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Article

Synthesis of New Dehydrodieugenol Derivatives via Olefin Cross Metathesis and In Vitro Evaluation of Their Trypanocidal Activity

by
Thalita S. Galhardo
1,
Anderson K. Ueno
2,
Wagner A. Carvalho
1,
Thais A. Costa-Silva
1,
Marina M. Gonçalves
1,
Mariana B. Abiuzi
3,
Andre G. Tempone
3,
João Henrique G. Lago
1,*,
Dalmo Mandelli
1,
Cedric Fischmeister
4,* and
Christian Bruneau
4
1
Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-180, Brazil
2
Institute of Environmental, Chemical, and Pharmaceutical Sciences, Federal University of São Paulo, Diadema 09972-270, Brazil
3
Center for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo 01246-902, Brazil
4
Institut des Sciences Chimiques de Rennes (ISCR)—UMR 6226, Université de Rennes, Centre National de la Recherche Scientifique (CNRS), 35042 Rennes, France
*
Authors to whom correspondence should be addressed.
Catalysts 2023, 13(7), 1097; https://doi.org/10.3390/catal13071097
Submission received: 19 June 2023 / Revised: 11 July 2023 / Accepted: 11 July 2023 / Published: 13 July 2023
(This article belongs to the Section Catalysis for Pharmaceuticals)
Browse Figures
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Abstract

:
Ruthenium-catalyzed cross metathesis using biseugenol (1) with electron-deficient olefins methyl (2a) and ethyl (2b) acrylates, acrylic acid (2c), acrylonitrile (2d), and methyl methacrylate (2e) derivatives have been conducted to afford respective derivatives 3a–3e with good yields and excellent conversion rates. Activity of prepared compounds against trypomastigote and amastigote forms of Trypanosoma cruzi and mammalian cytotoxicity have been evaluated. The results obtained indicate that the IC50 values for amastigotes of compounds 3b and 3d are quite similar to those of biseugenol (1), but unlike this compound, they show reduced toxicities with SI values similar to those of the standard drug benznidazol.

Graphical Abstract

1. Introduction

Over the last decade, natural products have been one of the most important references in drug discovery and development [1]. Indeed, over the last 30 years, half of all the new medicines introduced were based on natural products, which underlines their importance for lead generations [2,3]. After all, these compounds produced by nature are the result of millions of years of evolutionary selection and are therefore biologically pre-validated. All these factors have led to the validation of natural products as prime starting points for drug discovery.
Phenylpropanoid derivatives such as eugenol, isoeugenol, and their dimeric compounds (lignoids) correspond to an important class of natural products found in medicinal plants [4,5]. Consequently, these compounds have attracted considerable attention in the pharmaceutical industry due to their pharmacological potential. On the other hand, eugenol (the main component in clove oil), is a valuable starting compound for several drugs. It has been used in cosmetics and food products as a flavoring additive, antimicrobial, and antioxidant agent [6], as well as in dentistry where it is used in combination with zinc oxide as a pulp capping agent, temporary filling, and root conduit sealer [7]. However, eugenol causes allergenic contact dermatitis [8,9] and high concentrations of this compound have been reported to have some cytotoxic properties [10].
Biseugenol, also known as dehydrodieugenol (1), a symmetrical dimer of eugenol, is a natural product [11] which shows antioxidant [12,13] and anti-inflammatory [14,15] biological activity but with reduced cytotoxicity in comparison to eugenol [16]. The o-hydroxylated biphenyl structure found in the structure of compound 1 also exists in a large number of naturally occurring compounds, such as magnolol and honokiol, which have important pharmacological properties [17,18,19]. Furthermore, many studies have shown that compound 1 exhibits antineoplasic [20], antimicrobial [21,22], anti-inflammatory [23], antiarthritic [24], and antiproliferative activities [25]. It is also an apoptosis-inducing agent [26,27]. Bioactivity assays of natural biseugenol extracted from clove (Syzygium aromaticum) buds indicate antimutagenic activity [28], induction of cytotoxicity and apoptosis, inhibition of COX-2 gene expression [29], ability to treat cancer and other neoplasms [30], and possible inhibition of NFjB [14]. Additionally, chemical studies performed with Brazilian plant species Nectandra leucantha afforded compounds 1 and its methylated derivative which were evaluated in vitro against Trypanosoma cruzi [31]. As described, the presence of the phenol group was found to be crucial to the antiparasitic potential of compound 1 (IC50 values of 11.5 and 15.1 μM to trypomastigote and amastigote forms, respectively) but responsible for mammalian cytotoxicity (CC50 of 58.2 μM). On the other hand, methylated derivative exhibited reduced activity against T. cruzi (IC50 of 55.6 and >100 μM to trypomastigote and amastigote forms, respectively) and no toxicity to NCTC cells (CC50 > 200 μM).
As well as the modification of the substituent in the phenyl rings, it is possible to modify the allylic carbon-carbon double bond present in these neolignans when aiming at improving their biological activity. Miyazawa and Hisama found that the functionalization of the eugenol double bond induced a higher efficiency in inhibiting mutations that lead to the development of cancer [28]. Regarding this aspect, olefin metathesis could be considered an attractive way to transform these natural products since this process involves an efficient formation of new carbon-carbon double bonds [32]. Moreover, olefin metathesis reactions generally take place under mild reaction conditions, so this catalytic transformation has rapidly become an important synthetic tool for the production of biologically active organic molecules [33] and in total syntheses of natural products [33,34]. Due to their high tolerance to functional groups and robustness towards air and moisture, ruthenium complexes have been selected as catalysts of choice for these transformations. In particular, cross metathesis represents one type of bimolecular olefin metathesis process that has been used for the preparation of natural products such as prosophylline, lasiol, faranal, and meayamycin B [35,36,37]. Previous studies reporting the total synthesis of Δ12-prostaglandin, which displayed potent anticancer activity [38], as well as jasmonic acid derivatives, responsible for defense reactions after wounding or pathogen infestation [39], represent relevant examples of synthesis of biologically active molecules accomplished via olefin cross metathesis. Previous studies using eugenol in cross metathesis reactions with a variety of alkenes for the preparation of biologically active molecules have been reported [40,41]. Our group reported that eugenol was favorably involved in cross metathesis reactions in the presence of ruthenium catalysts allowing its straightforward functionalization [42,43,44]. More recently, dehydrodieugenol B and its methyl ether, both isolated from Nectandra leucantha, were used as starting materials for the preparation of new derivatives containing additional methoxycarbonyl units on allyl side chains and demonstrated activity against trypomastigotes and against intracellular amastigotes of Trypanosoma cruzi [45]. Based on these results and our knowledge of metathesis for the preparation of biologically active derivatives of eugenol, we report herein the preparation via cross metathesis with functional olefins of novel dehydrodieugenol derivatives 3a–3e using compound 1 as a starting material (Figure 1). We have evaluated the effect of the introduction of different functionalities of the allyl fragment on the biological activity of these new compounds against Trypanosoma cruzi (trypomastigote and intracellular amastigote forms).

