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Article

New Water-Soluble Condensed Heterocyclic Compounds with Antimicrobial Activity Based on Annulation Reactions of 8-Quinolinesulfenyl Halides with Natural Products and Alkenes

by
Vladimir A. Potapov
1,*,
Roman S. Ishigeev
1,
Lyudmila A. Belovezhets
1,
Irina V. Shkurchenko
1,2 and
Svetlana V. Amosova
1
1
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of The Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia
2
Pedagogical Institute, Irkutsk State University, 6 Nizhnyaya Naberezhnaya Str., 664003 Irkutsk, Russia
*
Author to whom correspondence should be addressed.
Appl. Sci. 2021, 11(18), 8532; https://doi.org/10.3390/app11188532
Submission received: 19 August 2021 / Revised: 9 September 2021 / Accepted: 10 September 2021 / Published: 14 September 2021
(This article belongs to the Special Issue Synthesis of Novel Heterocyclic Compounds and Evaluation of Their Antimicrobial Activity)
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Versions Notes

Abstract

:
The annulation reactions of 8-quinolinesulfenyl halides with natural products and alkenes affording new water-soluble [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives in high or quantitative yields are developed in this study. The reactions with styrene derivatives and terminal alkenes including allyl arenes proceed in a regioselective manner but with the opposite regiochemistry. The reactions with terminal alkenes including allyl arenes occur in an anti-Markovnikov fashion (regarding addition of the 8-quinolinesulfenyl electrophile to the double bond) to give 2-organyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium halides, while the reactions with styrene derivatives proceed in a Markovnikov fashion, leading to 3-substituted condensed heterocyclic compounds. In general, styrene derivatives demonstrate higher reactivity in the annulation reactions compared to the terminal alkenes. Antimicrobial activity of novel water-soluble compounds against Enterococcus durans, Bacillus subtilis and Escherichia coli are evaluated. The compounds with high antimicrobial activity are found. The annulation products of the reactions of 8-quinolinesulfenyl halides with 1H-indene, eugenol, methyl eugenol and 1-heptene, are superior in their activity compared to the antibiotic gentamicin.

