.50; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.67 (t, 3F, ³J = 8.6 Hz); IR (KBr) ν: 3066, 2947, 2815, 1663, 1609, 1510, 1490, 1406, 1343, 1293, 1162, 1029, 972, 811, 692, 657; HRMS (ESI) calc. for C₁₇H₁₂ClF₃O₂: [M + H]⁺ 341.0056; Found: 341.056.

(E)-3-(4-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1d). Pale yellow solid, Yield: 77%, m.p. 145–146 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.0 Hz), 7.04 (d, 2H, ³J = 9.1 Hz), 7.49–7.57 (m, 5H), 7.74 (m, 1H), 8.05 (d, 2H, ³J = 9.1 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.70 (q, ²J_C-F = 36.6 Hz), 114.79, 122.25, 124.93, 129.92, 131.06, 132.37, 132.68, 133.96, 143.30, 160.95, 188.49; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.67 (t, 3F, ³J = 8.7 Hz); IR (KBr) ν: 2946, 2812, 1668, 1609, 1511, 1487, 1349, 1305, 1293, 1254, 1180, 1161, 1079, 1028, 972, 808, 687; HRMS (ESI) calc. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051; Found: 385.0037.

(E)-3-(3-Nitrophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1e) [43]. Yellow solid, Yield: 94%, m.p. 169–171 °C (lit. 168–171 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.46 (q, 2H,³J = 7.9 Hz), 7.07 (d, 2H, ³J = 9.1 Hz), 7.62 (d, 1H, ³J = 15.9 Hz), 7.84 (d, 1H, ³J = 15.9 Hz) 7.92 (d, 1H, ³J = 7.6 Hz), 8.09 (d, 2H, ³J = 8.5 Hz), 8.26 (d, 1H, ³J = 8.5 Hz), 8.52 (s, 1H).

(E)-3-(2,5-Dimethoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1f) [43]. Yellow solid, Yield: 78%, m.p. 98–99 °C (lit. 97–99 °C); ¹H-NMR (CDCl₃) δ (ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.44 (q, 2H, ³J = 7.9 Hz), 6.87–6.89 (m, 1H), 6.93–6.96 (m, 1H), 7.03 (d, 2H, ³J = 8.8 Hz), 7.16–7.17 (m, 1H), 7.57 (d, 1H, ³J = 15.9 Hz), 8.04–8.09 (m, 3H).

(E)-3-(Furan-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1g) [43]. Light yellow crystalline solid, Yield: 61%, m.p. 94–96 °C (lit. 94.5–96.5 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.43 (q, 2H, ³J = 8.0 Hz), 6.52 (m, 1H), 6.72 (d, 1H, ³J = 3.5 Hz), 7.03 (d, 2H, ³J = 8.7 Hz), 7.45 (d, 1H, ³J = 15.3 Hz), 7.52 (s, 1H), 7.59 (d, 1H, ³J = 15.3 Hz), 8.07 (d, 2H, ³J = 8.7 Hz).

(E)-3-(5-Bromothiophen-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1h). Pale yellow solid, Yield: 93%, yield, m.p. 93–94 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.0 Hz), 7.03 (d, 2H, ³J = 8.7 Hz), 7.06 (d, 1H, ³J = 4.2 Hz), 7.10 (d, 1H, ³J = 4.2 Hz), 7.21 (d, 1H, ³J = 15.6 Hz), 7.81 (d, 1H, ³J = 15.6 Hz), 8.02 (d, 2H, ³J = 8.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.71 (q, ²J_C-F = 36.0 Hz), 114.80, 116.48, 120.69, 130.96, 131.51, 132.49, 132.60, 136.20, 142.12, 160.96, 187.84; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.68 (t, 3F, ³J = 7.6 Hz); IR (KBr) ν: 3068, 2829, 1648, 1605, 1510, 1422, 1353, 1294, 1249, 1168, 1159, 1069, 1028, 972, 826, 796, 675 cm⁻¹; HRMS (ESI) calcd. for C₁₅H₁₀BrF₃O₂S: [M + H]⁺ 390.9615; Found: 390.9608.

(E)-3-(2-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1i). Pale yellow solid, Yield: 81%, m.p. 107–108 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.43 (q, 2H, ³J = 7.9 Hz), 7.02 (d, 2H, ³J = 8.5 Hz), 7.24 (m, 1H), 7.34 (m, 1H), 7.39 (d, 1H, ³J = 15.7 Hz), 7.63 (d, 1H, ³J = 7.3 Hz), 7.71 (d, 1H,³J = 7.6 Hz), 8.04 (d, 2H, ³J = 8.5 Hz), 8.12 (d, 1H, ³J = 15.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.69 (q, ²J_C-F = 36.1 Hz), 114.77, 123.20 (q, ¹J_C-F = 277.60 Hz), 124.88, 125.99, 127.85, 128.02, 131.21, 131.45, 132.55, 133.72, 135.25, 143.11, 160.94, 188.78; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.67 (t, 3F, ³J = 7.7 Hz); IR (KBr) ν: 3072, 2952, 2821, 1660, 1607, 1511, 1463, 1435, 1344, 1299, 1220, 1184, 1076, 1027, 970, 865, 830, 757, 739, 688, 657 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051; Found: 385.0051.

(E)-3-(3-Bromophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1j). Pale yellow solid, Yield: 74%, m.p. 104–106 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 7.9 Hz), 7.04 (d, 2H, ³J = 8.9 Hz), 7.28–7.32 (m, 1H), 7.50–7.55 (m, 3H), 7.73 (m, 1H), 7.80 (s, 1H), 8.07 (d, 2H,³J = 8.9 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.70 (q, ²J_C-F = 36.4 Hz), 114.80, 122.95, 123.24, 127.43, 130.63, 130.90, 131.11, 132.57, 133.38, 137.17, 142.87, 161.01, 188.32; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.63 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3064, 2948, 2894, 2361, 1663, 1611, 1511, 1418, 1341, 1255, 1220, 1182, 1127, 1078, 1030, 971, 830, 780, 669, 661 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051; Found: 385.0019.

(E)-3-(4-Methoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1k). Yellow solid, Yield: 72%, m.p. 100–102 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.86 (s, 3H), 4.44 (q, 2H, ³J = 7.9 Hz), 6.94 (d, 2H, ³J = 8.8 Hz), 7.03 (d, 2H, ³J = 8.8 Hz),7.41 (d, 1H, ³J = 15.9 Hz), 7.61 (d, 2H, ³J = 8.8 Hz), 7.79 (d, 1H, ³J = 15.9 Hz), 8.05 (d, 2H, ³J = 8.8 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 55.56, 65.69 (q, ²J_C-F = 35.9 Hz), 114.57, 114.67, 119.41, 127.77, 130.36, 130.93, 133.15, 144.61, 160.68, 161.82, 188.85; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.69 (t, 3F, ³J = 7.7 Hz); IR (KBr) ν: 3042, 3073, 2957, 2839, 1657, 1603, 1572, 1510, 1423, 1344, 1295, 1249, 1168, 1033, 976, 813, 680 cm⁻¹; HRMS(ESI) calcd. for C₁₈H₁₅F₃O₃: [M + H]⁺ 337.1051 and [M + Na]⁺ 359.0871; Found: 37.1051 and 359.0864.

(E)-3-(3-Methoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1l). Pale yellow solid, Yield: 91%, m.p. 78–80 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.86 (s, 3H), 4.44 (q, 2H, ³J = 7.9 Hz), 6.96–6.98 (m, 1H), 7.04 (d, 2H, ³J = 8.7 Hz), 7.15–7.16 (m, 1H), 7.23 (s, 1H), 7.34 (t, 1H, ³J = 8.2 Hz), 7.54 (d, 1H, ³J = 15.7 Hz), 7.77 (d, 1H, ³J = 15.7 Hz), 8.06 (d, 2H, ³J = 8.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 55.51, 65.63 (q, ²J_C-F = 39.0 Hz), 113.63, 114.73, 116.37, 121.21, 122.06, 130.12, 131.07, 132.82, 136.41, 144.68, 160.09, 160.84, 188.82; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.66 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3079, 3004, 2941, 2833, 1650, 1606, 1510, 1426, 1314, 1264, 1217, 1158, 1026, 978, 818, 677 cm⁻¹; HRMS (ESI) Calc. for C₁₈H₁₅F₃O₃: [M + H]⁺ 337.1051 and [M + Na]⁺ 359.0871; Found: 337.1048 and 359.0865.

