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Article

Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents

by
Arianna Giovine
,
Marilena Muraglia
,
Marco Antonio Florio
,
Antonio Rosato
,
Filomena Corbo
*,
Carlo Franchini
,
Biagia Musio
,
Leonardo Degennaro
and
Renzo Luisi
*
Department of Pharmacy-Drug Science, University of Bari "A. Moro", Via E.Orabona 4, Bari 70125, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2014, 19(8), 11505-11519; https://doi.org/10.3390/molecules190811505
Submission received: 30 June 2014 / Revised: 15 July 2014 / Accepted: 21 July 2014 / Published: 4 August 2014
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
By using the Suzuki-Miyaura protocol, a simple straightforward synthesis of functionalized 2-arylaziridines has been developed. By means of this synthetic strategy from readily available ortho-, meta- and para-bromophenylaziridines and aryl- or heteroarylboronic acids, new aziridines could be obtained. The cross-coupling reactions occurred without ring opening of the three membered ring. Preliminary results on the antimicrobial activity of the heterosubstituted biaryl compounds have been also included.

Graphical Abstract

1. Introduction

The importance of aziridines as useful building blocks in organic chemistry has been extensively recognized over the past decades [1,2,3,4,5,6,7,8]. This three-membered ring heterocycle has been successfully exploited as precursors of amino acids [9,10], amino alcohols [11], azomethine ylides [12,13], monomer for polymerization [14], chiral auxiliary [15] and chiral ligand [16,17,18,19,20,21,22,23]. Aziridines are also interesting structural fragments in bioactive compounds and their pharmacological activity is often strictly related to the reactivity of the spring-loaded aziridine functionality [24,25,26], for example by endogenous nucleophiles. Due to their extensive use in organic and medicinal chemistry, several methodologies for the preparation of useful functionalized aziridines have been developed.
In a research work aimed at investigating the reactivity of arylaziridines, we embarked in the preparation of N-alkyl-2-arylaziridines functionalized on the aromatic ring. We envisaged two main paths for the functionalization of the aromatic ring depicted in Scheme 1. In particular, N-alkyl-2-arylaziridines could be obtained from readily available 2-aryloxiranes (path a) by a ring opening reaction, using primary amine, followed by a cyclization under Mitsunobu conditions [27]. However, the low yields observed with some substituted aryloxiranes, and the poor availability of the corresponding styrenes to be oxidized, limit this synthetic route. Alternatively, the reduction of readily available a-chloro imines also furnishes N-alkyl-2-arylaziridines (Scheme 1, path c) [28].Another synthetic strategy (Scheme 1, path b) relies on the use of aziridines metallated on the aromatic ring that can be functionalized with electrophiles or by a cross-coupling strategy [29].
Molecules 19 11505 g002 550
Scheme 1. Reaction pathways for the synthesis of N-alkylarylaziridines.
Scheme 1. Reaction pathways for the synthesis of N-alkylarylaziridines.
Molecules 19 11505 g002
In previous works we have reported that nitrogen-bearing small heterocycles, such as aziridine and azetidines, could promote the direct C-H ortho-metallation (lithiation) of the aryl ring [30,31], acting as a directing metallation group (DMG) [32,33]. The synthetic utility of such ortho-lithiated intermediates has been widely demonstrated even in a DoM-cross coupling strategy [34]. As a matter of fact, a new Suzuki-Miyaura reagent, the cyclic aziridinedifluoroborate 2, has been prepared from the N-methyl-2-phenylaziridine 1 (Scheme 2) [35]. It has been also demonstrated that the cyclic difluoroborate could be obtained only in the lithiation-borylation of 2-arylaziridines, while the use of ortho-lithiated benzylamines 3a,b led to the corresponding trifluorobrates 4a,b (Scheme 2) [35].
Molecules 19 11505 g003 550
Scheme 2. Lithiation-borylation sequence of 2-arylaziridines and benzylamines.
Scheme 2. Lithiation-borylation sequence of 2-arylaziridines and benzylamines.
Molecules 19 11505 g003
With the aim to verify this “ortho-effect” of the aziridine ring and set-up a procedure for the preparation of functionalized arylaziridines, we investigated the lithiation-borylation sequence in the meta and para positions of the aromatic ring of N-alkyl-2-arylaziridines. The results of this investigation are reported here, jointly to preliminary data on the potential antibacterial and antifungal profile against different bacterial and fungal strains belonging to American Type Culture Collection (ATCC) of ortho-, meta- and para- substituted N-alkyl-2-arylaziridines obtained by a Pd-mediated cross-coupling methodology.

