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Molecules 2014, 19(2), 2166-2180; doi:10.3390/molecules19022166
Published: 18 February 2014
Abstract: We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring.
Malaria is an infectious disease with an estimated 219 million cases and 660,000 deaths in 2010. Of these cases 86% correspond to children under 5 years old. In 2012, there were a total of 104 countries where malaria is considered to be endemic .
Plasmodium falciparum is the most dangerous form of the malaria parasite and it is responsible for a very high percentage of clinical attacks . Artemisinin-based combination therapies (ACTs) are the standard treatment against uncomplicated P. falciparum malaria. Nevertheless, resistance to ACTs containing dihydroartemisinin has been reported in Pailin (Cambodia)  and resistance to pyrethroids (used as insecticides) has been detected in 64 countries around the World . Other antimalarial drugs, such as chloroquine or mefloquine, are not effective enough . FCR-3 P. falciparum is a chloroquine-resistant strain, but sensitive to pyrimethamine and sulfadoxine .
Over the last years, our group has been working on the development and synthesis of new quinoxaline derivatives. As a result of this line of research, the activities of quinoxaline 1,4-di-N-oxide derivatives against Mycobacterium tuberculosis [6,7,8,9,10,11,12,13], Trypanosoma cruzi [14,15], Leishmania amazonensis , L. infantum , P. falciparum [16,17,18,19,20,21,22,23] and different tumor cells [24,25,26] have been reported. The presence of two N-oxides is associated with a significant increase in some biological properties, such as anticancer  or antioxidant  activity. On the other hand, some reduced quinoxalines showed good antitubercular activity .
In this article, we report the synthesis and antimalarial activity of some quinoxaline analogs of chalcones and other compounds derived from them (Figure 1). Chalcones or 1,3-diaryl-2-propen-1-ones are α,β-unsaturated ketones with a large number of biological activities . Different chalcones have been reported as anti-inflammatory , anticancer , antitubercular [33,34] or antimalarial [34,35,36,37,38] agents. With regard to antiplasmodial activity, previous structure-activity relationship studies found that the enone linker  and its trans-configuration  are essential in active chalcones.
Some of the compounds belonging to this study were previously tested against L. amazonensis  (series 1), T. cruzi and L. peruviana  (series 3) and as cytotoxic agents  (compound 1a) and anti-inflammatory/antioxidant [28,43] agents (series 1, 3 and 7). According to the structure-activity relationships, these reports affirm that compounds in series 3 have better antioxidant activity than their analogs in series 1 due to the fact that the former group of molecules lacks the N-oxide groups . On the other hand, compounds 1d and 3d have an interesting activity against different Leishmania strains, so the activity is associated with R6/R7 = Me/Me substitution [40,41]. Compound 1a stands out as both a good anti-inflammatory and cytotoxic agent [42,43].
With the aim of expanding the SAR study of these chalcone analogs and obtaining new compounds with improved antimalarial activity, we describe herein the synthesis and the relationships between structure and antiplasmodial activity against the FCR-3 P. falciparum strain of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives.
2. Results and Discussion
Synthesis of compounds in series 1, 3 and 7 were previously reported [25,40]. Benzofuroxans I with Ra/Rb = H/H, H/Cl and H/OMe are commercially available. Benzofuroxan with Ra/Rb = Me/Me was synthesized by an oxidative cyclization of 4,5-dimethyl-2-nitroaniline according to a previously described method .
Scheme 1 shows the entire synthetic route for obtaining compounds 1a–d, 2a and 3a, 3c and their cyclopropyl derivatives 4a–d, 5a and 6a, 6c. The starting reagents used, quinoxaline 1,4-di-N-oxides II and reduced quinoxalines III, were obtained following previously reported procedures [7,27]. Quinoxaline 1,4-di-N-oxides II were synthesized by a classic Beirut reaction , using CaCl2 and 1-aminoethanol as the catalysts . Their reduced analogs III were prepared by reduction of the N-oxide groups , for which a reaction temperature of 65 °C and a mixture of ethyl acetate/methanol 1:1 as the solvent  was established.