2. Results and Discussion

The synthesis of biseugenol 1 was achieved via the oxidative coupling of eugenol in the presence of K3[Fe(CN)6] as oxidant [46], and led to a 36% isolated yield of 1 with high purity after recrystallization (see experimental section). We have previously shown that the cross metathesis of eugenol with acrylates [42,43,44] was efficiently carried out in the presence of the second generation Hoveyda ruthenium catalyst Ru1 [47]. The isomerization of allylbenzene derivatives including 4-hydroxyphenylpropanoids in the presence of ruthenium olefin metathesis catalysts has been extensively described by van Otterlo [48], who suggested that the utilization of an isomerization inhibitor should be recommended to avoid this competing reaction leading to undesired metathesis products. From Figure 2, it appears that the cross metathesis of 1 with electron-deficient olefins should involve two successive steps leading to the mono cross metathesis products, the precursors of the di cross metathesis products 3a–3e.
In some experiments, we could intercept compounds 4a–4e, which proved to be very useful to get information on the characterization of this intermediate, especially the 1H NMR spectra, and evaluate the efficiency of the different catalytic systems that were tested. From the reaction with methyl methacrylate, the 1H NMR spectra shows that the signals of the five allylic protons present exactly the same chemical shifts in 4e as in substrate 1. Similarly, the aromatic and the hydroxyl protons in substrate 1 and products 3e and 4e appear at the same chemical shifts. Consequently, when they are present, the signals of the terminal protons of the allylic system in the region at δ 5.0–5.5 ppm in the crude reaction mixtures do not give information on the nature and ratio of the products 3 or 4 (see Supporting Information). We determined the conversion of 1 with the aid of the integration of the signals of the two terminal CH2 protons in the range at δ 5.0–5.2 ppm and the methoxy group at δ 3.9 ppm, which led to a conversion lower than the real one due to the impact of the presence of the intermediate 4 in the determination of the terminal allylic protons.
We started the investigations with methyl acrylate 2a as cross metathesis partner using the conditions that we previously optimized for the cross metathesis with eugenol [42,43,44]. Our first attempts were made at 80 °C in dimethyl carbonate [49] in the presence of 10 mol% of p-benzoquinone as an olefin isomerization inhibitor with 2 mol% of Ru1 as catalyst and a twofold molar excess of methyl acrylate (Table 1).
The batch reaction with a 2a/1 molar ratio of four with a biseugenol concentration of 0.075 mol/L in DMC provided 91% conversion of 1 after 16 h (Table 1, entry 1). Then, we used a protocol based on the slow addition of the catalyst into the reaction mixture, which consisted in the addition of the catalyst dissolved in 0.5 mL of solvent over 2 h using a syringe pump followed by 3 h of stirring with these two steps being performed at 80 °C. This process led to an improved conversion of 96% while reducing the reaction time from 16 h to 5 h (Table 1, entry 2). Increasing the catalyst loading or excess of methyl acrylate had no significant effect on the conversion (Table 1, entries 3 and 4), whereas dilution to 0.015 mol/L had a deleterious impact (Table 1, entry 5). Overall, the slow addition of the catalyst for 2 h followed by 3 h of reaction provided the best conditions with a conversion of 96% and only eventually traces of 4a (≤4%) leading to the isolation of 3a in 52% yield.
The 1H NMR analysis of the crude reaction mixture after elimination of the solvent and the excess of methyl acrylate (2a) not only gave an indication on the conversion of the substrate 1 but also provided information on the configuration of the formed carbon-carbon double bond. Indeed, only one stereoisomer was detected and the value of the coupling constant of 15.6 Hz between the two olefinic protons indicated that the cross metathesis was (E)-selective. It is noteworthy that this (E) stereoselectivity is perfectly in line with that observed during cross metathesis of 2a with the monomeric eugenol [42,43,44].
The cross metathesis of 1 with ethyl acrylate 2b was conducted under the optimized conditions leading to a conversion of 94%. However, the product was difficult to isolate and only 25% yield could be obtained after purification (Table 2, entry 2). Acrylic acid (2c) was involved as cross metathesis partner in order to prepare a new biseugenol derivative featuring carboxylic acid groups (3c). These latter are expected to bring new properties in terms of acidity and solubility in aqueous media able to enhance biological activity. Under the catalytic conditions used for the syntheses of 3a and 3b, the reaction took place even though the conversion was lower (71%). The resulting diacid 3c was isolated as a solid in 32% yield and the reaction exhibited the same high (E) stereoselectivity (Table 2, entry 3). The metathesis reactions with acrylonitrile in the presence of second-generation ruthenium catalysts such as Ru1 are known to require more drastic conditions [50,51,52]. For this reason, the cross metathesis of 1 with 2d was carried out in diethyl carbonate at 100 °C. A good conversion of 1 of 88% was obtained and the product 3d was isolated in 51% yield (Table 2, entry 4). As expected, the use of acrylonitrile did not promote the selective formation of the (E) isomer but produced a mixture of the two stereoisomers with a (Z)/(E) ratio of 2.5:1 based on the 1H NMR analysis of the allylic CH2 protons at δ 3.72 (Z-isomer) and 3.51 (E isomer), respectively [53,54]. Then, we investigated the behavior of the α,α-disubstituted methyl methacrylate 2e under the conditions that were previously optimized with eugenol [42,43,44]. Without additional solvent, the cross metathesis reaction took place in an excess of 2e at 90 °C for 16 h without using the slow addition protocol. The conversion of 1 reached 81% and 3e was isolated in 29% yield as a single (E)-stereoisomer (Table 2, entry 5). Structures of compounds 3a–3e are presented in Figure 3.
To the best of our knowledge, compounds 3a–3e shown in Figure 3 are described herein for the first time. Based on the anti-Trypanosoma cruzi effect observed with compound 1, these new products were tested against trypomastigote and amastigote forms of this parasite. As summarized in Table 3, it was noticed that the modification in the structure of compound 1 via cross metathesis reaction resulted in compounds with no detectable toxicity to the highest tested concentration (CC50 values > 200 µM for 3a–3e against a value of 58.2 µM for compound 1 and with potential against trypomastigote forms of parasite displaying IC50 values ranging from 11.6 to 79.5 μM. However, as described by the DNDi (Drugs for Neglected Diseases initiative), activity against intracellular (amastigote) forms of parasite is crucial to the development of new drugs for Chagas disease [55].
As also observed in Table 3, among all tested compounds, derivatives 3b and 3d exhibited activity against amastigotes with IC50 values of 17.7 and 15.5 μM. Considering the reduced toxicity of both compounds, the SI values were determined as >11.2 and >12.9, respectively, similar to the standard drug benznidazole (IC50 of 18.7 μM and SI > 10.7). Chemically, these data suggest that the insertion of an ethoxycarbonyl group (3b) and a cyanide (3d) group in the original structure of starting material 1 plays an important role in reducing toxicity on NCTC cells and maintaining anti-amastigote activity. Interestingly, the presence of methoxycarbonyl group (3a and 3e) or free carboxylic acid (3c) afforded inactive compounds. Therefore, compounds 3b and 3d can be considered as a promising starting point for the development of new prototypes for future drug discovery studies for Chagas disease [31].