2. Results and Discussion

2.1. Chemistry

In order to obtain the meta- and para- substituted boron derivatives, the bromine-lithium exchange on N-alkyl-2-arylaziridines 5a,b [36,37] was firstly considered (Scheme 3). The bromine-lithium permutation with n-BuLi at −78 °C in THF for 20 minutes on aziridines 5a,b generated the corresponding lithiated arylaziridines 5a,b–Li, as proved by quenching with a deuterium source affording 5a–D and 5b–D (>98% D).
Molecules 19 11505 g004 550
Scheme 3. Attempts for lithiation-borylation sequence by bromine-lithium permutation.
Scheme 3. Attempts for lithiation-borylation sequence by bromine-lithium permutation.
Molecules 19 11505 g004
However, all the attempts to obtain the meta- and para- boron derivatives by borylation of the lithiated intermediates failed, and only traces of the desired trifluoroborates 6a,b were detected by 11B-NMR (Scheme 3). Nevertheless, with brominated arylaziridines 5a,b in hand, we decided to use them as reactants in Suzuki-Miyaura reactions with promptly available aryl and heteroarylboronic acid derivatives. For the sake of comparison, the reactivity of the ortho-brominated aziridine 5c [30,31], which should complement the reactivity of difluoroborate 2, was also investigated.
In Table 1 are collected the results for the cross-coupling reactions of bromoarylaziridines 5a–c carried out using different boronic acids (1.5 equiv.), PdCl2 (dppf) as the catalyst, K2CO3 as the base (3 equiv.) in a mixture of THF/H2O (90/10) as the reaction solvent at 70 °C for 24 h. By using this procedure ortho-, meta- and para-functionalized arylaziridines 7a–i were obtained. It is worth noting that the reactions proceeded smoothly without aziridine ring opening with good yields in almost all cases. A very low yield was observed only in the coupling reaction of 5c with p-nitrophenylboronic acid to give 7h. However, the yield of 7h was improved by using aziridinedifluoroborate 2 and 4-bromonitrobenzene under the reaction conditions reported in the Scheme 4.
Table
Table 1. Suzuki-Miyaura reactions of bromoarylaziridines 5a–c. Molecules 19 11505 i001
Table 1. Suzuki-Miyaura reactions of bromoarylaziridines 5a–c. Molecules 19 11505 i001
Aziridine 5ArB(OH)2Product 7Yield a (%) b
Molecules 19 11505 i002
5a		 Molecules 19 11505 i003 Molecules 19 11505 i004
7a		80 (41)
Molecules 19 11505 i002
5a		 Molecules 19 11505 i005 Molecules 19 11505 i006
7b		80 (72)
Molecules 19 11505 i002
5a		 Molecules 19 11505 i007 Molecules 19 11505 i008
7c		80 (48)
Molecules 19 11505 i009
5b		 Molecules 19 11505 i010 Molecules 19 11505 i011
7d		85 (70)
Molecules 19 11505 i009
5b		 Molecules 19 11505 i012 Molecules 19 11505 i013
7e		73 (34)
Molecules 19 11505 i009
5b		 Molecules 19 11505 i014 Molecules 19 11505 i015
7f		85 (77)
Molecules 19 11505 i016
5c		 Molecules 19 11505 i017 Molecules 19 11505 i018
7g		(40)
Molecules 19 11505 i016
5c		 Molecules 19 11505 i019 Molecules 19 11505 i020
7h		(5)
Molecules 19 11505 i016
5c		 Molecules 19 11505 i021 Molecules 19 11505 i022
7i		65 (48)
a 1H-NMR yield; b Isolated yield.
It is worth mentioning that, to our knowledge, this is the first example of cross-coupling reactions involving haloarylaziridines [38,39]. By using this strategy, a series of ortho-, meta- and para-functionalized arylaziridines could be prepared.
Molecules 19 11505 g005 550
Scheme 4. Cross-coupling of aziridinedifluoroborate 2.
Scheme 4. Cross-coupling of aziridinedifluoroborate 2.
Molecules 19 11505 g005
With this series of aziridines in hand, and aware that many aziridine alkaloids have antimicrobial activity against selected pathogenic microorganisms [40,41,42,43], we decided to test preliminary all the aziridine derivatives described in this paper for a potential antibacterial and antifungal profile against different bacterial and fungal strains belonging to American Type Culture Collection (ATCC). For the biological evaluation, also the bisaziridines 8a–d and derivatives 9,10 were considered (Figure 1) [35].
Molecules 19 11505 g001 550
Figure 1. Other functionalized aziridines tested in this study.
Figure 1. Other functionalized aziridines tested in this study.
Molecules 19 11505 g001

