Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells

Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability.


Introduction
Cutaneous melanoma is a malignant tumour of melanocytes located in the basal epidermis. It is the most aggressive and lethal form of skin cancer because of its fast-metastatic development [1,2]. Its incidence has been increasing worldwide for several decades. While in its early stages remarkable outcomes can be achieved with surgery alone, metastatic melanoma requires therapeutic treatment intervention. Thanks to genomic studies, knowledge regarding the molecular biology of melanomas has improved, leading to recent FDA-approved therapies [3][4][5]. However, all the subtypes of the disease are not equally treated [5] and marked resistance mostly against kinase inhibitors rapidly occurs [6,7]. As the incidence among the worldwide fair-skinned population is increasing, this public health concern remains challenging.
Our group is working on the development of the imidazo[1,2-a]quinoxaline derivatives presented in Scheme 1, called imiqualines, as potential antitumoral agents, particularly for the treatment of melanoma [8,9]. The first generation of imiqualines was essentially substituted on position 1 by multiple aromatic moieties directly grafted to the main structure or via an alkyl linker. The second The second generation is characterized by the presence of the 3,4-dihydroxyphenyl moiety on position 1 since the presence of such catechol residue enhances global hydrophilicity. The chemical modulations of the first hits, EAPB0203 and EAPB0503, afforded new leads EAPB02303 and its Ndemethylated derivative EAPB02302, with impressive in vitro activities in the nanomolar range on the A375 human melanoma cancer cell line [10,11]. EAPB02302 and EAPB02303 are considered as promising anticancer agents but exhibit high lipophilicity (cLogP values estimated at 2.68 and 3.55, respectively), which might be critical for future preclinical in vivo studies. Indeed, their low solubility in water might be a major drawback for further development, especially in the case of intravenous use. In a preliminary study [12], the pharmacokinetic parameters of EAPB02303 were determined in mice after a single intraperitoneal administration. For this, the compound was solubilized in a mixture of DMSO, Tween 80 and sodium chloride solution 0.9% (10/10/80, v/v/v). The use of DMSO is recognized as toxic [13], in particular when used repeatedly as would be the case in an efficacy study. In order to optimize the results of efficacy studies, we chose to chemically modulate our lead compounds to obtain more soluble compounds with a moderate impact on the cytotoxic activity. The result of the introduction of various amino acids on position 4 of the heterocycle on both the physicochemical properties and biological activity was studied. Such an approach to increase solubility, which remains a key factor for potential pharmaceutical development, has already been described in the literature [14][15][16][17]. The introduction of amino acid moieties has been showed to increase the water solubility as well as selective cytotoxicity [18][19][20]. We present herein the synthesis of new imidazo[1,2-a]quinoxalines decorated with a panel of natural α-amino acids and their in vitro preliminary evaluation on A375 cell line.

Synthesis of Imidazo[1,2-a]quinoxaline Derivatives
The synthetic pathways and the structures of imidazo [1,2-a]quinoxalines used in this study are given in Schemes 2 and 3. Intermediates 1 to 5 were synthetized thanks to a route we previously described [9,21]. Briefly, the carbonylimidazole dimer 2 results from the condensation of the 2- EAPB02302 and EAPB02303 are considered as promising anticancer agents but exhibit high lipophilicity (cLogP values estimated at 2.68 and 3.55, respectively), which might be critical for future preclinical in vivo studies. Indeed, their low solubility in water might be a major drawback for further development, especially in the case of intravenous use. In a preliminary study [12], the pharmacokinetic parameters of EAPB02303 were determined in mice after a single intraperitoneal administration. For this, the compound was solubilized in a mixture of DMSO, Tween 80 and sodium chloride solution 0.9% (10/10/80, v/v/v). The use of DMSO is recognized as toxic [13], in particular when used repeatedly as would be the case in an efficacy study. In order to optimize the results of efficacy studies, we chose to chemically modulate our lead compounds to obtain more soluble compounds with a moderate impact on the cytotoxic activity. The result of the introduction of various amino acids on position 4 of the heterocycle on both the physicochemical properties and biological activity was studied. Such an approach to increase solubility, which remains a key factor for potential pharmaceutical development, has already been described in the literature [14][15][16][17]. The introduction of amino acid moieties has been showed to increase the water solubility as well as selective cytotoxicity [18][19][20]. We present herein the synthesis of new imidazo [1,2-a]quinoxalines decorated with a panel of natural α-amino acids and their in vitro preliminary evaluation on A375 cell line.