(E)-3-(3,4-Dimethoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1m). Yellow solid, Yield: 70%, m.p. 116–118 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.94 (s, 3H), 3.96 (s, 3H), 4.44 (q, 2H, ³J = 7.9 Hz), 6.90 (d, 1H, ³J = 8.9 Hz), 7.04 (d, 2H, ³J = 8.7 Hz), 7.16 (d, 1H, ³J = 1.9 Hz), 7.24 (dd, 1H, ³J = 8.3 Hz, ⁴J = 1.9 Hz) 7.38 (d, 1H, ³J = 15.7 Hz), 7.77 (d, 1H, ³J = 15.7 Hz), 8.05 (d, 2H, ³J = 8.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 56.12, 56.15, 65.69 (q, ²J_C-F = 36.0 Hz), 110.23, 111.26, 119.69, 123.28, 128.00, 130.96, 133.10, 144.95, 149.39, 151.58, 160.70, 188.89; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.67 (t, 3F, ³J= 7.6 Hz); IR (KBr) ν: 3079, 3003, 2941, 2833, 1651, 1606, 1590, 1510, 1425, 1361, 1236, 1217, 1180, 1141, 978, 817, 791, 677 cm⁻¹; HRMS (ESI) calcd. for C₁₉H₁₇F₃O₄: [M + H]⁺ 367.1157 and [M + Na]⁺ 389.0977; Found: 367.1157 and 389.0987.

(E)-3-(1H-Indol-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (1n). Yellow solid, Yield: 40%, m.p. 194–195 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.0 Hz), 7.05 (d, 2H, ³J = 8.0 Hz), 7.31–7.33 (m, 2H), 7.45–7.47 (m, 1H), 7.57–7.62 (m, 2H), 8.03 (dd, 1H, ³J = 6.7 Hz, ⁴J = 3.0 Hz), 8.09–8.13 (m, 3H), 8.61 (s, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 65.68 (q, ²J_C-F = 35.9), 112.14, 114.64, 117.50, 120.84, 121.92, 123.72, 125.48, 130.46, 130.80, 133.55, 137.38, 138.83, 160.47, 189.26; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.68 (t, 3F, ³J = 8.7 Hz); IR (KBr) ν: 3219, 2929, 1647, 1604, 1587, 1554, 1365, 1246, 1170, 1041, 815, 735, 677 cm⁻¹; HRMS (ESI) calcd. for C₁₉H₁₄F₃NO₂: [M + H]⁺ 346.1055; Found: 346.1051.

(E)-3-(4-Methylphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2a). Yellow solid, Yield: 80%, m.p. 107–108 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.42 (s, 3H), 4.45 (q, 2H, ³J = 8.1 Hz), 7.20 (dd, 1H, ³J = 8.2 Hz, ⁴J = 2.5 Hz), 7.24–7.27 (m, 2H), 7.46–7.50 (m, 2H), 7.56–7.58 (m, 3H), 7.72 (d, 1H, ³J = 8.0 Hz), 7.83 (d, 1H, ³J = 15.6 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 21.70, 65.99 (q, ²J_C-F = 36.1 Hz), 113.82, 120.10, 120.79, 122.84, 128.72, 129.90, 130.10, 132.12, 140.13, 141.50, 145.62, 157.76, 189.88; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.7 (t, 3F, ³J = 7.8 Hz); IR (KBr) ν: 3083, 3049, 2360, 1658, 1595, 1580, 1454, 1325, 1305, 1247, 1161, 1076, 1041, 967, 812, 800, 741, 674 cm⁻¹; HRMS (ESI) Calc. for C₁₈H₁₅F₃O₂: [M + H]⁺ 321.1124; Found: 321.1093.

(E)-3-(4-(Dimethylamino)phenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2b). Yellow solid, Yield: 71%, m.p. 134–136 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.05 (s, 6H), 4.44 (q, 2H, ³J = 8.1 Hz), 6.69 (d, 2H, ³J = 9.2 Hz), 7.16 (dd, 1H, ³J= 8.3 Hz, ⁴J = 2.5 Hz), 7.30 (d, 1H, ³J = 15.6 Hz), 7.44 (t, 1H, ³J = 7.9 Hz), 7.54–7.57 (m, 3H), 7.69 (d, 1H, ³J = 7.9 Hz), 7.81 (d, 1H, ³J = 15.6 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 40.27, 66.00 (q, ²J_C-F = 35.8 Hz), 111.96, 113.69, 116.56, 119.62, 122.61, 122.67, 129.93, 130.71, 140.92, 146.54, 152.30, 157.69, 189.86; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.71 (t, 3F, ³J = 7.6Hz); HRMS (ESI calc. for C₁₉H₁₈F₃NO₂: [M + H]⁺ 350.1368; Found: 350.1362.

(E)-3-(4-Chlorophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2c). Yellow solid, Yield: 73%, m.p. 117–118 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.1 Hz), 7.20 (dd, 1H, ³J = 8.8 Hz, ⁴J = 2.7 Hz) 7.40–7.42 (m, 2H), 7.46–7.50 (m, 2H), 7.58–7.60 (m, 3H), 7.70 (d, 1H, ³J = 7.9 Hz), 7.78 (d, 1H, ³J = 15.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.99 (q, ²J_C-F = 35.8 Hz), 113.90, 120.31, 122.17, 122.86, 129.45, 129.81, 130.19, 133.34, 136.80, 139.80, 143.97, 157.82, 189.50; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.76 (t, 3F, ³J = 8.7 Hz); IR (KBr) ν: 3104, 3081, 2945, 2360, 1664, 1610, 1581, 1490, 1451, 1295, 1273, 1250, 1170, 1152, 1045, 973, 914, 868, 821, 789, 690 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂ClF₃O₂: [M + H]⁺ 341.0556 and [M + Na]⁺ 363.0376; Found: 341.0555 and 363.0375.

(E)-3-(4-Bromophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2d). Pale yellow solid, Yield: 75%, m.p. 125–126 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.0 Hz), 7.20 (dd, 1H, ³J = 8.4 Hz, ⁴J = 2.7 Hz), 7.45–7.58 (m, 7H), 7.70 (d, 1H, ³J = 8.4 Hz), 7.76 (d, 1H, ³J = 15.6 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 66.64 (q, ²J_C-F = 36.5 Hz), 113.96, 120.32, 122.39, 122.88, 125.19, 130.01, 130.20, 132.41, 133.79, 139.90, 144.03, 157.84, 189.75; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.7 (t, 3F, ³J = 7.7 Hz); IR (KBr) ν: 3076, 2945, 2360, 1667, 1599, 1486, 1450, 1401, 1314, 1295, 1170, 1152, 1080, 1045, 973, 867, 816, 788, 688 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051 and [M + Na]⁺ 406.9871; Found: 385.0054 and 406.9879.

(E)-3-(3-Nitrophenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2e). Brown solid, Yield: 73%, m.p. 78–80 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 8.0 Hz), 7.23 (dd, 1H, ³J = 8.5 Hz, ⁴J = 3.0 Hz), 7.50 (t, 1H, ³J = 8.1 Hz), 7.59–7.65 (m, 3H), 7.74 (d, 1H, ³J = 7.8 Hz), 7.85 (m, 1H), 7.93 (d, 1H, ³J = 7.2 Hz), 8.27 (dd, ³J = 8.0 Hz, ⁴J = 2.7 Hz), 8.51–8.8.52 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 66.01 (q, ²J_C-F = 35.2 Hz), 113.95, 120.67, 122.58, 122.98, 124.36, 130.25, 130.34, 134.51, 136.62, 139.33, 142.28, 148.89, 157.91, 188.96; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.39 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3074, 2869, 2360, 1662, 1591, 528, 1444, 1357, 1309,1272, 1248, 1173, 1158, 1083, 1068, 974, 911, 857, 795, 780, 740, 675 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂F₃NO₄: [M + H]⁺ 352.0797; Found: 352.0789.