3. Materials and Methods

3.1. General Experimental Procedures

All reactions were conducted under an inert atmosphere of argon using standard Schlenk tube techniques. Solvents were dried by distillation or using a MBraun Solvent purification system prior to use. Dimethyl carbonate and diethyl carbonate were distilled under atmospheric pressure and stored under argon over activated 3 Å molecular sieves. Eugenol (99%) and hydrochloric acid (>37%) were purchased from Sigma-Aldrich, St. Gallen, Switzerland and used as received. Hoveyda Grubbs II catalyst (97%) was supplied by Umicore AG, Germany and used without further purification. Ethyl acrylate (99%), ammonium hydroxide solution (28–30%), acrylic acid (99%), and potassium hexacyanoferrate (III) (99%) were purchased from Alfa-Aesar, Le Mans, France and used without further purification. Methyl acrylate, methyl methacrylate, and anhydrous sodium sulfate were purchased from Acros Organics, Illkirch, France. Methyl acrylate and methyl methacrylate were stored under argon over activated 3 Å molecular sieves prior to use. Acrylonitirile was distilled under atmospheric pressure and stored under argon over activated 3 Å molecular sieves. Acetone, dimethylformamide, and anhydrous potassium carbonate (99%) were purchased from Fischer Chemical, Illkirch-Graffenstaden, France. Silica gel (0.040–0.063 mm) from Macherey-Nagel, Hœrdt, France was used for column chromatography, while silica gel (60 Å) from Merck, Darmstadt, Germany was used for analytical TLC. NMR spectra were recorded on a Bruker model Avance III, Wissemburg, Germany, operating at 400 MHz (1H) and 100 MHz (13C), and on a Varian 500, Palo Alto, CA, USA, operating at 500 MHz (1H) and 125 MHz (13C), while featuring spectrometers using CDCl3 or DMSO-d6 as solvent. ESI-HRMS spectra were measured on an Agilent 6510 QTOF LC/MS spectrometer, Santa Clara, CA, USA.