Synthesis of Imidazo[1,2-a]quinoxaline Derivatives
The synthetic pathways and the structures of imidazo [1,2-a]quinoxalines used in this study are given in Schemes 2 and 3. Intermediates 1 to 5 were synthetized thanks to a route we previously described [9,21]. Briefly, the carbonylimidazole dimer 2 results from the condensation of the irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo [1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. Table 1. Synthesis of imidazo [1,2-a]quinoxaline derivatives grafted with the α-amine of the amino acid as described in Scheme 2: cLogP, theoretical water solubility (mg/mL) at pH 7.4 calculated values and IC50 values against A375 (human melanoma cell line). irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2. irradiation to furnish the hydroxylated derivatives 9a-9i. A final step of deprotection of the amino acid moiety using TFA in CH2Cl2 was used to obtain the final compounds 11a-11i.

In Vitro Cytotoxic Activity on A375 Cell Line and Calculated ClogP
All new imidazo[1,2-a]quinoxaline derivatives 8b-d, 8f, 9a-9i, 10b-d and 11a-11i were tested for their in vitro antiproliferative activities on the human melanoma cell line A375. Their IC50 values (concentration of the compound (nM) producing 50% cell growth inhibition after 96 h of drug exposure) were determined using in vitro cytotoxicity assays and are displayed in Tables 1 and 2.  Lipophilicity, expressed as the logarithm of a compound's octanol/water partition coefficient (ClogP), is a physicochemical property of drugs that affects many biological mechanisms, especially drug absorption and distribution (absorption, plasma protein binding and membrane permeation) [22]. This parameter can also be correlated to solubility, metabolism and toxicity [23,24]. In a drug discovery process, compounds must be sufficiently lipophilic to cross the membrane barriers and at the same time be sufficiently water soluble to reach their targets. Therefore, a poor water solubility is a common cause of rejection during development [25]. This is why we also estimated the lipophilicity and hydrophilicity properties of all new compounds by predicting their ClogP and theoretical water solubility values thanks to fragmentation methods available on the ACDLabs ® software. These calculated values are purely theoretical but give a good estimate of what might be the solubility of the compounds in blood circulation (pH 7.4). This approach is used in pharmaceutical industry for the screening of new compounds [26,27]. Results of our new imidazo[1,2-a]quinoxaline derivatives were compared each other as well as with the first and second generation imiqualine leads as shown in Table 3. Compounds 8b, 8c, 8d and 8f have fully protected amino acid residues (side chain and carboxylic function) with 3,4-dimethoxy substitution on the phenyl ring in position 1. They exhibit weak IC 50 values higher than 10,000 nM. Compounds belonging to this chemical series are very lipophilic with estimated ClogP values higher than 5 (5.25, 5.61, 6.47, 6.98, 7.05 and 7.01 for compounds 8a, 8b, 8c, 8d, 8e and 8f, respectively). The theoretical water solubility of compounds 8 at pH 7.4 is very low since the order varies from 5.88 × 10 −4 to 3.43 × 10 −5 mg/mL for compounds 8a and 8f, respectively. Therefore, the presence of protective groups on the amino acids and the dimethoxy groups on the phenyl appears not to be valuable, both in terms of water solubility and cytotoxic efficiency.
Compounds 9a-9i are only protected on the amino acids moieties. These compounds exhibit various cytotoxic activities with IC 50 values ranging from 128 to 7180 nM, for 9d and 9c, respectively. These compounds show high lipophilicity since their ClogP values range from 4.99 to 7.99 for 9a and 9h respectively. Similarly, the theoretical values of water solubility are between 3.31 × 10 −5 and 1.79 × 10 −3 mg/mL for 9h and 9a, respectively. By comparing compounds 8 and 9, we note that the replacement of the methoxy groups by the hydroxy groups induces, for some residues, an important increase of the biological activities. Nevertheless, such modification, with conservation of the amino acid protection, does not improve the theoretical water solubility of the new synthesized compounds.