(E)-3-(2,5-Dimethoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2f). Yellow solid, Yield: 77%, m.p. 72–74 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.83 (s, 3H), 3.88 (s, 3H), 4.44 (q, 2H, ³J = 8.1 Hz), 6.89 (m, 1H), 6.94–6.97 (m,1H), 7.16–7.18 (m, 1H), 7.20 (d, 1H, ⁴J = 2.7 Hz), 7.46 (t, 1H, ³J = 8.0 Hz), 7.53–7.57 (m, 2H), 7.69 (d, 1H, ³J = 8.4 Hz), 8.09 (d, 1H, ³J = 16 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 56.01, 56.25, 66.05 (q, ²J_C-F = 35.90 Hz), 112.64, 113.90, 113.99, 117.60, 120.10, 122.01, 122.96, 124.49, 130.06, 140.25, 140.86, 153.56, 153.70, 157.77, 190.40; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.7 (t, 3F, ³J = 7.7 Hz); IR (KBr) ν: 2948, 2838, 2357, 1659, 1587, 1494, 1442, 1323, 1248, 1172, 1123, 1047, 985, 974, 848, 791, 693 cm⁻¹; HRMS (ESI) calc. for C₁₉H₁₇F₃O₄: [M + H]⁺ 367.1157; Found: 367.1158.

(E)-3-(Furan-2-yl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2g). Brown viscous liquid, Yield: 65%, ¹H-NMR (CDCl₃) δ (ppm): 4.39 (q, 2H, ³J = 7.90 Hz), 6.44–6.45 (m, 1H), 6.64 (d, 1H, ³J = 3.5 Hz), 6.9 (d, 1H, ³J = 8.4 Hz), 7.09–7.13 (m,1H), 7.21–7.22 (m, 1H), 7.36–7.46 (m, 3H), 7.64 (d, 1H, ³J = 8.0 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.58 (q, 2H, ³J = 36.2 Hz,) 112.94, 113.61, 116.87, 118.98, 120.29, 122.83, 130.14, 131.26, 139.89, 145.29, 157.76, 189.14; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.71 (t, ³J = 8.7 Hz); IR (KBr) ν: 3126, 1688, 1586, 1486, 1442, 1401, 1250, 1169, 1069, 1016, 973, 858, 789, 734, 680 cm⁻¹; HRMS (ESI) calc. for C₁₅H₁₁F₃O₃: [M + H]⁺ 297.0739; Found: 297.0730.

(E)-3-(5-Bromothiophen-2-yl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2h). Yellow solid, Yield: 85%, m.p. 103–105 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 8.1 Hz), 7.07 (m, 1H), 7.12 (m, 1H), 7.17–7.21 (m, 2H), 7.45–7.48 (m, 1H), 7.54–7.55 (m, 1H), 7.66 (d, 1H, ³J = 7.6 Hz), 7.83 (d, 1H, ³J = 15.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 65.94 (q, ²J_C-F = 36.1 Hz), 113.65, 116.90, 120.35, 120.59, 121.94, 122.74, 130.19, 131.55, 132.84, 136.85, 139.65, 141.89, 157.78, 188.82; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.75 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3073, 2941, 1658, 1579, 1488, 1423, 1346, 1264, 1247, 1162, 1070, 1057, 970, 917, 854, 814, 783, 716, 697 cm⁻¹; HRMS (ESI) calc. for C₁₅H₁₀BrF₃O₂S: [M + H]⁺ 390.9615; Found: 390.961.

(E)-3-(4-Methoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2k). Yellow solid, Yield: 73%, m.p. 79–82 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.86 (s, 3H) 4.44 (q, 2H, ³J = 8.0 Hz), 6.94 (d, 2H, ³J = 8.3 Hz), 7.18 (dd, 1H, ³J = 8.6 Hz, ⁴J = 2.6 Hz),7.38 (d, 1H, ³J = 15.6 Hz),7.46 (t, 1H, ³J = 8.2 Hz), 7.56–7.57 (m, 1H), 7.61 (d, 2H, ³J = 8.4 Hz), 7.70 (d, 1H, ³J = 8.0 Hz), 7.80 (d, 1H, ³J = 15.6 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 55.57, 65.95 (q, ²J_C-F = 35.40), 113.75, 114.59, 119.43, 119.98, 122.77, 127.57, 130.07, 130.51, 140.27, 145.38, 157.73, 161.98, 189.81; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.7 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3075, 3014, 2941, 2843, 1655, 1587, 1573, 1442, 1342, 1287, 1245, 1187, 1156, 1056, 1027, 972, 921, 872, 824, 798, 788, 669 cm⁻¹; HRMS (ESI) calc. for C₁₈H₁₅F₃O₃: [M + H]⁺ 337.1052; Found: 337.1048.

(E)-3-(3,4-Dimethoxyphenyl)-1-(3-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (2m). Yellow solid, Yield: 64%, ¹H-NMR (CDCl₃) δ (ppm): 3.94 (s, 3H), 3.96 (s, 3H), 4.44 (q, 2H, ³J = 8.1 Hz), 6.91 (d, 1H, ³J = 8.0 Hz), 7.17–7.18 (m,1H), 7.19–7.24 (dd, 1H),7.36 (d, 1H, ³J = 15.6 Hz), 7.47 (t, 1H, ³J = 8.0 Hz), 7.57 (s, 1H), 7.70 (d, 1H, ³J = 8.0 Hz), 7.78 (d, 1H, ³J = 15.6 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 55.94, 56.11, 65.94 (q, ²J_C-F = 36.1 Hz), 110.14, 111.20, 113.85, 119.68, 119.89, 122.78, 123.53, 127.80, 130.06, 140.23, 145.73, 149.37, 151.71, 157.72, 189.85; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.75 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3128, 2840, 1656, 1576, 1517, 1421, 1256, 1165, 1080, 1026, 977, 919, 785, 724, 679 cm⁻¹; HRMS (ESI) Calc. for C₁₉H₁₇F₃O₄: [M + H]⁺ 367.1157 and [M + Na]⁺ 389.0977; Found: 367.1154 and 389.0979.

(E)-3-(4-Methylphenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3a). Pale yellow solid, Yield: 82%, m.p. 80–82 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.38 (s, 3H), 4.44 (q, 2H, ³J = 8.0 Hz), 6.96 (d, 1H, ³J = 8.0 Hz), 7.15–7.17 (m, 1H), 7.20 (d, 2H, ³J = 8.0 Hz), 7.38 (m, 1H), 7.49 (d, 2H, ³J = 7.6 Hz), 7.64 (m, 1H), 7.70 (d, 1H, ³J = 7.8 Hz), 7.78 (d, 1H, ³J = 7.8 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 21.66, 66.53 (q, ²J_C-F = 35.8 Hz), 113.21, 123.05, 125.55, 128.65, 129.78, 130.36, 131.19, 132.27, 133.02, 141.11, 144.30, 155.60, 192.08; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.51 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 3115.70, 1648.15, 1604.14, 1484.69, 1449.97, 1403.88, 1330.59, 1265.53, 1163.65, 119.59, 978, 813.90, 761.55, 682.04 cm⁻¹; HRMS (ESI) calc. for C₁₈H₁₅F₃O₂: [M + H]⁺ 321.1102; Found: 321.1095.

(E)-3-(4-(Dimethylamino)phenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3b). Yellow solid, Yield: 72%, m.p. 64–66 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.05 (s, 6H), 4.44 (q, 2H, ³J = 8.1 Hz), 6.69–6.71 (m, 2H), 7.14–7.17 (m, 1H), 7.28–7.32 (m,1H), 7.44 (t, 1H), 7.54–7.57 (m, 3H), 7.68–7.70 (m, 1H), 7.79–7.83 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 40.27, 65.65 (q, ²J_C-F = 36.20 Hz), 111.93, 114.53, 116.43, 121.87, 122.72, 124.63, 130.54, 130.75, 133.63, 145.75, 152.14, 160.36, 188.96; ¹⁹F-NMR (CDCl₃) δ (ppm): −74.19 (t, 3F, ³J = 7.6 Hz); IR (KBr) ν: 2821, 2359, 1646, 1599, 1520, 1484, 1447, 1339, 1266, 1233, 1162, 1064, 1025, 970, 861, 815, 767, 753, 676 cm⁻¹; HRMS (ESI) calc. for C₁₉H₁₈F₃NO₂: [M + H]⁺ 350.1368; Found: 350.1366.