As previously described , in reactions of monosubstituted benzofuroxans 7-substituted quinoxaline 1,4-di-N-oxide derivatives prevail over the 6-isomers. While compound II with R6/R7= H/Cl was obtained as the major isomer and was isolated with a subsequent purification , 2-acetyl-7-methoxy-3-methylquinoxaline 1,4-di-N-oxide was obtained as the sole isomer .
Chalcone analogs 1a–d were synthesized by a previously reported base-catalyzed Claisen-Schmidt condensation , using 3% NaOH in methanol as the catalyst and establishing an optimum reaction temperature of −10 °C . Their reduced analogs 3a, 3c were synthesized using the same catalyst, but in this case, the condensation was performed at room temperature, as previously reported . The compounds 1a–d and 3a, 3c obtained have been previously described [28,47]. Compound 2a was first synthesized according to a previously reported method . It was a spontaneous reaction that gives the desired compound in good yield.
New cyclopropyl derivatives 4a–d, 5a and 6a, 6c were obtained according to a previously reported method . These reactions were carried out between compounds 1a–d, 2a and 3a, 3c and trimethylsulfoxonium iodide (TMSOI) in the presence of an aqueous solution of NaOH, with tetrabutylammonium bromide (TBAB) as a phase transfer catalyst and dichloromethane as the solvent. With regard to the reaction mechanism, Corey and Chaykovsky  demonstrated that trimethylsulfoxonium halides in the presence of a strong base allow the formation of a reactive compound named dimethylsulfoxonium methylide (DMSY), commonly known as Corey’s reagent . The reaction of DMSY with an α,β-unsaturated ketone involves the cyclopropanation of C=C double bond .
As their coupling constant values in the 1H-NMR spectra showed J values ≈ 16 Hz , the double bond geometries of compounds 1a–d and 3a, 3c were trans, just like the newly synthesized 2a. According to previous reports [55,56], the Corey-Chaykovsky reaction with TMSOI ocurrs with retention of stereochemistry, giving trans-cyclopropyl derivatives 4a–d, 5a and 6a, 6c .
Scheme 2 shows the synthetic route for obtaining compounds 7a–d. These chalcone analogs were obtained by a microwave-assisted Wittig reaction  between 2-formyl-3-methylquinoxaline 1,4-di-N-oxide derivatives V and a phosphonium ylide VII, both previously synthesized [28,45,57].
2.2. Biological Results
In this study, eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives were tested against a chloroquine-resistant FCR-3 strain of P. falciparum. All the synthesized compounds and their biological activities are shown in Table 1, Table 2 and Table 3.
|Table 1. In vitro activities of chalcone derivatives.|
|Compound||R6||R7||n||R||IC50 (μM) a||SD b|
a IC50, concentration required for inhibiting growth of FCR-3 P. falciparum strain by 50% (in μM). Mean values of two independent experiments performed in triplicate; b SD, standard deviation; c Chloroquine, control.
|Table 2. In vitro activities of cyclopropyl derivatives.|
|Compound||R6||R7||n||R||IC50 (μM) a||SD b|
a IC50, concentration required for inhibiting growth of FCR-3 P. falciparum strain by 50% (in μM). Mean values of two independent experiments performed in triplicate; b SD, standard deviation; c Chloroquine, control; d NA, not active.
|Table 3. In vitro activities of inverted chalcone derivatives.|
|Compound||R6||R7||IC50 (μM) a||SD b|
a IC50, concentration required for inhibiting growth of FCR-3 P. falciparum strain by 50% (in μM). Mean values of two independent experiments performed in triplicate; b SD, standard deviation; c Chloroquine, control.
Almost all the synthesized compounds exhibited some activity against P. falciparum, but none of them had better IC50 values than chloroquine itself. Compounds 1a and 2a have been chosen as lead compounds with interesting activities against the parasite. Although both leads were chalcone analogs with R6/R7 = H/H, compounds 7b and 4b had the best activities among inverted chalcone and cyclopropyl derivatives. In these cases, the presence of a halogen atom in position 7 led to an increase in the activity. In fact, 4b was the third most active compound of the study. These results coincide with previous reports , where the most active compounds were those without any substitution on the quinoxaline ring and with monosubstitution by an electron withdrawing group.