1. Introduction

The quinoline skeleton occurs in many natural products, including alkaloids. Some containing the quinoline ring natural products have been used as lead molecules for the development of novel biologically active compounds and drugs [1,2,3,4,5]. Many modern drugs have been designed based on the quinoline scaffold. The quinoline scaffold has often been used for the design and synthesis of various synthetic compounds with pharmacological properties [1,2,3,4,5,6,7,8].
The quinoline ring is a structural part of many biologically active compounds. Quinoline derivatives exhibit a variety of biological activities including antibacterial, antivirus, anticancer, antifungal, antimalarial, cardiovascular, anticonvulsant, analgesic, antimycobacterial, anti-inflammatory, antihelminthic, antiprotozoal and antioxidant properties [1,2,3,4,5,6,7,8,9,10]. Such antimalarial drugs as chloroquine, hydroxychloroquine, amodiaquine, and primaquine have been developed based on the quinoline scaffold [1,2,3,4,5,6,7,8].
Fluoroquinolone drugs are some of the most commonly used antibiotics in modern pharmacotherapy. These drugs are broad-spectrum bacteriocidals, which exhibit high activity against both Gram-negative and Gram-positive bacteria [1,2,3,4,5,6,7]. A number of fluoroquinolone antibiotics have a tricyclic core structure (pazufloxacin, rufloxacin, nadifloxacin), in which the quinoline ring is condensed with six-membered cycles (2,3-dihydro-1,4-thiazine, 2,3-dihydro-1,4-oxazine, Figure 1).
A variety of biologically active compounds are based on scaffolds in the form of a combination of nitrogen and sulfur heterocycles [11,12,13,14,15,16,17,18,19,20]. Pazufloxacin, rufloxacin and nadifloxacin antibiotics have the quinoline core structure condensed with six-membered heterocycles (Figure 1) [17,18,19]. The well-known antibiotics penicillin and cephalosporin are examples of drugs containing fused nitrogen and sulfur heterocycles.
The [1,4]thiazino[2,3,4-ij]quinolin-4-ium scaffold can be considered as being a result of annulation of the quinoline core structure with the thiazine heterocycle. The [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives exhibit a broad spectrum of biological activities [18,19,20,21,22,23], including anticancer [21], antibacterial [22] and anti-tuberculosis [23] properties. The commonly used fluoroquinolone antibiotic rufloxacin belongs structurally to this class of compounds (Figure 1).
Applsci 11 08532 g001 550
Figure 1. Known biologically active compounds structurally related to the 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium scaffold, which have the quinoline ring condensed with six-membered cycles (fluoroquinolone antibiotics [17,18,19], compounds with antibacterial [22] and anti-tuberculosis [23] activity).
Figure 1. Known biologically active compounds structurally related to the 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium scaffold, which have the quinoline ring condensed with six-membered cycles (fluoroquinolone antibiotics [17,18,19], compounds with antibacterial [22] and anti-tuberculosis [23] activity).
Applsci 11 08532 g001
In the last decade, we have developed efficient regioselective approaches to novel heterocyclic and condensed organochalcogen compounds by means of cyclization and annulation reactions based on chalcogen-containing reagents and unsaturated compounds [24,25,26,27,28,29,30,31,32,33]. Recently, we carried out the annulation reactions of 8-quinolinesulfenyl halides with vinyl heteroatom compounds and cycloalkenes to obtain novel [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives in high yields [32,33]. For example, the annulation reactions with divinyl sulfide and divinyl selenide proceeded with the addition of the sulfur atom of 8-quinolinesulfenyl electrophile at the β-position of the vinylchalcogenyl group (the Markovnikov direction), affording 3-(vinylsulfanyl)- and 3-(vinylselanyl)-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chlorides in 94% and 50% yields, respectively. However, in the case of tetravinyl silane, the attachment of the sulfur atom occurred at the α-carbon atom of the vinylsilyl group (the anti-Markovnikov direction), leading to 2-(trivinylsilyl)-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride in a 98% yield [32].
The reactions of 8-quinolinesulfenyl halides (chloride and bromide) with cycloalkenes (cyclopentene, cyclohexene, and cyclooctene), depending on the nature of the halogen and the reaction conditions, gave products of electrophilic addition or annulation products in high yields [33]. The reactions of 8-quinolinesulfenyl chloride with cycloalkenes afforded 8-[(2-chlorocycloalkyl)sulfanyl]quinolines in quantitative yields, while condensed tetracyclic compounds were synthesized in 90–100% yields from 8-quinolinesulfenyl bromide and cycloalkenes. Thus, the reaction of 8-quinolinesulfenyl chloride with cyclopentene at room temperature in methylene chloride gave 8-[(2-chlorocyclopentyl)sulfanyl]quinoline in a quantitative yield, whereas condensed tetracyclic compound, 8,9,10,10a-tetrahydro-7aH-cyclopenta[5,6][1,4]thiazino[2,3,4-ij]quinolin-11-ium bromide (1), was obtained in a 98% yield by the annulation reaction of 8-quinolinesulfenyl bromide with cyclopentene in chloroform under reflux (Scheme 1) [33].
Although some synthetic methods for the preparation of [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives have been developed [32,33,34,35,36,37,38,39,40], the annulation reactions of 8-quinolinesulfenyl halides with natural products such as eugenol, isoeugenol, methyleugenol, anethole as well as with 1H-indene, styrene derivatives (4-methylstyrene and α-methylstyrene) and simple alkenes (1-hexene and 1-heptene) have not been described in the literature.
The development of efficient selective methods for the preparation of new [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives with promising biological activity is an urgent task. The aim of this research is the development of the regioselective synthesis of new derivatives of [1,4]thiazino[2,3,4-ij]quinolin-4-ium based on annulation reactions of 8-quinolinesulfenyl halides with natural products (eugenol, isoeugenol, methyleugenol, trans-anethole) as well as with 1-hexene, 1-heptene, 1H-indene and styrene derivatives (4-methylstyrene and α-methylstyrene) and the evaluation of their antimicrobial activity.