3.2. Preparation of Dehydrodieugenol (1)

Preparation of dehydrodieugenol 1 was performed based on the methodology previously reported [46]. A saturated aqueous solution of K3[Fe(CN)6] (3.29 g in 14.5 mL of H2O, 10 mmol, 1 equiv.) was slowly transferred into a flask containing a solution of eugenol (1.64 g, 10 mmol, 1 equiv.) in 16 mL of acetone, 8 mL of distillated H2O and 25 mL of NH3·H2O (25%). The mixture was kept under magnetic stirring for 5 h at room temperature. Then, NH3·H2O was neutralized with concentrated HCl (22 mL) until the formation of a precipitate, which was washed three times with distillated H2O and recrystallized using absolute EtOH.

Dimethoxy-5,5′-diprop-2-enyl [1,1′-biphenyl]-2,2′-diol (biseugenol) 1

Colorless crystalline plates. 1H NMR Figure S1 (400 MHz, CDCl3, δ ppm) 6.75 (2H, d, J = 1.6 Hz, H-6/6′), 6.67 (2H, d, J = 1.6 Hz, H-4/4′), 5.99 (2H, s, 2- and 2′-OH), 5.98 (2H, ddt, J = 17.0, 10.1 and 6.7 Hz, H-8/H8′), 5.11 (2H, dd, J = 17.0 and 1.7 Hz, H-9a/H-9′a), 5.07 (2H, dd, J = 10.1 and 1.7 Hz, H-9b/H-9′b), 3.92 (s, 6H, 3- and 3′-OCH3), 3.36 (4H, d, J = 7.6 Hz, 2 × CH2). 13C NMR (100 MHz, CDCl3, δ ppm) 147.3 (C-2/C-2′), 141.1 (C-3/C-3′), 137.8 (C-8/C-8′), 132.1 (C-5/C-5′), 124.5 (C-1/C-1′), 123.3 (C-6/C-6′), 115.9 (C-9/C-9), 110.8 (C-4/C-4′), 56.2 (C-10/C-10′), 40.1 (C-7/C-7′). ESI-HRMS m/z 349.1418 [M + Na]+ (calculated for C20H22O4Na, 349.1416). These values are consistent with the data described in the literature [46].

3.3. General Procedure for Cross Metathesis Reactions

In a first study, several olefins were tested as metathesis partners in the modification of compound 1 according to conditions described in Table 1. In general, reactions were conducted in a dry and degassed Schlenk tube loaded under argon with 50 mg of compound 1 (0.15 mmol), 1.9 mg of Ru1 (3 × 10−3 mmol, 2 mol%), and 1.6 mg of p-benzoquinone (1.5 × 10−2 mmol, 10 mol%). A second study was performed using methyl acrylate as olefin metathesis partner and compound 1 as substrate aiming at optimizing the reaction conditions (Table 1). The variation of the p-benzoquinone amount (in the absence or in the presence of 1.5 × 10−3 mmol, 10 mol%) was performed in overnight tests. Variation of the amount of Ru1 catalyst (3–6 × 10−3 mmol, 2–4 mol%), solvent (2–10 mL), and methyl acrylate (2a, 0.61–1.86 mmol, 4–12 equiv.) was performed in a slow addition of the catalyst (0.25 mL h−1) procedure, as described: a dry and degassed Schlenk tube was loaded under argon with 50 mg of compound 1 (0.15 mmol), p-benzoquinone, and methyl acrylate (2a), and then closed by a rubber septum. Another dry and degassed Schlenk tube was loaded under argon with Hoveyda-Grubbs II catalyst and 0.5 mL of solvent. This solution was pumped into a 1 mL syringe and then slowly added into the first Schlenk tube through the septum by means of a syringe-pump for 2 h. After addition, the reaction mixture was stirred at 80 °C for an additional 3 h. In both procedures (overnight and slow addiction of catalyst), the solvent evaporation was performed and the products were purified by chromatography column on silica gel using heptane/EtOAc mixtures. After defining the best metathesis conditions for the different olefin partners, compounds 3a–3e were prepared in a dry and degassed Schlenk tube loaded under argon with 50 mg of compound 1, p-benzoquinone (10 mol%), and the selected olefin as follows:
i.
methyl acrylate (2a, 56 μL) to afford compound 3a
ii.
ethyl acrylate (2b, 65 μL) to afford compound 3b
iii.
acrylic acid (2c, 42 μL) to afford compound 3c
iv.
acrylonitrile (2d, 40 μL) to afford compound 3d
v.
methyl methacrylate (2e, 2 mL) to afford compound 3e
Hoveyda-Grubbs II catalyst (2 mol%) was slowly added during 2 h (0.25 mL/h) under stirring using a syringe-pump and the reaction proceeded for more than three hours. After solvent evaporation, the products were purified by chromatography column over silica gel using a mixture of heptane/EtOAc.