2.2. Biology

The biological data reported in Table 2 revealed that the majority of the evaluated aziridine derivatives exhibited moderate to good activity (MIC: 16–256 µg/mL) as compared to reference antimicrobial drugs.
Among the mentioned derivatives the most promising results were obtained with compounds 8a, 8c, 9, 7e, 7d, 7a and 2, bearing the aziridinic moiety. In this series, compounds 2 and 8a were the most active derivatives. In particular, 8a showed both a selective antibacterial activity against Enterococcus faecalis 29212 (MIC: 16 µg/mL) and an interesting antifungal action against Candida krusei 6258 (MIC: 16 µg/mL). An appreciable antibacterial profile against bacteria such as Staphylococcus aureus 29213 and Enterococcus faecalis 29212 with MIC values of 32 µg/mL and 16 µg/mL, respectively, was registered for compound 2. In addition, it is worth noting that compounds 8a, 8c, 7d and 7a revealed a significant broad spectrum of action.
Due to both the limited number of evaluated compounds, and the low diversity of the involved chemical features of the series herein reported, an attempt to analyze the structure-activity relationship (SAR) does not seem reasonable. Nevertheless, several comparisons on the results could be made.
Table
Table 2. Antimicrobial activity results a, b of functionalized aziridines derivatives 2, 4a,b, 7a–i, 8a–d, 9, 10 (MIC in µg/mL).
Table 2. Antimicrobial activity results a, b of functionalized aziridines derivatives 2, 4a,b, 7a–i, 8a–d, 9, 10 (MIC in µg/mL).
Microorganism
CompdBacterial strainsFungal strains
S. aureus c 29213E. faecalis c 29212E. coli c 25922C. albicans c 10231C. parapsilosis c 22019C. tropicalis c 750C. krusei c 6258
8a12816>12864323216
8b>128>128>128RRRR
8d256256>256>128>128>128>128
8c6464>128>128326432
7c>128>128>128>128>128128128
7f128128>128>12864128128
7i128128>128>128128>128>128
912832>128>128128128>128
10>128>128>128>128>128>128>128
7b128>128>128>128>128128128
7e64128>128>128128128128
7d6464>1281286412864
7h128128>128>128128128128
7g128128>128>128128128128
7a6464>12812812812864
23216>128>128>128>128>128
4a>128>128>128>128>128>128>128
4b>128>128>128>128>128>128>128
NRF c240.03
CAF c848
OXA c0.25016R
FLU c 0.5 1
AMB c 0.5111
a National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Sixth Edition. Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2 NCCLS, Wayne, PA, January, 2003; b National Committee for Clinical Laboratory Standards. Reference Methods for Broth Dilution Antifungal Susceptibility Testing of Yeast. Approved Standard, 2nd ed. M27-A2, Vol. 22, No. 15 NCCLS, Wayne, PA, January, 2002; c S. aureus: Staphylococcus aureus; E. faecalis: Enterococcus faecalis; E.coli: Escherichia coli; C. albicans: Candida albicans; C. parapsilosis: Candida parapsilosis; C. tropicalis: Candida tropicalis; C. krusei: Candida krusei; R: resistant; NRF: Norfloxacin; CAF: Chloroamphenicol; OXA: Oxacillin; FLU: Fluconazole; AMB: Amphotericin B.
First, the SAR analysis suggested that the N-methylaziridinyl group plays a noticeable role for producing an antimicrobial profile. In fact, replacing the aziridine ring with a dimethylamine or proline moiety, a marked reduction of the antimicrobial activity was observed (Table 2, see data 9 vs. 10 and 2 vs. 4a or 4b).
Interestingly, the MIC values of compound 2, ranging between 16 and 32 µg/mL, could likely be attributed to the combined action of the aziridine ring and the BF2 fragment respectively at C2 and C1 positions of the aromatic ring.
Among the biaryl derivatives 7 (Table 1) the replacement of the nitro group with a fluorine atom produced an enlargement of the antimicrobial spectrum (7e vs. 7d). In the same series, the change in the position of the aziridine ring from ortho to meta to para on the aromatic ring, generally was found to be important for enhancing the antimicrobial activity.
All the above considerations prompted us to take into accountalso bisaziridinyl derivatives such as compounds 8a–d. With reference to this last series, the biological data suggested that the insertion of an additional aziridine ring as in 8a, gave still a wide antifungal spectrum of action and a selective antibacterial profile against Enterococcus faecalis 29212. However, it was further observed that the substitution of the 4,4'-diphenyl core of 8a with the 4,4’-stilbene unit or the 5,5'-bisthienyl moiety resulted in a significant decreasing of the antimicrobial activity (Table 2, 8a vs. 8b and 8d). On the other hand the introduction of a rigidity element with the insertion of a 2,7-fluorenyl portion as in 8c, led to a wider spectrum of action.
However, these preliminary results showed that among all the tested aziridines, 2 and 8a were identified as the most interesting compounds with a remarkable antimicrobial profile. According to the studies herein described, we could point out that the aziridine ring likely could play an important role in the antimicrobial activity.