2. Results and Discussion

The starting compounds, 8-quinolinesulfenyl chloride 3 and bromide 4, were generated in situ from di(8-quinolinyl) disulfide (2) in methylene chloride or chloroform and used without isolation in further reactions with alkenes and natural products (eugenol derivatives, trans-anethole) (Scheme 2).
Taking into account the known data on the reactions of 8-quinolinesulfenyl halides with cycloalkenes [33], which produced electrophilic addition products of sulfenyl chloride 3 and annulation products in the case of sulfenyl bromide 4 (Scheme 1), it could be assumed that the reactions of 8-quinolinesulfenyl halides with 1-alkenes would proceed similarly. However, the reactions of sulfenyl chloride 3 with 1-alkenes gave a complex mixture of compounds including electrophilic addition products under the same conditions as indicated in Scheme 1. Nevertheless, the reactions of sulfenyl bromide 4 with 1-alkenes at room temperature in methylene chloride led to annulation products 5 and 6 in 85% and 81% yields, respectively (Scheme 3).
Compounds 5 and 6 are water-soluble light-yellow powders with a melting point of about 120 °C.
The naturally occurring products eugenol (4-allyl-2-methoxyphenol) and isoeugenol (2-methoxy-4-(1-propenyl)phenol) were involved in the annulation reactions with 8-quinolinesulfenyl chloride 3. The reaction of sulfenyl chloride 3 with isoeugenol smoothly proceeded at room temperature in chloroform, giving compound 7 in a 90% yield (Scheme 4).
The reaction of sulfenyl chloride 3 with eugenol under the same conditions as the synthesis of compound 7 was very sluggish (40% yield of the annulation product). However, carrying out the reaction of sulfenyl chloride 3 with eugenol under reflux in chloroform for 7 h allowed us to obtain annulation product 8 in a 75% yield (Scheme 4).
The reaction of sulfenyl chloride 3 with eugenol includes electrophilic addition of the sulfur atom of sulfenyl electrophile to the α-carbon atom of the vinyl group (the anti-Markovnikov direction), while the opposite regiochemistry is observed in the annulation reaction of sulfenyl chloride 3 with isoeugenol.
Another naturally occurring compound, trans-anethole (1-methoxy-4-(E-1-propenyl)benzene), appears to be very reactive in annulation reactions. The reaction of sulfenyl chloride 3 with trans-anethole was carried out at room temperature in methylene chloride, affording quinolinium chloride 9 in a quantitative yield (Scheme 5).
The reaction of sulfenyl chloride 3 with methyl eugenol (4-allyl-1,2-dimethoxybenzene) seems to proceed more slowly than with eugenol. Under the same conditions as the synthesis of product 9, the reaction of sulfenyl chloride 3 with methyl eugenol afforded the annulation product in a 57% yield. However, after refluxing the mixture of sulfenyl chloride 3 with methyl eugenol in chloroform for 3 h, annulation product 10 was obtained in a 98% yield (Scheme 5).
The double bond in trans-anethole and isoeugenol occurs in conjugation with the benzene ring, and these compounds demonstrate higher activity in the annulation reactions compared to eugenol and methyl eugenol bearing the allyl fragment without conjugation of the double bond.
Such substrates as styrene, 4-methylstyrene and α-methylstyrene and 1H-indene also have the double bond, which is in conjugation with the benzene ring. We assumed that these substrates may be active in the annulation and carried out the reactions of sulfenyl chloride 3 with them.
The reactions of quinoline sulfenyl chloride 3 with styrene proceeded smoothly in methylene chloride at room temperature for 24 h to give quinolinium chloride 11 in a 97% yield (Scheme 6).
Under the same conditions, the reactions of sulfenyl chloride 3 with 1H-indene afforded the condensed five-membered product in only a 43% yield. Refluxing the reaction mixture resulted in the formation of a small amount of by-product along with the target compound. However, when the reaction time was increased to 65 h at room temperature, pure annulation product 12 was obtained in an 80% yield (Scheme 6).
The reaction of sulfenyl chloride 3 with 4-methylstyrene was carried out at room temperature for 24 h in methylene chloride affording compound 13 in quantitative yield (Scheme 7). Under the same conditions as the synthesis of product 13, the reaction of sulfenyl chloride 3 with α-methylstyrene gave annulation product 14 in an 87% yield (Scheme 7).
The reaction of sulfenyl chloride 3 with α-methylstyrene seems to proceed more slowly than with 4-methylstyrene and styrene. The methyl substituent at position 4 of the benzene ring has little influence on the yield of the product, and compounds 11 and 13 (derived from both styrene and 4-methylstyrene) were obtained in 97% and quantitative yields, while the introduction of the methyl substituent to the α-position of the double bond affects on the annulation reaction and slightly decreases the the annulation product yield to 87% under the same conditions.
All the studied substrates can be schematically divided into two groups: terminal alkenes including allyl arenes and styrene derivatives, which contain the double bond in conjugation with the benzene ring. In general, the latter group of compounds demonstrates the higher activity in the annulation reactions compared to the terminal alkenes (Scheme 8).