(E)-3-(4-Chlorophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3c). Yellow solid, Yield: 73%, m.p. 61–63 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 8.0 Hz), 6.95 (d, 1H, ³J = 8.4 Hz), 7.17 (t, 1H, ³J = 7.7 Hz), 7.36–7.40 (m, 3H), 7.49–7.53 (m, 3H), 7.62 (m, 1H), 7.73 (dd, 1H, ³J = 7.6 Hz, ⁴J = 1.9 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 66.37 (q, ²J_C-F = 36.0 Hz), 112.94, 123.10, 126.91, 129.32, 129.73, 129.91, 131.40, 133.42, 133.58, 136.41, 142.31, 155.69, 191.49; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.70 (t, 3F, ³J = 7.6 Hz); IR (KBr) ν: 2884, 2361, 1651, 1602, 1588, 1485, 1447, 1330, 1260, 1227, 1196, 1069, 1024, 979, 863, 821, 769, 693 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂ClF₃O₂: [M + H]⁺ 341.0556 and [M + Na]⁺ 363.0376;Found: 341.0545 and 363.0363.

(E)-3-(4-Bromophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3d). Yellow solid, Yield: 73%, m.p. 68–71 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 8.0 Hz), 6.95 (d, 1H, ³J = 8.0 Hz), 7.17 (t, 1H, ³J = 7.4 Hz), 7.43 (d, 1H, ³J = 15.9 Hz), 7.45 (d, 2H, ³J = 8.0 Hz), 7.53 (d, 2H, ³J = 8.5 Hz), 7.61 (d, 1H, ³J = 15.9 Hz), 7.73 (d, 1H, ³J = 7.9 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 66.34 (q, ²J_C-F = 35.1 Hz), 112.89, 123.09, 124.62, 124.78, 126.98, 129.92, 131.40, 132.27, 133.44, 133.99, 142.33, 155.68, 191.46; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.54 (t, 3F, ³J = 7.6 Hz); IR (KBr) ν: 2855, 2361, 1652, 1603, 1586, 1486, 1450, 1329, 1276, 1198, 1071, 1022, 819, 764, 692 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051; Found: 385.0042.

(E)-3-(3-Nitrophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3e). Brown solid, Yield: 75%, m.p. 170–172 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.48 (q, 2H, ³J = 7.9 Hz), 6.96 (d, 1H, ³J = 8.4 Hz), 7.17–7.21 (m, 1H), 7.53–7.61 (m, 3H), 7.69–7.72 (m, 1H), 7.78 (dd, 1H, ³J = 7.7 Hz, ⁴J = 1.9 Hz), 7.89 (d, 1H, ³J = 8.1 Hz), 8.24 (d, 1H, ³J = 8.8 Hz), 8.46 (s, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 66.21 (q, ²J_C-F = 35.7 Hz), 112.66, 122.72, 123.14, 124.64, 129.04, 129.33, 130.06, 131.59, 133.92, 134.12, 136.91, 140.25, 148.87, 155.83, 190.86; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.67 (t, 3F, ³J = 8.7 Hz); IR (KBr) ν: 3113, 3093, 2954, 2359, 1651, 1604, 1527, 1487, 1448, 1331, 1271, 1230, 1061, 1021, 979, 865, 769, 747, 670 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂F₃NO₄: [M + H]⁺ 352.0796 and [M + Na]⁺ 374.0616; Found: 352.0798 and 374.0616.

(E)-3-(2,5-Dimethoxyphenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3f). Yellow solid, Yield: 62%, 77–79 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.79 (s, 3H), 3.82 (s, 3H), 4.43 (q, 2H, ³J = 8.1 Hz), 6.83–6.86 (m, 1H), 6.91–6.96 (m, 2H), 7.11–7.17 (m, 2H), 7.39–7.43 (m, 1H), 7.46–7.50 (m, 1H), 7.69 (dd, 1H, ³J = 7.7 Hz, ⁴J = 2.1 Hz), 8.02 (d, 1H, ³J = 16.0 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 55.84, 56.24, 66.64 (q, ²J_C-F = 35.8 Hz), 112.38, 112.69, 113.39, 118.18, 123.08, 124.51, 126.82, 130.61, 131.20, 132.91, 139.20, 153.43, 153.69, 155.63, 192.34; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.45 (t, 3F, ³J = 8.8 Hz); IR (KBr) ν: 2942, 2836, 2358, 1657, 1601, 1587, 1497, 1338, 1220, 1164, 1043, 978, 863, 820, 751, 680 cm⁻¹; HRMS (ESI) calc. for C₁₉H₁₇F₃O₄: [M + H]⁺ 367.1157; Found: 367.1132.

(E)-3-(Furan-2-yl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3g). Brown solid, Yield: 59%, m.p. 72–74 °C, ¹H-NMR (CDCl₃) δ (ppm): 4.44 (q, 2H, ³J = 7.9 Hz), 6.48–6.50 (m, 1H), 6.69 (d, 1H, ³J = 3.5 Hz), 6.95 (d, 1H, ³J = 8.4 Hz), 7.14–7.18 (m, 1H), 7.27–7.31 (m, 1H), 7.41–7.51 (m, 3H), 7.69 (d, 1H, ³J = 8 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 66.63 (q, ²J_C-F = 36.0 Hz), 112.68, 113.41, 115.88, 123.05, 124.17, 130.15, 130.27, 131.11, 133.08, 145.17, 151.79, 155.73, 191.56; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.54 (t, 3F, ³J = 8.7 Hz); IR (KBr) ν: 3040, 2901, 2360, 2342, 1645, 1603, 1587, 1487, 1449, 1330, 1295, 1206, 1016, 969, 868, 771, 746, 675 cm⁻¹; HRMS (ESI) calc. for C₁₅H₁₁F₃O₃: [M + H]⁺ 297.0738; Found: 297.0735.

(E)-3-(5-Bromothiophen-2-yl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3h). Yellow solid, Yield: 87%, m.p. 94–95 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 8.0 Hz), 6.94 (d, 1H, ³J = 8.4 Hz), 7.03–7.07 (m, 2H), 7.14–7.18 (m, 2H), 7.48–7.53 (m, 1H), 7.67–7.73 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 66.64 (q, ²J_C-F = 36.3 Hz), 113.00, 116.60, 123.08, 123.23 (q, ¹J_C-F = 279.6 Hz), 125.52, 129.83, 131.39, 132.20, 133.41, 135.25, 142.20, 142.60, 155.73, 190.75; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.3 (t, 3F, ³J = 7.5 Hz); IR (KBr) ν: 3096, 2361, 1645, 1580, 1597, 1568, 1427, 1347, 1296, 1270, 1170, 1159, 1023, 979, 966, 867, 773, 675 cm⁻¹; HRMS (ESI) calc. for C₁₈H₁₅F₃O₂: [M + H]⁺ 321.1102; Found: 321.1093.

(E)-3-(2-Bromophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3i). Pale yellow solid, Yield: 74%, m.p. 76–77 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.45 (q, 2H, ³J = 8.0 Hz), 6.96 (d, 1H, ³J = 8.4 Hz), 7.18 (t, 1H, ³J = 7.8 Hz), 7.20–7.23 (m, 1H), 7.32–7.37 (m, 2H), 7.49–7.54 (m, 1H), 7.61 (d, 1H, ³J = 7.4 Hz), 7.70–7.74 (m, 2H), 8.02 (d, 1H, ³J = 15.7 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 66.47 (q, ²J_C-F = 35.9 Hz), 113.03, 121.86, 123.12, 126.17, 127.83, 127.88, 128.99, 129.89, 131.37, 131.41, 133.36, 133.59, 142.33, 155.68, 191.73; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.48 (t, 3F, ³J = 6.5 Hz); IR (KBr) ν: 3060, 2902, 2342, 1646, 1604, 1486, 1450, 1329, 1278, 1201, 1149, 1120, 1023, 970, 864, 753, 693 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051 and [M + Na]⁺ 406.9871; Found: 385.0042 and 406.9854.