3. Experimental Section

3.1. Chemistry

Commercial reagents were purchased from Sigma–Aldrich (St. Louis, MO, USA), Alfa Aesar (Ward Hill, MA, USA) and were used without further purification unless otherwise noted. Tetrahydrofuran (THF) was freshly distilled under nitrogen over sodium/benzophenone ketyl. Water was deionized prior to use. Magnetic Resonance spectra were recorded using Varian 400 and 500 MHz (Cernusco s/N, MI, Italy) and Bruker 400, 500 and 600 MHz spectrometers (Milano, Italy,). For the 1H and 13C-NMR spectra (1H-NMR 400, 500, 600 MHz and 13C-NMR 100, 125, 150 MHz) CDCl3was used as solvent, using tetramethylsilane as internal standard and chemical shifts are reported as part per million (ppm). MS-ESI analyses were performed on LC/MSD trap system VL (Cernusco s/N, MI, Italy). GC-MS spectrometry analyses were carried out on a gas chromatograph (dimethylsilicon capillary column, 30 m, 0.25 mm i.d.) equipped with a mass selective detector operating at 70 eV (EI) (Cernusco s/N, MI, Italy). Analytical thin layer chromatography (TLC) was carried out on precoated 0.25 mm thick plates of Kieselgel 60 F254; visualization was accomplished by UV light (254 or 356 nm) or by spraying a solution of 5% (w/v) ammonium molybdate and 0.2% (w/v) cerium(III) sulphate in 100 mL 17.6% (w/v) aq. sulphuric acid and heating to 200 °C for some time until blue spots appear. Infrared spectra of the compounds were recorded neat, as film or as KBr disc as indicated, by a Perkin-Elmer 283 spectrometer (Waltham, MA, USA). For flash chromathography silica Gel 60, 0.04–0.063 mm particle size was used. CHN analyses were performed on a EuroEA 3000 analyzer (Milano, Italy).