The annulation reactions with the terminal alkenes, whose double bond is not in conjugation with the benzene ring, proceed with the attachment of the sulfur atom of sulfenyl halides 3, 4 at the α-position of the double bond (the anti-Markovnikov direction). In the case of styrene derivatives, the addition of the sulfur atom occurs at the terminal carbon atom of the double bond (the Markovnikov direction). Possible intermediates A and B, which correspond to two directions of these reactions, can be considered for the explanation of these trends (Scheme 8).
We assume that the reactions with terminal alkenes proceed via three-membered thiiranium intermediates A. It is known that the electrophilic addition reactions of sulfenyl chlorides [41,42,43,44,45,46,47,48,49,50,51,52,53,54] with linear 1-alkene mainly give anti-Markovnikov products [41,42,43], and thiiranium cations are regarded as intermediates of these reactions [42,43,44,45]). Nucleophilic attack of the nitrogen atom of the quinoline ring occurs at the unsubstituted carbon atom of thiiranium intermediates A due to the steric factor, which determines the anti-Markovnikov direction of the reactions (Scheme 8).
It is assumed that linear carbocations B are involved as intermediates in the reactions with styrene derivatives. In this case, linear carbocations B are energetically favorable due to their stabilization by the benzene ring that provides the Markovnikov direction of the reactions (Scheme 8). It is known that electrophilic addition of sulfenyl chlorides to styrene leads to Markovnikov products [52,53].
The antibacterial activity of the synthesized compounds was evaluated. The minimal inhibitory concentration (MIC) was determined using the broth standard microdilution method [55].
The obtained results are presented in Table 1. Compounds 1, 5–14 were tested in vitro for antimicrobial activity against strains of the Gram-positive bacteria Bacillus subtilis B-406 and Enterococcus durans B-603 (which are similar in properties and taxonomic affiliation to bacteria Staphylococcus aureus) and the Gram-negative bacteria Escherichia coli B-1238 (the bacterial strains were taken from the All-Russian Collection of Microorganisms).
As can be seen from the presented data (Table 1), compound 1 is active against Enterococcus durans, but has low activity against other microorganisms. Compounds 5 and 6 differ only by one group, CH2, but the activity of these compounds varies considerably. Compound 5 with a shorter carbon chain shows low activity, while compound 6 is superior to antibiotic gentamicin against both the Gram-positive Enterococcus durans and the Gram-negative Escherichia coli (Table 1).
The obtained results were compared with the activity of standard aminoglycoside antibiotic gentamicin, the minimal inhibitory concentrations of which are 25, 50 and 100 μg/mL against Enterococcus durans, Bacillus subtilis and Escherichia coli, respectively.
Having the same molecular formula, products 7 and 8 are isomeric compounds obtained by the reactions of sulfenyl chloride 3 with isoeugenol and eugenol, respectively. These compounds differ significantly (by about 10 times) in activity (Table 1). The eugenol-derived product 8, as well as that obtained from methyl eugenol, compound 10, are highly active against bacteria Enterococcus durans and Bacillus subtilis and are superior in their activity compared the antibiotic gentamicin against these microorganisms.
The structurally related compounds 7 and 9 (obtained from methyl isoeugenol and trans-anethole), which formally differ in one hydroxyl group, show activity against Gram-positive bacteria Enterococcus durans and Bacillus subtilis, but are inferior to gentamicin (Table 1).
Comparison of the structurally related compounds 11, 13 and 14 reveals the higher activity of products 11 and 13 (obtained from styrene and 4-methylstyrene), which are superior to the activity of gentamicin against bacteria Enterococcus durans. α-methylstyrene-derived product 14 shows lower activity (Table 1).
The highest level of activity was shown by product 12 (obtained from 1H-indene), which significantly exceeds the activity of gentamicin and all the obtained compounds against the bacteria Enterococcus durans and is more than 15 times higher than the activity of this antibiotic against Bacillus subtilis.
The structural assignments of synthesized compounds were made using 1H- and 13C-NMR spectroscopy including J-modulation 13C-NMR experiments and confirmed by elemental analysis (see more in Supplementary Materials).
The groups SCH-CH2N+, SCH2-CHN+ and SCH-CHN+ provide characteristic signals in the 1H- and 13C-NMR spectra. Thus, the carbon atoms of these groups, bonded with one or two protons, reveal characteristic signals in the 13C-NMR spectra. For example, the CH2N+ group manifests itself at ~62 ppm, while signals of the CHN+ moiety are observed in the lowfield region of ~69–75 ppm in the 13C-NMR spectra of the obtained compounds. The regiochemistry of the products was determined based on the 1H- and 13C-NMR spectra, taking into account the number of protons bonded with the carbon atoms of these groups.