3.3.1. (9. E,9’E)-dimethyl 7,7’-(2,2’-dihydroxy-3,3’-dimethoxy-[1,1’-biphenyl]-5,5’-diyl)bis(but-9-enoate), 3a

Yellowish oil (yield 52%). 1H NMR (400 MHz, CDCl3, δ ppm) 7.10 (2H, dt, J = 15.6 and 6.8 Hz, H-8/H-8′), 6.72 (2H, d, J = 1.8 Hz, H-6/H-6′), 6.68 (2H, d, J = 1.8 Hz, H-4/H-4′), 5.98 (2H, s, 2- and 2′-OH), 5.86 (2H, d, J = 15.6 Hz, H-9/H-9′), 3.91 (6H, s, 3- and 3′-OCH3), 3.72 (6H, s, H-11/H-11′), 3.49 (4H, d, J = 6.8 Hz, H-7/H-7′). 13C NMR (100 MHz, CDCl3, δ ppm) 167.1 (C-10/C-10′), 147.9 (C-8/C-8′), 147.5 (C-2/C-2′), 141.6 (C-3/C-3′), 129.5 (C-5/C-5′), 124.5 (C-1/C-1′), 123.5 (C-6/C-6′), 121.9 (C-9/C-9′), 110.9 (C-4/C-4′), 56.3 (C-11/C-11′), 51.6 (3- and 3-OCH3), 38.4 (C-7/C-7′). ESI-HRMS m/z 465.1520 [M + Na]+ (calculated for C24H26O8Na, 465.1525).

3.3.2. (9. E,9’E)-diethyl 7,7’-(2,2’-dihydroxy-3,3’-dimethoxy-[1,1’-biphenyl]-5,5’-diyl)bis(but-2-enoate) 3b

Yellowish oil (yield 25%). 1H NMR (400 MHz, CDCl3, δ ppm) 7.09 (2H, dt, J = 15.5 and 6.8 Hz, H-8/H-8′), 6.73 (2H, d, J = 1.8 Hz, H-6/H-6′), 6.69 (2H, d, J = 1.8 Hz, H-4/H-4′), 6.00 (2H, s, 2- and 2’-OH), 5.85 (2H, d, J = 15.5 Hz, H-9/H-9′), 4.18 (4H, q, J = 7.1 Hz, H-11/H-11′), 3.92 (6H, s, 3- and 3’-OCH3), 3.49 (4H, d, J = 6.8 Hz, H-7/H-7′), 1.27 (6H, t, J = 7.1 Hz, H-12/H-12′). 13C NMR (100 MHz, CDCl3, δ ppm) 166.7 (C-10/C-10′), 147.6 (C-8/C-8′), 147.5 (C-2/C-2′), 141.6 (C-3/C-3′), 129.6 (C-5/C-5′), 124.5 (C-1/C-1′), 123.5 (C-6/C-6′), 122.2 (C-9/C-9′), 111.0 (C-4/C-4′), 60.4 (C-11/C-11′), 56.3 (3- and 3’-OCH3), 38.4 (C-7/C-7′), 14.4 (C-12/C-12′). ESI-HRMS m/z 493.1835 [M + Na]+ (calculated for C26H30O8Na, 493.1838).

3.3.3. (9. E,9’E)-7,7’-(2,2’-dihydroxy-3,3’-dimethoxy-[1,1’-biphenyl]-5,5’-diyl)bis(but-2-enoic acid) 3c

Brownish amorphous solid (yield 32%). 1H NMR (500 MHz, DMSO-d6, δ ppm) 8.24 (s, 2H, 2- and 2′-OH), 6.91 (2H, dt, J = 15.5 and 7.0 Hz, H-8/H-8′), 6.78 (2H, d, J = 1.8 Hz, H-6/H-6′), 6.54 (2H, d, J = 1.8 Hz, H-4/H-4′), 5.78 (2H, d, J = 15.5 Hz, H-9/H-9′), 3.80 (6H, s, 3- and 3′-OCH3), 3.43 (4H, d, J = 7.0 Hz, H-7/H-7′). 13C NMR (125 MHz, DMSO-d6, δ ppm) 167.1 (C-10/C-10′), 148.0 (C-8/C-8′), 147.8 (C-2/C-2′), 142.2 (C-3/C-3′), 128.0 (C-5/C-5′), 125.9 (C-1/C-1′), 123.1 (C-6/C-6′), 122.1 (C-9/C-9′), 111.1 (C-4/C-4′), 55.9 (4- and 4’-OCH3), 37.2 (C-7/C-7′). ESI-HRMS m/z 437.1209 [M + Na]+ (calculated for C22H22O8Na 437.1212).

3.3.4. 7,7’-(2,2’-dihydroxy-3,3’-dimethoxy-[1,1’-biphenyl]-5,5’-diyl)bis(but-2-enenitrile) 3d