3.2. General Procedure for the Synthesis of Aziridine 7

To a degassed solution of N-methyl-2-(bromophenyl)aziridine (106 mg, 0.5 mmol) in THF/H2O (90:10) (5 mL) were added arylboronic acid (0.75 mmol), K2CO3 (207 mg, 1.5 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), (PdCl2(dppf)∙CH2Cl2), (20 mg, 0.025 mmol). The reaction mixture was stirred at 70 °C, until aziridine had been completely consumed as determined by TLC or GC-MS. The reaction mixture was allowed to cool to room temperature and diluted with water (10 mL) followed by extraction with Et2O (15 mL × 3). The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography to yield the pure product.
2-(4'-Fluorobiphenyl-4-yl)-1-methylaziridine 7a. The general procedure was followed using N-methyl-2-(4-bromophenyl)aziridine 5a (106 mg, 0.5 mmol) and 4-fluorophenylboronic acid (105 mg, 0.75 mmol). Flash chromatography (Hexane/Et2O 10:90) yielded 7a (41%, 47 mg, 0.205 mmol) as a white solid (m.p. 84 °C,). 1H-NMR (600 MHz, CDCl3) δ 1.69 (d, J = 6.4 Hz, 1H, CH2), 1.96 (d, J = 3.2 Hz, 1H, CH2), 2.33 (dd, J = 6.5, 3.2 Hz, 1H, CH), 2.53 (s, 3H, CH3), 7.11–7.14 (m, 2H, ArH), 7.31 (m, 2H, ArH), 7.49 (m, 2H, ArH), 7.52–7.55 (m, 2H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.4, 42.0, 47.8, 115.5 (d, 2J (C-F) = 21.5 Hz), 126.4, 126.8, 128.45 (d, 3J (C-F) = 8.0 Hz), 137.0 (d, 4J (C-F) = 3.4 Hz), 138.8, 139.4, 162.3 (d, 1J (C-F) = 246.7 Hz). FT-IR (KBr, cm−1) υ 3041, 2974, 2951, 2918, 2852, 2784, 1601, 1497, 1450, 1383,1237, 1213, 1161, 1110, 1070, 1013, 828. GC-MS (70 eV) m/z (%) 227(28, M+), 226 (100, M-H+), 185 (15), 183 (21). Anal. Calcd (%) for C15H14FN: C, 79.27; H, 6.21; N, 6.16. Found: C, 79.18; H, 6.29; N, 6.08.
2-(4'-Nitrobiphenyl-4-yl)-1-methylaziridine 7b. The general procedure was followed using N-methyl-2-(4-bromophenyl)aziridine 5a (106 mg, 0.5 mmol) and 4-nitrophenylboronic acid (125 mg, 0.75 mmol). The crude mixture was suspended in hexane and then filtered. The filtrate was concentrated in vacuo to yield 7b as an orange waxy solid (72%, 91 mg, 0.36 mmol). 1H-NMR (400 MHz, CDCl3) δ 1.68 (d, J = 6.5 Hz, 1H, CH2), 1.91 (d, J = 3.3 Hz, 1H, CH2), 2.31 (dd, J = 6.5, 3.3 Hz, 1H, CH), 2.49 (s, 3H, CH3), 7.32 (m, 2H, ArH), 7.53 (m, 2H, ArH), 7.68 (m, 2H, ArH), 8.25 (m, 2 H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.6, 41.9, 47.8, 124.1, 126.8, 127.2, 127.5, 137.2, 141.5, 146.9, 147.3. FT-IR (film, cm−1) υ 2963, 1596, 1513, 1447, 1400, 1338, 1260, 1094, 1019, 864, 800, 696. GC-MS (70 eV) m/z (%) 254 (25, M+), 253 (100, M-H+), 207 (26), 165 (24). Anal. Calcd (%) for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02; O, 12.58. Found: C, 70.80; H, 5.59; N, 11.05; O, 12.57.
2-[4-(Furan-2-yl)-phenyl]-1-methylaziridine 7c. The general procedure was followed using N-methyl-2-(4-bromophenyl)aziridine 5a (106 mg, 0.5 mmol) and 2-furanylboronic acid (84 mg, 0.75 mmol). Flash chromatography (Hexane/EtOAc 50:50) yielded 7c as a yellow oil (48%, 48 mg, 0.24 mmol).1H-NMR (400 MHz, CDCl3) δ 1.61 (d, J = 6.4 Hz, 1H, CH2), 1.88 (d, J = 3.3 Hz, 1H, CH2), 2.24 (dd, J = 6.4, 3.3 Hz, 1H, CH), 2.46 (s, 3H, CH3), 6.41–6.43 (m, 1H, ArH), 6.58–6.57 (m, 1H, ArH), 7.20 (m, 2H, ArH), 7.41 (m, 1H, ArH), 7.57 (m, 2 H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.4, 42.2, 47.9, 104.6, 111.6, 123.7, 126.3, 129.6, 139.4, 141.8, 153.9. FT-IR (film, cm−1) υ 3114, 3042, 2973, 2945, 2849, 2780, 1518, 1482, 1450, 1412, 1385, 1278, 1242, 1217, 1186, 1156, 1112, 1078, 1008, 903, 884, 846, 782, 766, 733, 667. GC-MS (70 eV) m/z (%) 199 (40, M+), 198 (100, M-H+), 157 (20), 128 (19). Anal. Calcd (%) for C13H13NO: C, 78.36; H, 6.58; N, 7.03; O, 8.03. Found: C, 78.29; H, 6.56; N, 6.99; O, 8.07.
2-(4'-Fluorobiphenyl-3-yl)-1-methylaziridine 7d. The general procedure was followed using N-methyl-2-(3-bromophenyl)aziridine 5b (106 mg, 0.5 mmol) and 4-fluorophenylboronic acid (105 mg, 0.75 mmol). Flash chromatography (Hexane/Et2O 10:90) yielded 7d as a yellow oil (70%, 80 mg, 0.35 mmol). 1H-NMR (400 MHz, CDCl3) δ 1.65 (d, J = 6.5 Hz, 1 H, CH2), 1.93 (d, J = 3.3 Hz, 1 H, CH2), 2.31 (dd, J = 6.5, 3.3 Hz, 1 H, CH), 2.49 (s, 3 H, CH3), 7.06–7.11 (m, 2 H, ArH), 7.18–7.20 (m, 1 H, ArH), 7.32–7.39 (m, 3 H, ArH), 7.50–7.55 (m, 2 H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.5, 42.3, 48.0, 115.5 (d, 2J (C-F) = 21.4 Hz), 124.6, 125.0, 125.6, 128.7 (d, 3J (C-F) = 8.0 Hz), 128.8 (s overlapping d), 137.2 (d, 4J (C-F) = 3.2 Hz), 140.3, 140.9, 162.5 (d, 1J (C-F) = 246.7 Hz). FT-IR (film, cm−1) υ 3044, 2946, 2849, 1608, 1514, 1483, 1450, 1400, 1367, 1224, 1180, 1158, 1096, 1070, 1013, 837, 807, 773, 702. GC-MS (70 eV) m/z (%) 227 (26, M+), 226 (100, M-H+), 183 (21). Anal. Calcd (%) for C15H14FN: C, 79.27; H, 6.21; N, 6.16. Found: C, 79.20; H, 6.25; N, 6.12.