(E)-3-(3-Bromophenyl)-1-(2-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one (3j). Yellow solid, Yield: 74%, m.p. 97–98 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.47 (q, 2H, ³J = 7.9 Hz), 6.96 (d, 1H, ³J = 8.4 Hz), 7.17–7.21 (m, 1H), 7.27–7.30 (m, 2H), 7.43–7.47 (m, 1H), 7.52 (d, 2H, ³J = 8.4 Hz), 7.58–7.62 (m, 1H), 7.73–7.76 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 66.36 (q, ²J_C-F = 36.1 Hz), 112.90, 123.08, 127.14, 127.67, 129.76, 130.51, 131.20, 131.40, 133.23, 133.52, 137.20, 141.90, 155.72, 191.33; ¹⁹F-NMR (CDCl₃) δ (ppm): −73.49 (t, 3F, ³J = 7.7 Hz); IR (KBr) ν: 3039, 2870, 2361, 2343, 1647, 1605, 1588, 1451, 1325, 1289, 1266, 1119, 1056, 1024, 969, 865, 767, 667 cm⁻¹; HRMS (ESI) calc. for C₁₇H₁₂BrF₃O₂: [M + H]⁺ 385.0051 and [M + Na]⁺ 406.9871; Found: 385.0057 and 406.9874.

(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(4-methylphenyl)-prop-2-en-1-one (4a) [44]. Yellow solid, Yield: 78%, m.p. 110.1–110.7 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.39 (s, 3H), 4.30 (dt, 2H, ³J_H-H = 3.8 Hz, ³J_H-F = 28.1 Hz), 4.80 (dt, 2H, ³J_H-H = 4.1 Hz, ²J_H-F = 47.2 Hz), 7.00–7.02 (m, 2H), 7.22–7.24 (m, 2H), 7.48–7.56 (m, 3H), 7.77–7.81(m,1H), 8.04(d, 2H, J = 8.4 Hz).

(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one (4e) [44]. Pale yellow solid, Yield: 66%, m.p. 116–118 °C (lit. 115–117 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.32 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 27.1 Hz,), 4.81 (dt, 2H, ³J_H-H = 3.9 Hz,²J_H-F = 47.1 Hz,), 7.04 (m, 2H), 7.60–7.69 (m, 2H), 7.81–7.85 (m, 1H), 7.91 (d, 1H, ³J = 7.7 Hz), 8.08 (d, 2H, ³J = 8.7 Hz), 8.25 (d, 1H, ³J = 8.0 Hz), 8.52 (s, 1H).

(E)-3-(2,5-Dimethoxyphenyl)-1-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (4f). Yellow solid, Yield: 80%, m.p. 76–77 °C (lit. 75–77 °C); ¹H-NMR (CDCl₃) δ (ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.30 (dt, 2H, ³J_H-H = 4.9 Hz, ³J_H-F = 25.6 Hz), 4.80 (dt, 2H, ³J_H-H = 4.7 Hz, ²J_H-F = 46.4 Hz), 6.87–6.89 (m, 1H), 6.92–6.95 (m, 1H), 7.01 (d, 2H, ³J = 8.8 Hz), 7.16–7.17 (m, 1H), 7.57–7.61 (m, 1H), 8.02–8.09 (m, 3H); ¹³C-NMR (CDCl₃) δ (ppm): 55.99, 56.26, 67.31 (d, ²J_C-F = 20.7 Hz), 81.82 (d, ¹J_C-F = 170.9 Hz), 112.57, 113.92, 114.45, 117.13, 123.03, 124.78, 131.01, 131.43, 131.97, 139.67, 153.42, 153.62, 162.15, 189.46; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.52 to −223.92 (m, 1F); IR (KBr) ν: 2946, 2838, 1656, 1607, 1598, 1572, 1496, 1453, 1427, 1341, 1318, 1281, 1249, 1185, 1116, 1073, 1052, 974, 950 cm⁻¹; HRMS (ESI) calcd. for C₁₉H₁₉FO₄: [M + H]⁺ 331.1346 and [M + Na]⁺ 353.1165; Found: 331.1359 and 353.1171.

(E)-1-(4-(2-Fluoroethoxy)phenyl)-3-(furan-2-yl)prop-2-en-1-one (4g) [44]. Brown solid, Yield: 67%, m.p. 75–76 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.30 (dt, 2H, ³J_H-H = 4.1 Hz, ³J_H-F = 26.9 Hz), 4.79 (dt, 2H, ³J_H-H = 3.5 Hz, ²J_H-F = 48.0 Hz), 6.51 (dd, 1H, ³J = 3.1 Hz, ³J = 1.7 Hz), 6.7 (d, 1H, ³J = 3.9 Hz), 6.99–7.02 (m, 2H), 7.44–7.60 (m, 3H), 8.04–8.06 (m, 2H).

(E)-3-(2-Bromophenyl)-1-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (4i). Pale yellow solid, Yield: 76%, m.p. 115–116 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.31 (dt, 2H, ³J_H-H = 3.8 Hz, ³J_H-F = 28.3 Hz), 4.80 (dt, 2H, ³J_H-H = 4.0 Hz, ²J_{H- F} = 47.5 Hz), 7.02 (d, 2H, ³J = 8.8 Hz), 7.32–7.45 (m, 3H), 7.64 (d, 1H, ³J = 8.1 Hz), 7.72–7.74 (m, 1H), 8.03–8.06 (m, 2H), 8.10–8.14 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.35 (d, ²J_C-F = 20.6 Hz), 81.77 (d, ¹J_C-F = 172.1 Hz), 114.57, 122.78, 125.03, 125.95, 127.82, 128.00, 131.17, 131.33, 133.68, 135.37, 142.69, 162.42; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.50 to −223.90 (m, 1F); IR (KBr) ν: 3696, 3311, 2360, 1657, 1599, 1575, 1509, 1464, 1368, 1332, 1316, 1273, 1222, 1187, 1092, 1017, 918, 886, 829, 757, 740, 671, 647, 579, 509 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₄BrFO₂: [M + H]⁺ 349.0239; Found: 349.0233.

(E)-3-(4-Bromophenyl)-1-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (5d). Yellow solid, Yield: 69%, m.p. 122–124 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.30 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 27.9 Hz), 4.8 (dt, 2H, ³J_H-H = 4.1 Hz, ²J_H-F = 47.4 Hz), 7.17–7.19 (m,1H), 7.43 (t, 1H, ³J = 8.0 Hz), 7.48–7.57 (m, 6H), 7.62–7.64 (m, 1H), 7.72–7.76 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.45 (d, ²J_C-F = 20.60 Hz), 81.90 (d, ¹J_C-F = 171.3 Hz), 113.65, 120.19, 121.75, 122.53, 125.03, 127.64, 129.97, 132.37, 133.86, 139.55, 143.67, 158.90, 189.88; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.49 to −223.89 (m, 1F); IR (KBr) ν: 2968, 1660, 1597, 1577, 1459, 1486, 1443, 1313, 1181, 1113, 1072, 1049, 1007, 975, 945, 893, 876, 834, 819, 793, 770, 691, 678, 612, 491 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₄BrFO₂ : [M + H]⁺ 349.0239 and [M + Na]⁺ 371.0059; Found: 349.0233 and 371.0059.