Apart from compound 4b, changing the double bond in chalcones (compounds 1a–d, 2a and 3a, 3c) for a cyclopropyl structure led to a dramatic drop in the antiplasmodial activity in each case (compounds 4a–d, 5a and 6a, 6c). The same trend was noted when comparing cyclopropyl derivatives 4a–d with their analogs in series 7.
With regard to series 1 and 7, the inversion of the chalcone did not lead to a change in the antimalarial activity, except for compound 1a, whose IC50 was significantly lower than that of the others. Therefore, the orientation of the enone moiety does not appear to be a determining factor for the antimalarial activity. Finally, only reduced chalcones 3a and 3c showed some interesting activity, while reduced cyclopropyl derivatives 6a and 6c were completely inactive. According to previous reports , a minimum requirement for the antimalarial activity was the oxygenation of N-1 and N-4 of the quinoxaline ring, because mono and reduced compounds were not active. Nevertheless, in this study the presence of N-oxides was not decisive for the synthesized compounds to be active.
3.1. General Information
All of the synthesized compounds were chemically characterized by thin layer chromatography (TLC), melting point, proton nuclear magnetic resonance (1H-NMR), infrared spectroscopy (IR) and elemental microanalyses (CHN). Alugram SIL G/UV254 (0.2 mm layer, Macherey-Nagel GmbH & Co. KG., Düren, Germany) was used for TLC, and silica gel 60 (0.040–0.063 mm, Merck, Darmstadt, Germany) was used for column chromatography. The 1H-NMR spectra were recorded on a Bruker 400 Ultrashield instrument (400 MHz, Bruker, Billerica, MA, USA), using TMS as the internal standard and DMSO-d6 as the solvent. Chemical shifts are reported in ppm (δ) and coupling constants (J) values are given in Hertz (Hz). Signal multiplicities are represented by: s (singlet), d (doublet), t (triplet), q (quadruplet), dd (double doublet) and m (multiplet). The IR spectra were recorded on a Thermo Nicolet Nexus FTIR (Madison, WI, USA) in KBr pellets. Frequencies (ν) are reported in cm−1 and peak intensities are represented by: w (weak), m (medium), s (strong) and vs (very strong). Elemental microanalyses were obtained on a CHN-900 Elemental Analyzer (Leco, Tres Cantos, Madrid, Spain) from vacuum-dried samples. The analytical results for C, H and N were within ±0.4 of the theoretical values, indicating a purity of >95%. All reagents and solvents were purchased from commercial sources: E. Merck (Darmstadt, Germany), Panreac Química S.A. (Barcelona, Spain), Sigma-Aldrich Química S.A. (Alcobendas, Madrid, Spain), Acros Organics (Janssen Pharmaceuticalaan, Geel, Belgium), Scharlau (F.E.R.O.S.A., Barcelona, Spain) and Lancaster (Bischheim-Strasbourg, France).
3.2. General Procedure of Synthesis
3.2.1. Synthesis of 3-Methyl-2-[3-(naphth-2-yl-prop-2-enoyl)] quinoxaline 1,4-di-N-oxide Derivatives (Series 2)
The appropriate quinoxaline di-N-oxide II (2-acetyl-3-methylquinoxaline 1,4-di-N-oxide, 3 mmol) and 2-naphthaldehyde (3 mmol) were dissolved in methanol (30 mL). 5% NaOH in methanol (10 mL) was added dropwise and the reaction mixture was magnetically stirred at room temperature for 15 min, until a yellow precipitate appeared. The solid obtained was filtered off and washed with diethyl ether.