1-Methyl-2-(4'-nitrobiphenyl-3-yl)aziridine 7e. The general procedure was followed using N-methyl-2-(3-bromophenyl)aziridine 5b (106 mg, 0.5 mmol) and 4-nitrophenylboronic acid (125 mg, 0.75 mmol). Flash chromatography (Hexane/EtOAc 40:60) yielded 7e as a yellow oil (34%, 43 mg, 0.17mmol). 1H-NMR (400 MHz, CDCl3) δ 1.67 (d, J= 6.5 Hz, 1H, CH2), 1.92 (d, J = 3.3 Hz, 1H, CH2), 2.34 (dd, J = 6.5, 3.3 Hz, 1H, CH), 2.49 (s, 3H, CH3), 7.28 (m, 1H, ArH), 7.36–7.45 (m, 3H, ArH), 7.70 (m, 2H, ArH), 8.24 (m, 2H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.6, 42.2, 47.9, 124.0, 124.8, 125.9, 126.8, 127.8, 129.1, 138.8, 141.4, 147.0, 147.5. FT-IR (film, cm−1) υ 3046, 2946, 2850, 2783, 1596, 1515, 1480, 1449, 1400, 1345, 1262, 1243, 1187, 1107, 1070, 1013, 961, 854, 802, 777, 751, 696. GC-MS (70 eV) m/z (%) 254 (26, M+), 253 (100, M-H+), 207 (29), 165 (24). Anal. Calcd (%) for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02; O, 12.58. Found: C, 70.87; H, 5.51; N, 11.08; O, 12.61.
2-[3-(Furan-2-yl)phenyl]-1-methylaziridine 7f. The general procedure was followed using N-methyl-2-(3-bromophenyl)aziridine 5b (106 mg, 0.5 mmol) and 2-furanylboronic acid (84 mg, 0.75 mmol). Flash chromatography (Hexane/EtOAc 50:50) yielded 7f as a yellow oil (77%, 77 mg, 0.385mmol). 1H-NMR (400 MHz, CDCl3) δ 1.62 (d, J = 6.5 Hz, 1 H, CH2), 1.91 (d, J = 3.2 Hz, 1 H, CH2), 2.27 (dd, J = 6.5, 3.2 Hz, 1 H, CH), 2.47 (s, 3 H, CH3), 6.42–6.43 (m, 1 H, ArH), 6.62–6.63 (m, 1 H, ArH), 7.09 (m, 1 H, ArH), 7.26–7.30 (m, 1 H, ArH), 7.42 (m, 1 H, ArH), 7.50–7.52 (m, 2 H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.3, 42.3, 47.9, 105.1, 111.6, 121.3, 122.3, 125.0, 128.6, 130.9, 140.7, 141.9, 153.9. FT-IR (film, cm−1) υ 2954, 2849, 2782, 1613, 1450, 1386, 1219, 1187, 1155,1068, 1012, 912, 771, 732. GC-MS (70 eV) m/z (%) 199 (35, M+), 198 (100, M-H+), 128 (17). Anal. Calcd (%) for C13H13NO: C, 78.36; H, 6.58; N, 7.03; O, 8.03. Found: C, 78.31; H, 6.52; N, 7.08; O, 8.09.
2-(4'-Fluorobiphenyl-2-yl)-1-methylaziridine 7g. The general procedure was followed using N-methyl-2-(2-bromophenyl)aziridine 5c (106 mg, 0.5 mmol) and 4-fluorophenylboronic acid (105 mg, 0.75 mmol). Flash chromatography (Hexane/Et2O 10:90) yielded 7g as a yellow oil (40%, 45 mg, 0.2 mmol). 1H-NMR (400 MHz, CDCl3) δ 1.51 (d, J = 6.5 Hz, 1H, CH2), 1.90 (d, J = 3.4 Hz, 1H, CH2), 2.21 (dd, J = 6.5, 3.4 Hz, 1H, CH), 2.32 (s, 3H, CH3), 7.08–7.13 (m, 2H, ArH), 7.18–7.19 (m, 1H, ArH), 7.22–7.30 (m, 3H, ArH), 7.32–7.38 (m, 2H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.4, 40.6, 47.6, 115.0 (d, 2J (C-F) = 21.3 Hz), 125.5, 126.6, 127.7, 129.5, 131.1 (d, 3J (C-F) = 8.0 Hz), 137.0 (d, 4J (C-F) = 3.3 Hz), 137.4, 140.8, 162.1 (d, 1J (C-F) = 246.0 Hz). FT-IR (film, cm−1) υ 3041, 2945, 2849, 2778, 1606, 1513, 1482, 1449, 1413, 1381, 1222, 1158, 1093, 1009, 838, 761, 741. GC-MS (70 eV) m/z (%) 227 (24, M+), 226 (100, M-H+), 184 (42), 183 (90). Anal. Calcd (%) for C15H14FN: C, 79.27; H, 6.21; N, 6.16. Found: C, 79.31; H, 6.19; N, 6.11.
2-[2-(Furan-2-yl)phenyl]-1-methylaziridine 7i. The general procedure was followed using N-methyl-2-(2-bromophenyl)aziridine 5c (106 mg, 0.5 mmol) and 2-furanylboronic acid (84 mg, 0.75 mmol). The crude mixture was suspended in hexane and then filtered. The filtrate was concentrated in vacuo to yield 7i as a brown oil (48%, 48 mg, 0.24 mmol). 1H-NMR (400 MHz, CDCl3) δ 1.65 (d, J = 6.5 Hz, 1H, CH2), 1.86 (d, J = 3.4 Hz, 1H, CH2), 2.48 (s, 3H, CH3), 2.63 (dd, J = 6.5, 3.4 Hz, 1H, CH), 6.49–6.50 (m, 1H, ArH), 6.63 (m, 1H, ArH), 7.24–726 (m, 2H, ArH), 7.40–7.42 (m, 1H, ArH), 7.51 (m, 1H, ArH), 7.59–7.61 (m, 1H, ArH). 13C-NMR (100 MHz, CDCl3) δ 39.1, 41.3, 47.8, 108.8, 111.3, 126.6, 126.8, 127.1, 127.9, 130.0, 136.6, 142.0, 153.1. FT-IR (film, cm−1) υ 3056, 2965, 2850, 1483, 1450, 1262, 1156, 1081, 1051, 1029, 1010, 803, 761, 735. GC-MS (70 eV) m/z (%) 199 (46, M+), 198 (78, M-H+), 182 (23), 170 (100), 144 (33), 128 (32). Anal. Calcd (%) for C13H13NO: C, 78.36; H, 6.58; N, 7.03; O, 8.03. Found: C, 78.40; H, 6.49; N, 7.06; O, 7.98.