(E)-3-(2,5-Dimethoxyphenyl)-1-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (5f). Yellow viscous solid, Yield: 75%, ¹H-NMR (CDCl₃) δ (ppm): 3.82 (s, 3H), 3.87 (s, 3H), 4.30 (dt, 2H, ³J_H-H = 4.2 Hz, ³J_H-F = 27.9 Hz), 4.79 (dt, 2H, ³J_H-H = 4.4 Hz, ²J_H-F = 47.0 Hz), 6.86–6.89 (m, 1H), 6.94–6.97 (m, 1H), 7.12–7.18 (m, 2H), 7.42 (t, 1H, ³J = 8.0 Hz), 7.54–7.58 (m, 2H), 7.62–7.64 (m, 1H), 8.07–8.10 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 56.01, 56.26, 67.44 (d, ²J_C-F = 20.1 Hz), 81.97 (d, ¹J_C-F = 171.20 Hz), 112.62, 113.62, 113.85, 117.51, 119.97, 121.86, 123.15, 124.58, 129.82, 140.04, 140.52, 153.52, 153.66, 158.81, 190.81; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.46 to −223.86 (m, 1F); IR (KBr) ν: 2952, 2836, 2066, 1866, 1660, 1585, 1495, 1438, 1326, 1259, 1180, 1118, 1046, 990, 946, 859, 865, 747, 710, 612, 564 cm⁻¹; HRMS (ESI) calcd. for C₁₉H₁₉FO₄:[M + H]⁺ 331.1346 and [M + Na]⁺ 353.1165; Found: 331.1338 and 353.1157.

(E)-1-(3-(2-Fluoroethoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5k). Pale yellow solid, Yield: 90%, m.p. 104–105 °C; ¹H-NMR (CDCl₃) δ (ppm): 3.86 (s, 3H), 4.30 (dt, 2H, ³J_H-H = 4.1 Hz,³J_H-F = 28.4 Hz,), 4.79 (dt, 2H, ³J_H-H = 3.9 Hz, ²J_H-F = 47.2 Hz), 6.93–6.95(m, 2H), 7.15–7.17 (m, 1H), 7.38–7.44(m, 2H), 7.56–7.64 (m, 4H), 7.77–7.81(m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 55.57, 67.41 (d, ²J_C-F = 20.2 Hz), 81.97 (d, ¹J_C-F = 170.9 Hz), 113.55, 114.57, 119.76, 119.86, 121.67, 127.69, 129.82, 130.44, 140.08, 145.04, 158.83, 161.88, 190.26; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.51 to −223.91 (m, 1F); IR (KBr) ν: 2972, 1657, 1594, 1575, 1511, 1486, 1418, 1326, 1309, 1286, 1254, 1182, 1172, 1112, 1074, 1046, 1030, 976, 890, 875, 830, 793, 739, 680, 536, 516 cm⁻¹; HRMS (ESI) calcd. for C₁₈H₁₇FO₃ :[M + H]⁺ 301.1240 and [M + Na]⁺ 323.1059; Found: 301.1233 and 323.1050.

(E)-3-(2-Bromophenyl)-1-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (6i). Yellow solid, Yield: 76%, m.p. 86–88 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.33 (dt, 2H, ³J_H-H = 3.7 Hz, ³J_H-F = 28.6 Hz), 4.76 (dt, 2H, ³J_H-H = 4.0 Hz, ²J_H-F = 47.5 Hz), 6.96–6.98 (m, 1H), 7.08–7.11 (m, 1H), 7.19–7.24 (m, 1H), 7.30–7.34 (m, 1H), 7.46–7.50 (m, 2H), 7.60–7.62 (m, 1H), 7.71–7.78 (m, 2H), 8.01–8.05 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.91 (d, ²J_C-F = 19.7 Hz), 81.77 (d, ¹J_C-F = 171.40 Hz), 112.60, 121.75, 126.14, 127.82, 127.96, 127.98, 129.43, 131.17, 131.21, 133.43, 133.54, 135.22, 141.21, 157.17, 192.15; ¹⁹F-NMR (CDCl₃) δ (ppm): −222.76 to 223.16 (m, 1F); IR (KBr) ν: 3331, 2893, 1646, 1606, 1484, 1464, 1450, 1329, 1281, 1262, 1166, 1119, 1064, 1042, 1026, 975, 922, 880, 814, 756, 670, 648, 616, 578, 530, 467, 446 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₄BrFO₂: [M + H]⁺ 349.0239 and [M + Na]⁺ 371.0059; Found: 349.0243 and 371.0057.

(E)-3-(4-(2-Fluoroethoxy)phenyl)-1-phenylprop-2-en-1-one (7i) [44]. Yellow solid, Yield: 76%, m.p. 79–80 °C (lit. 78–80 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.27 (dt, 2H, ³J_H-H = 4.2 Hz, ³J_H-F = 27.6 Hz), 4.79 (dt, 2H, ³J_H-H = 3.8 Hz, ²J_H-F = 47.6 Hz), 6.96–6.98 (m, 2H), 7.41–7.45 (m, 1H), 7.49–7.52 (m, 2H), 7.56–7.58 (m, 1H), 7.61–7.63 (m, 2H), 7.77–7.81 (m, 1H), 8.00–8.02 (m, 2H).

(E)-3-(4-(2-Fluoroethoxy)phenyl)-1-(3-nitrophenyl)prop-2-en-1-one (7ii) [44]. Pale yellow solid, Yield: 59%, 122–124 °C (lit. 122–124 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.44 (s, 3H), 4.27 (dt, 2H, ³J_H-H = 4.1 Hz, ³J_H-F = 27.5 Hz), 4.78 (dt, 2H, ³J_H-H = 4.2 Hz, ²J_H-F = 47.4 Hz), 6.96 (d, 2H, ³J = 8.9 Hz), 7.30 (d, 2H, ³J = 8.0 Hz), 7.42–7.45 (m, 1H), 7.60–7.62 (m, 2H), 7.76–7.80 (m, 1H), 7.92–7.94 (m, 2H).

(E)-1-(2,4-Dichlorophenyl)-3-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (7iii). Pale yellow solid, Yield: 67%, m.p. 85–87 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.26 (dt, 2H, ³J_H-H = 4.2 Hz, ³J_H-F = 27.6 Hz), 4.78 (dt, 2H, ³J_H-H = 4.1 Hz, ²J_H-F = 47.4 Hz), 6.94–6.97 (m, 2H), 7.01 (s, 1H), 7.33–7.36 (m, 1H), 7.39–7.41 (m, 1H), 7.43–7.48 (m, 2H), 7.52–7.54 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 67.27 (d, ²J_C-F = 21.20 Hz), 81.76 (d, ¹J_C-F = 171.5 Hz), 115.22, 124.17, 127.39, 127.64, 130.29, 130.47, 130.67, 132.42, 136.84, 137.80, 146.52, 160.98, 192.82; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.92 to −223.52 (m, 1F); IR (KBr) ν: 3072, 2968, 1897, 1731, 1660, 1592, 1572,1516, 1456, 1427, 1374, 1337, 1296, 1253, 1267, 1208, 1180, 1048, 1025, 984, 921, 885, 863, 793, 682, 579, 519 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₃Cl₂FO₂: [M + H]⁺ 339.0355 and [M + Na]⁺ 361.0174; Found: 339.0342 and 361.0155.

(E)-3-(4-(2-Fluoroethoxy)phenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (7iv) [44]. Yellow solid, Yield: 73%, m.p. 88–89 °C (lit. 87–89 °C); ¹H-NMR (CDCl₃) δ (ppm): 3.89 (s, 3H), 4.42 (dt, 2H, ³J_H-H = 3.9 Hz, ³J_H-F = 28.2 Hz), 4.77 (dt, 2H, ³J_H-H = 4.0 Hz, ²J_H-F = 47.6 Hz), 6.93 (d, 2H, ³J = 8.7 Hz), 6.98–7.05 (m, 2H), 7.22–7.25 (m, 1H), 7.46 (t, 1H, ³J = 8.0 Hz), 7.52–7.55 (m, 2H), 7.58–7.60 (m, 2H).

(E)-1-(2-Bromophenyl)-3-(4-(2-fluoroethoxy)phenyl)prop-2-en-1-one (7vii) [44]. Yellow solid, Yield: 71%, m.p. 107–108 °C (lit. 107–109 °C); ¹H-NMR (CDCl₃) δ (ppm): 4.27 (dt, 2H, ³J_H-H = 4.1 Hz, ³J_H-F = 27.7 Hz), 4.78 (dt, 2H, ³J_H-H = 3.9 Hz, ²J_H-F = 46.4 Hz), 6.97 (d, 2H, ³J = 7.5 Hz), 7.17 (m, 2H), 7.38–7.42 (m, 1H), 7.60–7.62 (m, 2H), 7.77–7.81 (m, 1H), 8.03–8.07 (m, 2H).