3. Experimental Section

3.1. General Information

1H (400.1 MHz) and 13C (100.6 MHz) NMR spectra were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in a 2–5% solution with D2O or DMSO-d6. 1H and 13C chemical shifts (δ) are reported in parts per million (ppm), relative to tetramethylsilane (external) or to the residual solvent peaks of D2O (δ = 4.79) and DMSO-d6 (δ = 2.50 and 39.52 ppm for 1H and 13C NMR, respectively). Elemental analysis was performed on a Thermo Scientific FLASH 2000 Organic Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus (Wagner & Munz GmbH, München, Germany). Absolute solvents were used in the reactions.

3.2. Synthesis of Products 5 and 6 from 1-Alkenes

2-Butyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium bromide (5). A solution of bromine (0.072 g, 0.45 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.144 g, 0.45 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of hexene-1 (0.076 g, 0.9 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 48 h at room temperature and left overnight. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.248 g, 85% yield) in the form of a yellow powder, mp 220–221 °C.
1H-NMR (400 MHz, DMSO-d6): δ 0.90 (t, J = 7.3 Hz, 3H, CH3), 1.31–1.39 (m, 2H, CH2), 1.47–1.54 (m, 2H, CH2), 1.61–1.68 (m, 1H, CH2), 1.80–1.89 (m, 1H, CH2), 3.94 (m, 1H, SCH), 5.01 (dd, J = 13.9, 8.5 Hz, 1H, NCH2), 5.36 (d, J = 13.9 Hz, 1H, NCH2), 7.88–7.92 (m, 1H, Hquino), 8.12–8.14 (m, 1H, Hquino), 8.18–8.22 (m, 2H, Hquino), 9.28–9.30 (m, 1H, Hquino), 9.39–9.41 (m, 1H, Hquino).
13C-NMR (101 MHz, DMSO-d6): δ 13.75 (CH3), 21.65 (CH2), 28.03 (CH2), 30.81 (CH2), 36.21 (SCH), 62.05 (NCH2), 122.25 (Cquino), 126.40 (Cquino), 126.87 (Cquino), 129.39 (Cquino), 130.59 (Cquino), 133.14 (Cquino), 133.61 (Cquino), 148.65 (Cquino), 150.23 (Cquino).
Anal. Calcd for C15H18BrNS: C 55.56, H 5.59, N 4.32, Br 24.64, S 9.89. Found: C 55.69, H 5.96, N 4.44, Br 24.86, S 10.10.
2-Pentyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium bromide (6). A solution of bromine (0.130 g, 0.80 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.261 g, 0.80 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of heptene-1 (0.157 g, 1.6 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 48 h at room temperature and left overnight. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.438 g, 81% yield) in the form of a yellow powder, mp 219–220 °C.
1H-NMR (400 MHz, DMSO-d6): δ 0.88 (s, 3H, CH3), 1.30–1.32 (m, 4H, CH2), 1.49–1.56 (m, 2H, CH2), 1.58–1.65 (m, 1H, CH2), 1.81–1.84 (m, 1H, CH2), 3.94 (m, 1H, SCH), 5.01 (dd, J = 13.7, 8.3 Hz, 1H, NCH2), 5.35 (d, J = 13.7 Hz, 1H, NCH2), 7.88–7.92 (m, 1H, Hquino), 8.12–8.13 (m, 1H, Hquino), 8.18–8.22 (m, 2H, Hquino), 9.27–9.30 (m, 1H, Hquino), 9.39–9.41 (m, 1H, Hquino).
13C-NMR (101 MHz, DMSO-d6): δ 13.78 (CH3), 21.82 (CH2), 25.48 (CH2), 30.60 (CH2), 31.01 (CH2), 36.18 (SCH), 61.97 (NCH2), 122.21 (Cquino), 126.36 (Cquino), 126.81 (Cquino), 129.33 (Cquino), 130.54 (Cquino), 132.54 (Cquino), 133.10 (Cquino), 148.60 (Cquino), 150.19 (Cquino).
Anal. Calcd for C16H20BrNS: C 56.80, H 5.96, N 4.14, Br 23.62, S 9.48. Found: C 57.02, H 6.11, N 4.24, Br 23.97, S 9.72.