3.3. Synthesis of 1-Methyl-2-(4'-nitrobiphenyl-2-yl)aziridine 7h

To a degassed solution of aziridinedifluoroborate 2 (127 mg, 0.7 mmol) in THF/H2O (90:10) (10 mL) were added K2CO3 (290 mg, 2.1 mmol), 1-bromo-4-nitrobenzene (141 mg, 0.7 mmol) and PdCl2(dppf)∙CH2Cl2 (28 mg, 0.035 mmol). The reaction mixture was stirred at 70 °C for 24 h, was allowed to cool to room temperature, diluted with water (10 mL) and extracted with Et2O (15 mL ×3). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica gel (Hexane/EtOAc 50:50) to yield aziridine 7h (30%, 53 mg, 0.21 mmol) as a pale brown solid (m.p. 74 °C). 1H-NMR (400 MHz, CDCl3) δ 1.53 (d, J = 6.5 Hz, 1 H, CH2), 1.90 (d, J = 3.3 Hz, 1 H, CH2), 2.14 (dd, J = 6.5, 3.3 Hz, 1 H, CH), 2.31 (s, 3 H, CH3), 7.19–7.35 (m, 4 H, ArH), 7.57 (m, 2 H, ArH), 8.26 (m, 2 H, ArH).13C-NMR (100 MHz, CDCl3) δ 39.5, 40.4, 47.6, 123.4, 126.0, 126.9, 128.3, 128.8, 129.2, 130.5, 137.3, 130.4, 148.0. FT-IR (film, cm−1) υ 3059, 2946, 2850, 2779, 1596, 1515, 1478, 1449, 1381, 1347, 1313, 1241, 1201, 1185, 1103, 1071, 1008, 855, 802, 770, 750, 700. GC-MS (70 eV) m/z (%) 254 (26, M+), 253 (100, M-H+), 207 (22), 165 (53), 164 (26). Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02; O, 12.58. Found: C, 70.83; H, 5.54, N, 11.09; O, 12.53.