(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(4-methylphenyl)-prop-2-en-1-one (8ii) [44]. Yellow solid, Yield: 70%, m.p. 81–82 °C (lit. 80–82 °C); ¹H-NMR (CDCl₃) δ (ppm): 2.5 (s, 3H), 4.33 (dt, 2H, ³J_H-H = 3.9 Hz, ³J_H-F = 28.1 Hz), 4.85 (dt, 2H, ³J_H-H = 3.7 Hz, ²J_H-F = 47.7 Hz), 7.04–7.06 (m, 1H), 7.32–7.43 (m, 4H), 7.58–7.60 (m, 1H), 7.80–7.84 (m, 1H), 7.99–8.01 (m, 2H).

(E)-1-(2,4-Dichlorophenyl)-3-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (8iii). Pale yellow solid, Yield: 80%, m.p. 101–102 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.28 (dt, 2H, ³J_H-H = 4.2 Hz, ³J_H-F = 27.6 Hz), 4.76 (dt, 2H, ³J_H-H = 4.4 Hz, ²J_H-F = 47.9 Hz), 6.91–6.93 (m, 1H), 7.01–7.04 (m, 1H), 7.24–7.28 (m, 1H), 7.33–7.48 (m, 4H), 7.58 (d, 1H, ³J = 7.4 Hz), 7.82–7.86 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.87 (d, ²J_C-F = 20.6 Hz), 81.71 (d, ¹J_C-F = 171.5 Hz), 112.59, 121.74, 123.91, 126.82, 127.30, 129.85, 130.28, 130.69, 132.40, 132.57, 136.89, 137.76, 142.10, 157.74, 193.12; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.56 to −223.95 (m, 1F); IR (KBr) ν: 2966, 1671, 1600, 1572, 1493, 1450, 1372, 1320, 1280, 1248, 1203, 1130, 1073, 1041, 1016, 987, 928, 887, 824, 762, 745, 575 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₃Cl₂FO₂: [M + H]⁺ 339.0355 and [M + Na]⁺ 361.0174; Found: 339.0350 and 361.0164.

(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (8iv). Pale yellow paste, Yield: 86%, ¹H-NMR (CDCl₃) δ (ppm): 3.89 (s, 3H), 4.28 (dt, 2H, ³J_H-H = 4.3 Hz, ³J_H-F = 26.9 Hz), 4.78 (dt, 2H, ³J_H-H = 5.1 Hz, ²J_H-F = 45.7 Hz), 6.90–6.92 (m, 1H), 6.98–7.05 (m, 3H), 7.34 (t, ³J = 7.8 Hz), 7.43–7.48 (m, 2H), 7.61 (d, 2H, ³J = 8.0 Hz), 7.94–7.98 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 55.81, 67.78 (d, ²J_C-F = 20.7 Hz), 81.80 (d, ¹J_C-F = 171.8 Hz), 111.67, 112.44, 120.75, 121.56, 124.68, 128.02, 129.36, 129.65, 130.46, 131.54, 132.77, 138.77, 157.56, 158.17, 193.78; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.45 to −223.85 (m, 1F); IR (KBr) ν: 2962, 1658, 1604, 1485, 1438, 1403, 1281, 1246, 1179, 1163, 1114, 1055, 1028, 982, 886, 761, 678, 655 cm⁻¹; HRMS (ESI) calcd. for C₁₈H₁₇FO₃: [M + H]⁺ 301.1240 and [M + Na]⁺ 323.1059; Found: 301.1206 and 323.1029.

(E)-1-(4-Bromophenyl)-3-(3-(2-fluoroethoxy)phenyl)prop-2-en-1-one (8v). Yellow solid, Yield: 74%, m.p. 122–123 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.33 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 27.9 Hz), 4.85 (dt, 2H, ³J_H-H = 3.9 Hz, ²J_H-F = 47.7 Hz), 7.05–7.08 (m, 1H), 7.32–7.34 (m, 2H), 7.40–7.44 (m, 1H), 7.50–7.54 (m, 1H), 7.71–7.73 (m, 2H),7.82–7.86 (m, 1H), 7.94–7.96 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 67.38 (d, ²J_C-F = 20.8 Hz), 81.97 (d, ¹J_C-F = 170.50 Hz), 114.43, 117.08, 121.96, 122.01, 128.13, 130.17, 130.27, 132.10, 136.31, 136.95, 145.21, 158.95, 189.44; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.19 to −223.59 (m, 1F); IR (KBr) ν: 2928, 1659, 1604, 1491, 1310, 1262, 1213, 1178, 1048, 1027, 990, 883, 824, 778, 755, 666, 467 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₄BrFO₂: [M + H]⁺ 349.0239; Found: 349.0232.

(E)-3-(3-(2-Fluoroethoxy)phenyl)-1-(3-methylphenyl)-prop-2-en-1-one (8ix). Pale yellow solid, Yield: 90%, m.p. 82–84 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.44 (s, 3H), 4.27 (dt, 2H, ³J_H-H = 27.8 Hz, ³J_H-F = 3.9 Hz), 4.79 (dt, 2H, ³J_H-H = 47.3 Hz, ²J_H-F = 4.0 Hz), 6.98–7.00 (m,1H), 7.20 (s, 1H), 7.28–7.37 (m, 3H), 7.50–7.54 (m, 1H), 7.74–7.78 (m, 1H), 7.93–7.95 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 21.82, 67.39 (d, ²J_C-F = 20.4 Hz), 81.99 (d, ¹J_C-F = 171.90 Hz), 114.33, 116.82, 121.86, 122.71, 128.81, 129.50, 130.19, 135.70, 136.69, 143.88, 144.18, 158.95, 190.09; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.48 to −223.88 (m, 1F); IR (KBr) ν: 3055, 2920, 1658, 1600, 1576, 1494, 1439, 1372, 1311, 1205, 1182, 1096, 1078, 1055, 1030, 1016, 994, 884, 848 cm⁻¹; HRMS (ESI) calcd. for C₁₈H₁₇FO₂: [M + H]⁺ 285.1291 and [M + Na]⁺ 307.1110; Found: 285.1286 and 307.1104

(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-phenylprop-2-en-1-one (9i). Pale yellow viscous liquid, Yield: 81%, ¹H-NMR (CDCl₃) δ (ppm): 4.33 (dt, 2H, ³J_H-H = 3.9 Hz, ³J_H-F = 27.5 Hz), 4.85 (dt, 2H, ³J_H-H = 4.2 Hz, ²J_H-F = 47.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.37 (t, 1H, ³J = 8.3 Hz), 7.48–7.52 (m, 2H), 7.56–7.58 (m, 1H), 7.62–7.64 (m, 1H), 7.76–7.80 (m, 1H), 8.04–8.09 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 67.68 (d, ²J_C-F = 21.2 Hz), 81.87 (d, ¹J_C-F = 171.70 Hz), 112.36, 121.65, 123.68, 128.35, 128.71, 130.58, 131.70, 132.79, 133.09, 138.55, 140.49, 157.83, 191.21; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.86 to −223.46 (m, 1F); IR (KBr) ν: 2958, 2360, 1661, 1600, 1573, 1488, 1448, 1334, 1279, 1248, 1215, 1180, 1112, 1052, 1017, 927, 886, 753, 734, 694, 578 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₅FO₂: [M + H]⁺ 271.1134 and [M + Na]⁺ 293.0954 ; Found: 271.1131 and 293.0945.