3-Methyl-2-[3-(naphth-2-yl-prop-2-enoyl)] quinoxaline 1,4-di-N-oxide (2a). Yield 57%. mp 184 °C. 1H-NMR (DMSO-d6) δ ppm: 2.40 (s, 3H, CH3); 7.37 (d, 1H, Hb, Jb-a,trans = 16.4 Hz); 7.58 (m, 2H, H6+H7); 7.91 (d, 1H, H3'); 8.01 (m, 5H, H4'+H5'+H6'+H7'+H8'); 8.03 (d, 1H, Ha, Ja-b,trans = 16.0 Hz); 8.24 (s, 1H, H1'); 8.47 (d, 1H, H8, J8–7 = 8.6 Hz); 8.58 (d, 1H, H5, J5–6 = 8.4 Hz). IR (KBr) ν cm−1: 3091 (w, νarC-H); 3055 (w, νalkC-H); 3018 (w, νC-H); 1675 (m, νC=O); 1600 (s, νarC=C); 1331 (vs, νN-O). Anal. Calc. for C22H16N2O3: C = 74.14%, H = 4.53%; N = 7.86%; Found: C = 74.19%, H = 4.40%; N = 7.85%.
3.2.2. Synthesis of 3-Methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide Derivatives (Series 4), 3-Methyl-2-[2-(2-naphthyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide Derivatives (Series 5) and 3-Methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline Derivatives (Series 6)
The appropriate chalcone 1a–d, 2a and 3a, 3c (1 mmol), trimethylsulfoxonium iodide (TMSOI, 2 mmol) and tetrabutylammonium bromide (TBAB, 0.2 mmol) were dissolved in dichloromethane (40 mL) and stirred magnetically at room temperature for 15 min. Then a 15% aqueous solution of NaOH (10 mL) was added dropwise and the reaction mixture was stirred magnetically at room temperature for 24 h, until the solution turned dark. At this point, excess dichloromethane and water were added to the reaction. The organic phase was extracted, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate as the eluent. The desired compounds 4a–d, 5a and 6a, 6c were obtained after recrystallization from ethanol.
3-Methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide (4a). Yield 56%. mp 178–179 °C. 1H-NMR (DMSO-d6) δ ppm: 1.86 (m, 2H, Hc+Hc'); 2.40 (s, 3H, CH3); 2.78 (m, 1H, Ha); 2.91 (m, 1H, Hb); 3.59 (s, 3H, p-OCH3); 3.75 (s, 6H, m-OCH3); 6.55 (s, 2H, H2'+H6'); 7.98 (m, 2H, H6+H7); 8.44 (d, 1H, H8, J8–7 = 8.2 Hz); 8.49 (d, 1H, H5, J5–6 = 8.2 Hz). IR (KBr) ν cm−1: 3071 (w, νarC-H); 2998 and 2965 (w, νC-H); 1690 (m, νC=O); 1590 (m, νarC=C); 1329 (s, νN-O); 1128 (s, νC-O-C). Anal. Calc. for C22H22N2O6: C = 64.37%, H = 5.41%; N = 6.83%; Found: C = 64.08%, H = 5.74%; N = 6.69%.
7-Chloro-3-methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide (4b). Yield 9%. mp 143–144 °C. 1H-NMR (DMSO-d6) δ ppm: 1.88 (m, 2H, Hc+Hc'); 2.39 (s, 3H, CH3); 2.79 (m, 1H, Ha); 2.87 (m, 1H, Hb); 3.60 (s, 3H, p-OCH3); 3.76 (s, 6H, m-OCH3); 6.54 (s, 2H, H2'+H6'); 8.01, 8.02 (dd, 1H, H6, J6–8 = 2.3 Hz, J6–5 = 9.2 Hz); 8.42 (d, 1H, H8, J8–6 = 2.2 Hz); 8.48 (d, 1H, H5, J5–6 = 9.2 Hz). IR (KBr) ν cm−1: 3101 (w, νarC-H); 2935 (w, νC-H); 1695 (m, νC=O); 1592 (m, νarC=C); 1326 (s, νN-O); 1128 (s, νC-O-C). Anal. Calc. for C22H21N2O6Cl: C = 59.39%, H = 4.77%; N = 6.30%; Found: C = 59.52%, H = 4.93%; N = 6.15%.