3.4. Biology

3.4.1. Test Organisms

Three bacteria strains available as freeze-disces, belonging to ATCC collection were used: Gram-positive such as Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and Gram-negative Escherichia coli ATCC 25922.
Four yeast strains (ATCC) were used: Candida albicans 10231, Candida parapsilosis 22019, Candida tropicalis 750 and Candida Krusei 6258. To preserve the purity of cultures and to ensure the reproducibility, it was set up a series of criovials of all microbial strains in glycerolic medium and stored at −80 °C.
The in vitro Minimum Inhibitory Concentrations (MICs, μg/mL) of the prepared compounds were carried out by the broth microdilution method, using a 96 well plates (Microtiter®), according to the National Committee for Clinical Laboratory Standards (CLSI) formerly NCCLS [44].
Stock solutions of the tested compounds 2; 4a,b; 7a–i; 8a–d; 9; 10 were obtained in DMSO. Stock solutions of lower concentrations were prepared for the substances which did not dissolve well. Then two-fold serial dilutions in the suitable starting from 256 μg/mL were plated. In each well 200 μL of these solutions was added. To be sure that no adverse effect on bacterial growth could be caused by the solvent, a control test was carried out by using DMSO at its maximum concentration along with the medium.

3.4.2. Antibacterial Activity

Pre-cultures of each bacterial strain were prepared in Cation Adjusted Muller-Hinton broth (CAMHB, Merck–Darmstadt, Germany) and incubated at 37 °C until the growth was complete. The absorbance of these cellular suspensions calibrated at a wavelength of 625 nm using spectrophotometric method (Thermo Spectronic, Genesis 20, Waltham, MA, USA), should range between 0.08 and 0.10 for the 0.5 McFarland standard, corresponding approximately to 108 CFU/mL.
Further the standardized suspension was diluted 1:100 with CAMHB to have 1–2 × 106100 CFU/mL. Every well were seeded with 100 µL of inoculums. The plates were incubated at 37 °C ± 1 for 24 h, and the MIC values recorded as the last well containing no bacterial growth. A number of wells containing only inoculated broth as control growth were prepared. Norfloxacin, Chloramphenicol and Oxacillin were used as standard drugs.

3.4.3. Antifungal Activity

Pre-cultures of each yeast strain were prepared in Sabouraud broth 2% glucose (SAB), and incubated at 35 °C ± 1 until the growth was complete. The turbidity of yeast stock was calibrated to 0.5 McFarland standard by spectrophotometric method (530 nm, absorbance range 0.12–0.15) and further the standardized suspension was diluted firstly 1:50 with SAB and then 1:20 in the same medium to have 1–5 × 106CFU/mL [45].
Every well was seeded with 100 µL of inoculums. The plates were incubated at 35 °C ± 1 for 24–48 h, and the MIC values recorded as the last well containing no fungal growth. Amphotericin B and Fluconazole were used as standard drugs.

4. Conclusions

In conclusion, we reported the synthesis and a preliminary antimicrobial evaluation of novel functionalized arylaziridines. The synthetic strategy relies on the cross-coupling reactions between bromoarylaziridines and boronic acids. A series of ortho-, meta- and para-functionalized arylaziridines have been synthesized.
In addition, all the collected data could furnish very valuable information in order to design and synthesize new, versatile and attractive motifs potentially useful in the antimicrobial research investigation.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/19/8/11505/s1.

Supplementary Files

Supplementary File 1

Acknowledgments

This work was carried out under the framework of the National Project “FIRB—Futuro in Ricerca” (code: CINECA RBFR083M5N) and supported by the University of Bari. We thank also Interuniversity Consortium CINMPIS.

Author Contributions

RL, FC and CF planned the experiments, wrote the manuscript and supervised the research activities. MAF, MM and AR were responsible for the biological tests. RL, LD, BM and AG synthesized and characterized all the molecules reported in the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the prepared compounds are available from the authors.

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MDPI and ACS Style

Giovine, A.; Muraglia, M.; Florio, M.A.; Rosato, A.; Corbo, F.; Franchini, C.; Musio, B.; Degennaro, L.; Luisi, R. Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents. Molecules 2014, 19, 11505-11519. https://doi.org/10.3390/molecules190811505

AMA Style

Giovine A, Muraglia M, Florio MA, Rosato A, Corbo F, Franchini C, Musio B, Degennaro L, Luisi R. Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents. Molecules. 2014; 19(8):11505-11519. https://doi.org/10.3390/molecules190811505

Chicago/Turabian Style

Giovine, Arianna, Marilena Muraglia, Marco Antonio Florio, Antonio Rosato, Filomena Corbo, Carlo Franchini, Biagia Musio, Leonardo Degennaro, and Renzo Luisi. 2014. "Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents" Molecules 19, no. 8: 11505-11519. https://doi.org/10.3390/molecules190811505

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