Yellowish oil (yield 51%). 1H NMR (400 MHz, CDCl3, δ ppm) (Z)-3d: 6.75 (2H, d, J = 1.7 Hz, H-6/H-6′), 6.73 (2H, d, J = 1.7 Hz, H-4/H-4′), 6.63 (2H, dt, J = 10.8 and 7.7 Hz, H-8/H-8′), 5.98 (2H, s, 2- and 2′-OH), 5.39 (2H, d, J = 10.8 Hz, H-9/H-9′), 3.93 (6H, s, 3- and 3’-OCH3), 3.72 (4H, d, J = 7.6 Hz, H-7/H-7′). (E)-3d: 6.89 (2H, dt, J = 16.3 and 6.5 Hz, H-8/H-8′), 6.69 (2H, d, J = 1.7 Hz, H-6/H-6′), 6.65 (2H, d, J = 1.7 Hz, H-2/H-2′), 5.97 (2H, s, 2- and 2’-OH), 5.33 (2H, dt, J = 16.2 and 1.6 Hz, H-9/H-9′), 3.93 (6H, s, 3- and 3’-OCH3), 3.51 (4H, d, J = 6.5 Hz, H-7/H-7′). 13C NMR (100 MHz, CDCl3, δ ppm) (Z)-3d: 153.2 (C-8/C-8′), 147.5 (C-2/C-2′), 141.8 (C-3/C-3′), 128.6 (C-1/C-1′), 124.4 (C-6/C-6′), 123.1 (C-5/C-5′), 116.1 (C-10/C-10′), 110.7 (C-4/C-4′), 99.7 (C-9/C-9′), 56.3 (3- and 3’-OCH3), 37.8 (C-7/7′). (E)-3d: 154.3 (C-8/C-8′), 147.5 (C-2/C-2′), 141.9 (C-3/C-3′), 127.7 (C-1/C-1′), 124.3 (C-6/C-6′), 123.5 (C-5/C-5′), 117.4 (C-10/C-10′), 110.8 (C-4/C-4′), 100.8 (C-9/C-9′), 56.3 (3- and 3′-OCH3), 39.1 (C-7/C-7′). ESI-HRMS m/z 399.1313 [M + Na]+ (calculated for C22H20N2O4Na, 399.1321).

3.3.5. (9. E,9’E)-dimethyl 7,7’-(2,2’-dihydroxy-3,3’-dimethoxy-[1,1’-biphenyl]-5,5’-diyl)bis(9-methylbut-9-enoate) 3e

Yellowish oil (yield 29%). 1H NMR (400 MHz, CDCl3, δ ppm) 6.93 (2H, t, J = 7.5 Hz, H-8/H-8′), 6.72 (2H, br s, H-6/H-6′), 6.70 (2H, br s, H-4/H-4′), 5.96 (2H, s, 2- and 2′-OH), 3.92 (6H, s, 3- and 3’-OCH3), 3.73 (6H, s, H-11/H-11′), 3.49 (4H, d, J = 7.5 Hz, H-7/H-7′), 1.95 (6H, s, H-12/H-12′). 13C NMR (100 MHz, CDCl3, δ ppm) 168.7 (C-10/C-10′), 147.5 (C-2/C-2′), 141.4 (C-3/C-3′), 140.8 (C-6/C-6′), 130.9 (C-1/C-1′), 128.1 (C-9/C-9′), 124.5 (C-5/C-5′), 123.1 (C-8/C-8′), 110.7 (C-4/C-4′), 56.3 (3- and 3’-OCH3), 51.9 (C-11/C-11′), 34.8 (C-7/C-7′), 12.7 (C-12/C-12′). ESI-HRMS m/z 493.1829 [M + Na]+ (calculated for C26H30O8Na, 493.1838).

3.4. Experimental Animals

BALB/c mice were obtained by the animal breeding facility at the Instituto Adolfo Lutz—São Paulo, SP, Brazil. The animals were maintained in sterilized boxes with absorbent material under a controlled environment and received water and food ad libitum. BALB/c mice were used to obtain peritoneal macrophages and for T. cruzi maintenance infection. Animal procedures were performed with the approval of the Research Ethics Commission (project CEUA-IAL 05/2018), in agreement with the Guide for the Care and Use of Laboratory Animals from the National Academy of Sciences.

3.5. Parasites and Mammalian Cell Maintenance

Trypanosoma cruzi trypomastigotes (Y strain) were maintained in Rhesus monkey kidney cells (LLC-MK2—ATCC CCL 7), using RPMI-1640 medium supplemented with 2% FBS at 37 °C in a 5% CO2-humidified incubator. The murine conjunctive cells (NCTC clone 929, ATCC) and LLC-MK2 were maintained in RPMI-1640 supplemented with 10% FBS at 37 °C in a 5% CO2—humidified incubator. Macrophages were obtained from the peritoneal cavity of BALB/c mice by washing them with RPMI—1640 medium supplemented with 10% FBS and were maintained at 37 °C in a 5% CO2-humidified incubator.

3.6. Determination of Anti-Trypomastigote and Anti-Amastigote Activity

The 50% inhibitory concentration (IC50) of tested compounds 3a–3e against T. cruzi was determined in trypomastigotes and amastigotes forms. Trypomastigotes were obtained from LLC-MK2 cultures previously infected. The parasites were counted in a Neubauer hemocytometer, seeded at 1 × 106 cells/well (96-well plates), and incubated with serial dilutions of the tested compounds 3a–3e (1.71–150 µM) for 24 h at 37 °C in a 5% CO2-humidified incubator, with benznidazole as the standard drug. The trypomastigote viability was evaluated by the resazurin (Sigma) assay [56]. To determine the activity against intracellular amastigotes, peritoneal macrophages from BALB/c mice were infected with trypomastigotes forms of T. cruzi. The macrophages obtained from the peritoneal cavity of BALB/c mice were plated on a 16-well chamber slide (NUNC plate, Thermo; 1 × 105/well) and incubated for 24 h at 37 °C in a 5% CO2-humidified incubator. Trypomastigotes obtained as described above were washed in RPMI-1640 medium, and then counted and used to infect the macrophages (parasite to macrophage ratio = 10:1). After an incubation for 2 h at 37 °C in a 5% CO2-humidified incubator, residual free parasites were removed by washing with medium. Next, tested compounds were incubated with infected macrophages (48 h at 37 °C, 5% CO2) at different concentrations using benznidazole as the standard drug. At the end of the assay, slides were fixed with MeOH and stained with Giemsa prior to counting under a light microscope. The IC50 values were calculated as previously described [56].