7-Methoxy-3-methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide (4c). Yield 13%. mp 174–175 °C. 1H-NMR (DMSO-d6) δ ppm: 1.84 (m, 2H, Hc+Hc'); 2.37 (s, 3H, CH3); 2.79 (m, 1H, Ha); 2.90 (m, 1H, Hb); 3.61 (s, 3H, p-OCH3); 3.77 (s, 6H, m-OCH3); 3.98 (s, 3H, 7-OCH3); 6.54 (s, 2H, H2'+H6'); 7.58, 7.61 (dd, 1H, H6, J6–8 = 2.8 Hz, J6–5 = 9.5 Hz); 7.74 (d, 1H, H8, J8–6 = 2.7 Hz); 8.40 (d, 1H, H5, J5–6 = 9.5 Hz). IR (KBr) ν cm−1: 3005 (w, νarC-H); 2945 (w, νC-H); 1689 (m, νC=O); 1587 (m, νarC=C); 1323 (s, νN-O); 1120 (m, νC-O-C). Anal. Calc. for C23H24N2O7: C = 62.71%, H = 5.50%; N = 6.36%; Found: C = 62.55%, H = 5.83%; N = 6.64%.
3,6,7-Trimethyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide (4d). Yield 24%. mp 187–189 °C. 1H-NMR (DMSO-d6) δ ppm: 1.84 (m, 2H, Hc+Hc'); 2.37 (s, 3H, CH3); 2.47–2.51 (m, 6H, 6,7-CH3); 2.76 (m, 1H, Ha); 2.90 (m, 1H, Hb); 3.59 (s, 3H, p-OCH3); 3.75 (s, 6H, m-OCH3); 6.54 (s, 2H, H2'+H6'); 8.18 (s, 1H, H8); 8.25 (s, 1H, H5). IR (KBr) ν cm−1: 2932 (w, νC-H); 1683 (m, νC=O); 1589 (m, νarC=C); 1326 (s, νN-O); 1132 (s, νC-O-C). Anal. Calc. for C24H26N2O6: C = 65.73%, H = 5.99%; N = 6.39%; Found: C = 65.41%, H = 5.79%; N = 6.40%.
3-Methyl-2-[2-(2-naphthyl)cyclopropanecarbonyl] quinoxaline 1,4-di-N-oxide (5a). Yield 66%. mp 176–177 °C. 1H-NMR (DMSO-d6) δ ppm: 1.93 (m, 1H, Hc); 1.99 (m, 1H, Hc'); 2.40 (s, 3H, CH3); 3.01 (m, 2H, Ha+Hb); 7.38 (d, 1H, H3’); 7.47 (m, 2H, H6'+H7'); 7.80 (s, 1H, H1'); 7.85 (m, 3H, H4'+H5'+H8'); 7.96 (m, 2H, H6+H7); 8.42 (d, 1H, H8, J8–7 = 8.2 Hz); 8.48 (d, 1H, H5, J5–6 = 8.5 Hz). IR (KBr) ν cm−1: 3091 (w, νarC-H); 2959 (w, νC-H); 1689 (s, νC=O); 1597 (w, νarC=C); 1328 (s, νN-O). Anal. Calc. for C23H18N2O3: C = 74.57%, H = 4.91%; N = 7.56%; Found: C = 74.57%, H = 4.90%; N = 7.57%.
3-Methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline (6a). Yield 41%. mp 155–156 °C. 1H-NMR (DMSO-d6) δ ppm: 1.77 (s, 1H, Hc); 1.84 (s, 1H, Hc'); 2.69 (s, 1H, Ha); 2.86 (s, 3H, CH3); 3.57 (m, 1H, Hb); 3.61 (s, 3H, p-OCH3); 3.77 (s, 6H, m-OCH3); 6.59 (s, 2H, H2'+H6'); 7.88 (m, 1H, H6); 7.96 (m, 1H, H7); 8.08 (m, 1H, H8); 8.18 (m, 1H, H5). IR (KBr) ν cm−1: 2961 and 2935 (w, νC-H); 1679 (s, νC=O); 1589 (m, νarC=C); 1132 (s, νC-O-C). Anal. Calc. for C22H22N2O4: C = 69.81%, H = 5.87%; N = 7.40%; Found: C = 69.86%, H = 5.83%; N = 7.40%.