3.3. Synthesis of Compounds 7–10 from Natural Products

3-(4-Hydroxy-3-methoxyphenyl)-2-methyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (7). A solution of sulfuryl chloride (0.113 g, 0.83 mmol) in chloroform (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.268 g, 0.83 mmol) in chloroform (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of isoeugenol (0.274 g, 1.6 mmol) in chloroform (10 mL) was added dropwise, and the reaction mixture was stirred for 45 h at room temperature and left overnight. The formed precipitate was filtered off, washed with hexane and dried in vacuum, giving the product (0.54 g, 90% yield) in the form of a yellow powder, mp 156–159 °C.
1H-NMR (400 MHz, DMSO-d6): δ 1.40 (d, J = 7.0 Hz, 3H, CH3,), 3.70 (s, 3H, OCH3), 3.96 (m, 1H, SCH), 5.73 (m, 1H, NCH), 6.58 (m, 1H, Ar), 6.61 (m, 1H, Ar), 6.80 (m, 1H, Ar), 7.94–7.98 (m, 1H, Hquino), 8.14–8.16 (m, 1H, Hquino), 8.24–8.27 (m, 1H, Hquino), 8.32–8.34 (m, 1H, Hquino), 9.43–9.45 (m, 1H, Hquino), 9.48–9.50 (m, 1H, Hquino).
13C-NMR (101 MHz, DMSO-d6): δ 20.04 (CH3), 37.46 (SCH2), 55.74 (OCH3), 73.69 (NCH), 110.39, 115.40, 117.77, 122.94, 124.85, 127.68, 129.08, 129.70, 130.87, 132.96, 133.95, 147.17, 148.03, 150.25, 151.10.
Anal. Calcd for C19H18NClO2S: C 63.41, H 5.04, N 3.89, Cl 9.85, S 8.91. Found: C 63.69, H 5.23, N 4.07, Cl 10.09, S 9.21.
2-[(4-Hydroxy-3-methoxyphenyl)methyl]-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (8). A solution of sulfuryl chloride (0.167 g, 1.2 mmol) in chloroform (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.396 g, 1.2 mmol) in chloroform (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of eugenol (0.394 g, 2.4 mmol) in chloroform (10 mL) was added dropwise. The reaction mixture was stirred for 1 h at room temperature and 7 h at reflux and left overnight. The formed precipitate was filtered off, washed with hexane and dried in vacuum, giving the product (0.648 g, 75% yield) in the form of a yellow powder, mp 195–197 °C.
1H-NMR (400 MHz, D2O): δ 2.88–2.94 (m, 1H, CH2), 3.02 (dd, J = 14.2, 6.0 Hz, 1H, CH2), 3.68 (s, 3H, CH3), 3.92–3.97 (m, 1H, SCH), 4.94 (dd, J = 14.4, 6.8 Hz, 1H, NCH2), 5.21 (dd, J = 14.4, 2.4 Hz, 1H, NCH2), 6.48–6.53 (m, 2H, Ar), 6.68 (s, 1H, Ar) 7.69–7.73 (m, 1H, Hquino), 7.80–7.82 (m, 1H, Hquino), 7.92–7.98 (m, 2H, Hquino), 8.96–9.00 (m, 2H, Hquino).