Compounds 10b-10d are deprotected on the amino acid residues but still present dimethoxy groups on the phenyl substitution at position 1. These compounds exhibit IC 50 values higher than 5000 nM (IC 50 values at 5 947 nM for 10b and higher than 10,000 nM for 10c and 10d). However, ClogP values are below 5 and theoretical water solubilities are higher than 0.8 mg/mL. The transition from compounds 8 to compounds 10 provides a significant decrease of lipophilicity as well as an improvement of theoretical water solubility. The comparison of the compounds according to the grafted residue permits to highlight this improvement. Actually, ClogP values decrease from 5.61 to 3.21, from 6.47 to 4.07 and from 6.98 to 4.58 for compounds 8b to 10b, 8c to 10c and 8d to 10d, respectively. Even more impressive, the theoretical water solubility values increase from 3.8 × 10 −4 to 6.01, 1.35.10 −4 to 1.91 and 7.43 × 10 −5 to 0.89 mg/mL for compounds 8b to 10b, 8c to 10c and 8d to 10d, respectively. The deprotection of the amino acid residues does not improve the cytotoxic activity but clearly improve the theoretical water solubility. The presence of dihydroxy groups on the phenyl substitution at position 1 appears to be necessary for the conservation of the cytotoxic activity.
Compounds 11a-11i are fully deprotected on the amino acid residues as well as on the catechol group at the position 1. Among these compounds, five have attractive IC 50 values below 1000 nM: 403, 584, 673, 838 and 951 for 11a, 11b, 11e, 11d and 11g, respectively. These compounds show ClogP values ranged from 2.57 to 4.32 for 11f and 11d. Several compounds present very interesting theoretical water solubility: compounds 11a, 11b, 11c, 11d, 11g and 11h exhibit values higher than 3 mg/mL. Very high values are obtained for compounds 11a and 11b at 47.18 and 19.92 mg/mL, respectively. The presence of an alkyl or aryl moiety on the side chain of the amino acid residue does not decrease the water solubility for these compounds. Nevertheless, the tendency appears to not be the same for compounds 11e, 11f and 11i with theoretical water solubility values less than 1 × 10 −2 mg/mL. These compounds possess ornithine (grafted by the α-amine or by the amine of the side chain of the amino acid) or lysine residues. These two residues are therefore not valuable for increasing the water solubility of the compounds at pH 7.4.
Compounds 11a, 11b, 11c and 11d present an alkyl chain at position 4 while compounds 11g and 11h display an aryl chain on this same position. Saturated alkyl groups appear to be most interesting for our compounds. A trend that seems to stand out in these four compounds is that when the carbon number of the alkyl chain increases, the biological activity and the theoretical solubility decrease (except for 11c which activity does not follow this tendency). Moreover, the presence of a phenyl group causes an increase in lipophilicity and a decrease in biological activities, in particular with the presence of a phenol (compound 11h) on the side chain of the amino acid moiety. The compounds with lysine or ornithine residues did not show favorable results neither for biological activities or water solubility.
The transition of compounds 9 to compounds 11 is carried out by the cleavage of all the protecting groups of the amino acid moieties. Such a deprotection step forms less lipophilic compounds (lower ClogP) with similar or higher activity for all the amino acids tested, except for compounds 11d and 11f with the leucine and ornithine residues grafted by the amine in the α-position, respectively. It should be noted that the presence of an ornithine amino acid residue grafted by the α-amine or the amine of the side chain of the amino acid does not result in any significant differences in the biological activity (IC 50 values at 3404 nM for 11f and 5168 nM for 11i) or to the solubility (theoretical water solubility values at 5.82 × 10 −3 and 3.05 × 10 −3 mg/ mL for 11f and 11i, respectively). Surprisingly, compound 11e which present a butan-1-amine substitution on the lateral chain of the amino acid show an higher biological activity than compound 11f with a propan-1-amine substitution on its lateral chain (IC 50 values at 673 nM for 11e and 3 404 nM for 11f) with equivalent theoretical water solubilities (values of 4.34.10 −3 and 5.82.10 −3 mg/mL for 11e and 11f, respectively).