(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(4-methylphenyl)-prop-2-en-1-one (9ii). Yellow viscous liquid, Yield: 83%, m.p. 69–70 °C; ¹H-NMR (CDCl₃) δ (ppm): 2.43 (s, 3H), 4.33 (dt, 2H, ³J_H-H = 4.2 Hz, ³J_H-F = 27.5 Hz), 4.85 (dt, 2H, ³J_H-H = 4.0 Hz, ²J_H-F = 47.4 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.29–7.31 (m, 2H), 7.34–7.38 (m, 1H), 7.62–7.64 (m, 1H), 7.77–7.80 (m, 1H), 7.95–7.97 (m, 2H), 8.04–8.08 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 21.81, 67.67 (d, ²J_C-F = 20.6 Hz), 81.88(d, ¹J_C-F = 171.90 Hz), 112.34, 121.62, 123.73, 124.59, 128.84, 129.42, 130.55, 131.55, 135.98, 140.02, 143.59, 157.79, 190.69; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.82 to −223.43 (m, 1F); IR (KBr) ν: 2860, 2361, 1659, 1598, 1490, 1449, 1280, 1251, 1181, 1126, 1040, 930, 884, 742, 572, 474 cm⁻¹; HRMS (ESI) calcd. for C₁₈H₁₇FO₂: [M + H]⁺ 285.1291 and [M + Na]⁺ 307.1110 ; Found: 285.1288 and 307.1105.

(E)-1-(2,4-Dichlorophenyl)-3-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (9iii). Yellow solid, Yield: 89%, m.p. 93–94 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.28 (dt, 2H, ³J_H-H = 4.3 Hz, ³J_H-F = 27.7 Hz), 4.77 (dt, 2H, ³J_H-H = 4.2 Hz, ²J_H-F = 47.0 Hz), 6.92 (m, 1H), 7.01–7.04 (m, 1H), 7.24 (s,1H), 7.28–7.48 (m, 4H), 7.57–7.59 (m, 1H), 7.84 (d, 1H, ³J = 16.5 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 67.86 (d, ²J_C-F = 20.6 Hz), 81.71 (d, ¹J_C-F = 171.80 Hz), 112.58, 112.74,123.90, 126.82, 127.30, 129.86, 130.28, 130.69, 132.40, 132.57, 136.90, 137.76, 142.11, 157.74, 193.13; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.85 to −223.46 (m, 1F); IR (KBr) ν: 2966, 1671, 1600, 1584, 1572, 1493, 1450, 1371, 1334, 1320, 1280, 1247, 1202, 1167, 1130, 1111, 1072, 1042, 1016, 987, 928, 886, 824, 790, 762, 745, 609, 575, 520, 454 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₃Cl₂FO₂ : [M + H]⁺ 339.0355; Found: 339.0344.

(E)-1-(4-Bromophenyl)-3-(2-(2-fluoroethoxy)phenyl)prop-2-en-1-one (9v). Pale yellow solid, Yield: 78%, m.p. 84–86 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.33 (dt, 2H, ³J_H-H = 6.2 Hz, ³J_H-F = 23.0 Hz), 4.86 (dt, 2H, ³J_H-H = 3.7 Hz, ²J_H-F = 48.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.36–7.40 (m, 1H), 7.57–7.65 (m, 3H), 7.74–7.78 (m, 1H), 7.83–7.85 (m, 1H), 7.90–7.93 (m, 1H), 8.03–8.07 (m, 1H); ¹³C-NMR (CDCl₃) δ (ppm): 67.60 (d, ²J_C-F = 20.7 Hz), 81.86 (d, ¹J_C-F = 171.30 Hz), 112.34, 121.67, 123.16, 124.26, 129.88, 130.24, 130.95, 131.89, 131.99, 137.27, 141.12, 157.91, 190.08; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.51 to −223.91 (m, 1F); IR (KBr) ν: 2960, 1919, 1684, 1657, 1600, 1571, 1490, 1448, 1394, 1333, 1274, 1252, 1205, 1177, 1128, 1064, 1008, 983, 930, 884, 822, 740, 667, 608, 580, 540, 468 cm⁻¹; HRMS (ESI) calcd. for C₁₇H₁₄BrFO₂: [M + H]⁺ 349.0239 and [M + Na]⁺ 371.0053; Found: 349.0230 and 371.0044.

(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(4-fluorophenyl)prop-2-en-1-one (9vii). Yellow solid, Yield: 71%, m.p. 44–45 °C; ¹H-NMR (CDCl₃) δ (ppm): 4.33 (dt, 2H, ³J_H-H = 4.3 Hz, ³J_H-F = 27.6 Hz), 4.86 (dt, 2H, ³J_H-H = 3.9 Hz, ²J_H-F = 47.5 Hz), 6.93–6.95 (m, 1H), 7.02–7.06 (m, 1H), 7.10–7.19 (m, 2H), 7.36–7.40 (m, 1H), 7.60–7.62 (m, 1H), 7.76–7.80 (m, 1H), 8.03–8.10 (m, 2H); ¹³C-NMR (CDCl₃) δ (ppm): 67.66 (d, ²J_C-F = 20.6 Hz), 81.87 (d, ¹J_C-F = 172.4), 112.35, 115.69, 115.90, 121.67, 123.34, 130.88, 130.96, 131.05, 131.24, 131.33, 131.79, 140.79, 189.77; ¹⁹F-NMR (CDCl₃) δ (ppm): −105.71 to −105.78 (m, 1H) and −223.46 to −223.86 (m, 1H); HRMS (ESI) calcd. for C₁₇H₁₄F₂O₂: [M + H]⁺ 289.1040 and [M + Na]⁺ 311.0860; Found: 289.1025 and 311.0843.

(E)-3-(2-(2-Fluoroethoxy)phenyl)-1-(2-methylphenyl)-prop-2-en-1-one (9viii). Pale yellow viscous liquid, Yield: 85%, ¹H-NMR (CDCl₃) δ (ppm): 2.46 (s, 3H), 4.27 (dt, 2H, ³J_H-H = 4.0 Hz, ³J_H-F = 27.1 Hz), 4.75 (dt, 2H, ³J_H-H = 4.1 Hz, ²J_H-F = 48.1 Hz), 6.90–6.92 (m, 1H), 7.00–7.04 (m, 1H), 7.25–7.29 (m, 3H), 7.34–7.39 (m, 2H), 7.52–7.54 (m, 1H), 7.58–7.60 (m, 1H), 7.83 (d, 1H, ³J =16.4 Hz); ¹³C-NMR (CDCl₃) δ (ppm): 20.49, 67.79 (d, ²J_C-F = 20.40 Hz), 81.75 (d, ¹J_C-F = 172.6 Hz), 112.48, 121.67, 124.27, 125.54, 127.70, 128.43, 129.53, 130.52, 131.39, 131.92, 137.16, 139.34, 141.36, 15s7.54, 197.15; ¹⁹F-NMR (CDCl₃) δ (ppm): −223.53 to −223.93 (m, 1F); IR (KBr) ν: 3707, 3314, 2869, 1636, 1600, 1489, 1459, 1390, 1310, 1276, 1245, 1168, 1112, 1064, 994, 922, 882, 748, 607, 458 cm⁻¹; HRMS (ESI) calcd. for C₁₈H₁₇FO₂: [M + H]⁺ 285.1291 and [M + Na]⁺ 307.1110; Found: 285.1286 and 307.1102.

4. Conclusions

In summary, we have reported the synthesis of a series of 2,2,2-trifluoroethoxy- and 2-fluoroethoxychalcones and their in vitro antiplasmodial evaluation against P. falciparum (3D7). It was found for the first time that 2,2,2-trifluoroethoxychalcones exhibited position-dependent antiplasmodial activity and the compounds 3a and 3f exhibited good activity with negligible toxic effects on normal erythrocytes and mammalian cells. The influence of the number of fluorine atoms on antiplasmodial activity was also demonstrated with 2-fluoroethoxychalcones. The results showed that chalcones with 2,2,2-trifluoroethoxy groups on the o-position of the 1-phenyl ring and 2-fluoroethoxy chalcones could be considered as viable alternatives to current drugs of future interest. Based on this result, a detailed study on the antiplasmodial activity of 2,2,2-trifluoroethoxychalcones in which the 2,2,2-trifluoroethoxy group is substituted on the 3-phenyl ring and 2-fluoroethoxychalcones will be undertaken.

Supplementary Materials

Supplementary materials are available online.

Author Contributions

T.M.R., R.P.S., and P.C.G. conceived and planned the experiments; K.D. and Ayushee performed the synthetic work and M.S. and R.P.S. compiled the supporting data. V.R. performed the biological works. V.R. and P.C.G. compiled and interpreted the activity data. T.M.R., R.P.S., and V.R. wrote the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.