3.7. Determination of Cytotoxicity against Mammalian Cells

Cytotoxicity was performed in mice fibroblasts NCTC cells-clone L929. The cells (6 × 104 cells/well) were seeded and individually incubated with tested compounds 3a–3e (1.56–200 µM) for 48 h at 37 °C in a 5% CO2 incubator. The 50% cytotoxic concentration (CC50) was determined by MTT assay [57]. The optical density was determined in FilterMax F5 (Molecular Devices) at 570 nm. The selectivity index (SI) values were calculated for both forms of the parasite (trypomastigotes and amastigotes) using the equation: CC50 against NCTC cells/IC50 against parasites.

3.8. Statistical Analysis

All data were expressed as mean ± SEM. Comparisons between groups were made using ANOVA followed by Newman-Keuls correction factor as a post-test. The GraphPad Prism program, version 6.0, was used to perform statistical analysis and graph construction. For p values < 0.05, the differences between means were considered significant.

4. Conclusions

Five new compounds have been synthesized by cross metathesis of biseugenol (1) with electron deficient olefins. The products resulting from the reactions with acrylates and acrylic acid present almost perfect (E)-configuration, whereas a mixture of (Z) and (E)-isomers with the (Z)-isomer as the major product was obtained from acrylonitrile. These compounds were characterized by NMR and HRMS techniques and their biological activity was evaluated against Trypanosoma cruzi. Among all the synthesized compounds, higher potency against T. cruzi was obtained for compounds 3b and 3d with IC50 values of 17.7 and 15.5 μM, respectively, to amastigote forms of the parasite. Contrasting to the starting material 1, these compounds exhibited no mammalian toxicity (CC50 > 200 μM) with elevated SI values. Based on these results, compounds 3b and 3d can be considered promising materials for future studies of Chagas disease.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal13071097/s1, Figure S1. 1H NMR (δ, CDCl3, 400 MHz) of 1; Figure S2. 13C NMR (δ, CDCl3, 100 MHz) of 1; Figure S3. ESI-HRMS (positive mode) of 1; Figure S4. 1H NMR (δ, CDCl3, 400 MHz) of 3a; Figure S5. 13C NMR (δ, CDCl3, 100 MHz) of 3a; Figure S6. ESI-HRMS (positive mode) of 3a; Figure S7. 1H NMR (δ, CDCl3, 400 MHz) of 3b; Figure S8. 13C NMR (δ, CDCl3, 100 MHz) of 3b; Figure S9. ESI-HRMS (positive mode) of 3b; Figure S10. 1H NMR (δ, CDCl3, 500 MHz) of 3c; Figure S11. 13C NMR (δ, CDCl3, 125 MHz) of 3c; Figure S12. ESI-HRMS (positive mode) of 3c; Figure S13. 1H NMR (δ, CDCl3, 400 MHz) of 3d; Figure S14. 13C NMR (δ, CDCl3, 100 MHz) of 3d; Figure S15. ESI-HRMS (positive mode) of 3d; Figure S16. 1H NMR (δ, CDCl3, 400 MHz) of 3e. Figure S17. 13C NMR (δ, CDCl3, 100 MHz) of 3e; Figure S18. ESI-HRMS (positive mode) of 3e; Figure S19. 1H NMR (δ, CDCl3, 400 MHz) of 4e - mono cross metathesis of 1 with methyl methacrylate (2e).

Author Contributions

Conceptualization, W.A.C., J.H.G.L., D.M., C.F. and C.B.; methodology, T.S.G., M.M.G., A.K.U., W.A.C., T.A.C.-S., M.B.A., A.G.T., J.H.G.L., D.M., C.F. and C.B.; formal analysis, T.S.G., M.M.G., A.K.U., W.A.C., T.A.C.-S., M.B.A., A.G.T., J.H.G.L., D.M., C.F. and C.B.; investigation, T.S.G., M.M.G., A.K.U., T.A.C.-S. and M.B.A.; resources, W.A.C., A.G.T., J.H.G.L., D.M., C.F. and C.B.; writing—original draft preparation, T.S.G., A.G.T., J.H.G.L., D.M., C.F. and C.B.; writing—review and editing, J.H.G.L., D.M., C.F. and C.B.; supervision, J.H.G.L., D.M., C.F. and C.B.; project administration, J.H.G.L., D.M., C.F. and C.B.; funding acquisition, J.H.G.L., D.M., C.F. and C.B. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank CAPES−COFECUB (project PHC 884-17-France; 883/2017-Brazil) for financial support and a post-doctoral fellowship to TSG (process 88887.198050/2018-00). They are also grateful to Umicore AG for the supply of Hoveyda catalyst M72. Authors are also thankful for the financial support and fellowships provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES, Finance Code 001), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, for grants to OS, AGT and JHGL) and to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2021/02789-7, 2021/04464-8, 2018/07885-1, 2017/50333-7 and 2018/10279-6). D.M. and W.A.C thank projects CNPq (312288/2019-0, 422290/2016-5, and 404843/2018-2), FAPESP (2018/01258-5 and 2021/12342-0) and the Sustainable Technologies Unit of UFABC (NuTS).