7-Methoxy-3-methyl-2-[2-(3,4,5-trimethoxyphenyl)cyclopropanecarbonyl] quinoxaline (6c). Yield 29%. mp 163–164 °C. 1H-NMR (DMSO-d6) δ ppm: 1.76 (m, 1H, Hc); 1.84 (m, 1H, Hc'); 2.69 (m, 1H, Ha); 2.83 (s, 3H, CH3); 3.58 (m, 1H, Hb); 3.63 (s, 3H, p-OCH3); 3.80 (s, 6H, m-OCH3); 3.96 (s, 3H, 7-OCH3); 6.60 (s, 2H, H2'+H6'); 7.52 (d, 1H, H8, J8–6 = 2.8 Hz); 7.58, 7.60 (dd, 1H, H6, J6–8 = 2.8 Hz, J6–5 = 9.2 Hz); 7.98 (d, 1H, H5, J5–6 = 9.2 Hz). IR (KBr) ν cm−1: 2936 (w, νC-H); 1680 (s, νC=O); 1587 (m, νarC=C); 1130 (s, νC-O-C). Anal. Calc. for C23H24N2O5: C = 67.62%, H = 5.93%; N = 6.86%; Found: C = 67.23%, H = 6.13%; N = 6.74%.
3.3. In Vitro Antiplasmodial Drug Assay
Chloroquine-resistant FCR-3 strain of P. falciparum was cultivated at 37 °C in 5% CO2, 5% O2 in a balanced N2 atmosphere environment on RPMI 1640 medium supplemented with gentamicin 0.1 mg/mL and 10% heat-inactivated A+ human serum, as previously described . The drugs, dissolved in dimethyl sulfoxide, were added at final concentrations ranging from 250 to 0.1 μM. The final DMSO concentration was never greater than 0.1%. In vitro antimalarial activity was measured using the [3H]-hypoxanthine (MP Biomedicals, Santa Ana, CA, USA) incorporation assay . Briefly, 250 μL of total culture medium with the diluted drug and the suspension of human red blood cells in medium (A+ group, 5% hematocrit) with 1% parasitemia were placed into the wells of 96-well microtiter plates. On the third day of the test, radioactivity was assessed. All experiments were performed in triplicate. Results were expressed as the concentration resulting in 50% inhibition (IC50), which was calculated by a nonlinear regression logistic dose response model. The mean IC50 values and standard deviation for each compound was calculated.
Eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives have been synthesized with the aim of studying their antimalarial activity. The SAR study suggested that the chalcone and inverted chalcone moieties can act as useful linkers in the search for antimalarial ligands. Moreover, the similar activities of series 1, 3 and 7 allow us to affirm that the enone moiety plays an important role in the antimalarial activity of these compounds, but not its orientation. Compounds 1a and 2a showed the best antiplasmodial activity. In general, the addition of cyclopropyl moiety dramatically reduces the biological activity in each case. We are not able to unequivocally confirm that N-oxides are essential for the antiplasmodial activity. These results show that further structural modifications may provide better antimalarial compounds.
We wish to express our gratitude to the PIUNA Project of the University of Navarra for the financial support provided. Ana Gil is grateful to the Navarra Government for a grant.
The listed authors contributed to this work as described in the following. Ana Gil together with Silvia Galiano carried out much of the synthetic work and prepared the manuscript. Asunción Burguete carried out the synthesis of chalcones. Adriana Pabón together with Eric Deharo conducted assays against P. falciparum and helped interpreting the results. Ignacio Aldana proposed the subject and monitored the progress of the ongoing research. Silvia Pérez-Silanes and Antonio Monge contributed with valuable discussions and scientific input. All authors helped preparing the manuscript and approved the final version.
Conflicts of Interest
The authors declare no conflict of interest.
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- Sample Availability: Samples of the synthesized compounds are available from the authors.
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