Consequently, compounds 11a, 11b, 11d and 11g in particular hold our attention, both in terms of improvement of the solubility and in terms of conservation of the biological activity. The activities of these compounds are in the same potency order as the leads of the first generation of imiqualines (IC 50 values of 200 and 1570 nM for EAPB0503 and EAPB0203, respectively), presented in Table 3. Moreover, these new compounds show highly improved water solubility. Indeed, the values for the first generation compounds were only 2.60 × 10 −3 and 3.46 × 10 −3 mg/mL for EAPB0203 and EAPB0503, respectively. On the other hand, the second generation imiqualine compounds exhibit higher activities than the new compounds, with IC 50 values at 10 and 60 nM for EAPB02303 and EAPB02302 respectively. However, the solubility values of these compounds are low, with values of 1.74 × 10 −2 mg/mL for EAPB02303 and 4.28 × 10 −2 mg/mL for EAPB02302.
All of these data and results allow us to put forward a preferential amino acid with a small alkyl side chain in order to get a good compromise between maintaining the activity and increasing water solubility. From the close analysis of Tables 1 and 2, it can be observed that compounds 11a, 11b, 9d, 11d, 11e and 11g are the most active members of this series against the tested melanoma A375 cell line (IC 50 values less than 1000 nM). Surprisingly, compound 9d shows the lowest IC 50 value among these new synthesized compounds. Among these six attractive compounds, only 11a, 11b, 11d, 11e and 11g show a marked and considerable improvement of the theoretical water solubility.

General Information
All solvents and reagents were obtained from Sigma Aldrich Chemical Co. (Saint Louis, MO, USA), Iris Biotech GmbH (Marktredwitz, Germany), Alfa Aesar Co. (Karlsruhe, Germany), VWR (Radnor, PA, USA) and FluoroChem UK (Hadfield, UK) and used without further purification unless indicated otherwise. Silica gel chromatography was conducted with 230-400 mesh 60 Å silica gel (Sigma Aldrich Chemical Co.). The progress of reaction was monitored by TLC exposure to UV light (254 nM and 366 nM). Thin layer chromatography plates (Kieselgel 60 F254) were purchased from Merck (Darmstadt, Germany). Microwave assisted organic syntheses were performed on a Biotage Initiator 2.0 microwave system (Uppsala, Sweden). 1 H (400 MHz) and 13 C-NMR (100 MHz) spectra were obtained on a Brüker AC-400 spectrometer (Billerica, MA, USA). Chemical shifts are given as parts per million (ppm) using residual dimethylsulfoxide signal for protons (δ DMSO = 2.46 ppm) and carbons (δ DMSO = 40.00 ppm). Coupling constants are reported in Hertz (Hz). Spectral splitting partners are designed as follow: singlet (s); doublet (d); triplet (t); quartet (q); multiplet (m). Mass spectral data were obtained on a Waters Micromass Q-Tof (Milford, MA, USA) spectrometer equipped with ESI source (Laboratoires de Mesures Physiques, Plateau technique de l'Institut des Biomolecules Max Mousseron, Université de Montpellier, Montpellier, France). Mass spectra were recorded in positive mode between 50 and 1500 Da, capillary and cone tension were 3000 and 20 V, respectively. The High Resolution Mass Spectroscopy (HRMS) analyses are carried out by direct introduction on a Synapt G2-S mass spectrometer (Waters, SN: UEB205) equipped with ESI source. The mass spectra were recorded in positive mode, between 100 and 1500 Da. The capillary tension is 1000 V and the cone tension is 30 V. The source and desolvation temperature are 120 • C and 250 • C, respectively. NMR 1 H and 13 C spectra of all compounds are in Supplementary Materials.