Data Availability Statement

Data is contained within the article or supplementary material.

Acknowledgments

We are thankful for the technical support of the Federal University of ABC, Instituto Adolfo Lutz, and Université de Rennes.

Conflicts of Interest

We wish to confirm that there are no known conflict of interest associated with this publication and that there has been no significant financial support for this work that could have influenced its outcome.

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Catalysts 13 01097 g001 550
Figure 1. Biseugenol (1), olefins 2a–2e, and cross metathesis products 3a–3e.
Figure 1. Biseugenol (1), olefins 2a–2e, and cross metathesis products 3a–3e.
Catalysts 13 01097 g001
Catalysts 13 01097 g002 550
Figure 2. General scheme for cross metathesis of biseugenol 1.
Figure 2. General scheme for cross metathesis of biseugenol 1.
Catalysts 13 01097 g002
Catalysts 13 01097 g003 550
Figure 3. New dehydrodieugenol derivatives 3a–3e resulting from cross metathesis with acrylic olefins and 1.
Figure 3. New dehydrodieugenol derivatives 3a–3e resulting from cross metathesis with acrylic olefins and 1.
Catalysts 13 01097 g003
Table
Table 1. Cross metathesis of biseugenol 1 with methyl acrylate (2a) a.
Table 1. Cross metathesis of biseugenol 1 with methyl acrylate (2a) a.
Entry2a
(Eq.)		DMC
(mL)		Ru1
(mol%)		Time
(h)		Conversion
(%)
14221691
2422(2 + 3) b96
3424(2 + 3) b97
41222(2 + 3) b96
54102(2 + 3) b87
a General conditions: 1 (0.15 mmol), T = 80 °C, p-benzoquinone (10 mol%); b slow addition of the catalyst (0.25 mL/h). Eq. = equivalent; DMC = dimethyl carbonate.
Table
Table 2. Cross metathesis of 1 with electron deficient olefins 2a–2e a.
Table 2. Cross metathesis of 1 with electron deficient olefins 2a–2e a.
EntrySubstrateOlefinProductConversion (%)Yield (%)
11Methyl acrylate (2a)3a9652
21Ethyl acrylate (2b)3b9425
31Acrylic acid (2c)3c7132
4 b1Acrylonitrile (2d)3d8851
5 c1Methyl methacrylate (2e)3e8129
a Conditions: DMC (2 mL), p-benzoquinone (10 mol%), Ru1 (2 mol%), slow addition of the catalyst (0.25 mL·h−1) (2 + 3 h), T = 80 °C; b DEC (2 mL) and T = 100 °C; c without solvent (2 mL of methyl methacrylate), T = 90 °C, 16 h, single addition of the catalyst.
Table
Table 3. Anti-Trypanosoma cruzi activity and cytotoxicity in mammalian cells of compounds 1 and 3a–3e.
Table 3. Anti-Trypanosoma cruzi activity and cytotoxicity in mammalian cells of compounds 1 and 3a–3e.
CompoundIC50/µMCC50/µMSI
TrypomastigoteAmastigoteNCTCTrypomastigoteAmastigote
111.5 ± 2.515.1 ± 3.458.23.93.8
3a19.9 ± 0.1NA>200>10.0-
3b11.9 ± 0.717.7 ± 8.0>200>16.8>11.2
3c79.5 ± 9.3NA>200>2.5-
3d23.5 ± 2.015.5 ± 1.8>200>8.5>12.9
3e11.6 ± 2.1NA>200>17.2-
benznidazole5.5 ± 0.9 18.7 ± 4.1>200>36.4>10.7
IC50—50% inhibitory concentration; CC50—50% cytotoxic concentration; SI—selectivity index, calculated by the ratio CC50 against NCTC cells/IC50 against parasites (trypomastigote and amastigote forms); NA: not active.
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MDPI and ACS Style

Galhardo, T.S.; Ueno, A.K.; Carvalho, W.A.; Costa-Silva, T.A.; Gonçalves, M.M.; Abiuzi, M.B.; Tempone, A.G.; Lago, J.H.G.; Mandelli, D.; Fischmeister, C.; et al. Synthesis of New Dehydrodieugenol Derivatives via Olefin Cross Metathesis and In Vitro Evaluation of Their Trypanocidal Activity. Catalysts 2023, 13, 1097. https://doi.org/10.3390/catal13071097

AMA Style

Galhardo TS, Ueno AK, Carvalho WA, Costa-Silva TA, Gonçalves MM, Abiuzi MB, Tempone AG, Lago JHG, Mandelli D, Fischmeister C, et al. Synthesis of New Dehydrodieugenol Derivatives via Olefin Cross Metathesis and In Vitro Evaluation of Their Trypanocidal Activity. Catalysts. 2023; 13(7):1097. https://doi.org/10.3390/catal13071097

Chicago/Turabian Style

Galhardo, Thalita S., Anderson K. Ueno, Wagner A. Carvalho, Thais A. Costa-Silva, Marina M. Gonçalves, Mariana B. Abiuzi, Andre G. Tempone, João Henrique G. Lago, Dalmo Mandelli, Cedric Fischmeister, and et al. 2023. "Synthesis of New Dehydrodieugenol Derivatives via Olefin Cross Metathesis and In Vitro Evaluation of Their Trypanocidal Activity" Catalysts 13, no. 7: 1097. https://doi.org/10.3390/catal13071097

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