13C-NMR (101 MHz, D2O): δ 36.84 (CH2), 37.18 (SCH), 55.34 (CH3), 61.78 (CH2N), 112.80, 114.59, 121.35, 121.70, 125.61, 126.51, 127.91, 129.14, 130.46, 132.69, 133.07, 143.36, 146.56, 148.55, 148.68.
Anal. Calcd for C19H18NClO2S: C 63.41, H 5.04, N 3.89, Cl 9.85, S 8.91. Found: C 63.73, H 5.21, N 4.01, Cl 10.31, S 9.29.
3-(4-Methoxyphenyl)-2-methyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (9). A solution of sulfuryl chloride (0.103 g, 0.76 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.243 g, 0.76 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of trans-anethole (0.226 g, 1.52 mmol) in methylene chloride (10 mL) was added dropwise, and the reaction mixture was stirred for 48 h at room temperature. The solvent was removed by rotary evaporator. The residue was dried in vacuum, giving the product (0.523 g, quantitative yield) in the form of a yellow powder, mp 97–100 °C.
1H-NMR (400 MHz, D2O): δ 1.43 (d, J = 7.0 Hz, 3H, CH3), 3.65 (s, 3H, OCH3), 3.92 (dd, J = 7.0, 3.1 Hz, 1H, SCH), 6.39 (d, J = 3.1 Hz, 1H, NCH), 6.70 (d, J = 9.0 Hz, 2H, Ar), 6.74 (d, J = 9.0 Hz, 2H, Ar), 7.84–7.88 (m, 1H, Hquino), 7.93–7.95 (m, 1H, Hquino), 8.04–8.08 (m, 1H, Hquino), 8.18–8.20 (m, 1H, Hquino), 9.15–9.16 (m, 1H, Hquino), 9.21–9.23 (m, 1H, Hquino).
13C-NMR (101 MHz, D2O): δ 19.25 (CH3), 38.18 (SCH), 55.23 (OCH3), 74.33 (NCH), 114.17, 122.18, 124.12, 126.68, 127.75, 129.65, 130.30, 131.09, 133.18, 134.52, 150.10, 150.25, 159.10.
Anal. Calcd for C19H18NClOS: C 66.36, H 5.28, N 4.07, Cl 10.31, S 9.33. Found: C 66.46, H 5.34, N 4.15, Cl 10.84, S 9.91.
2-[(3,4-Dimethoxyphenyl)methyl]-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (10). A solution of sulfuryl chloride (0.067 g, 0.50 mmol) in chloroform (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.160 g, 0.50 mmol) in chloroform (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of methyl eugenol (0.178 g, 1.0 mmol) in chloroform (10 mL) was added dropwise, and the reaction mixture was stirred for 1 h at room temperature and 3 h at reflux temperature. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.366 g, 98% yield) in the form of a yellow powder, mp 179–180 °C.
1H-NMR (400 MHz, D2O): δ 2.76–2.82 (m, 1H, CH2), 2.93–2.98 (m, 1H, CH2), 3.56 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.83–3.86 (m, 1H, SCH), 4.82–4.85 (m, 1H, NCH2), 5.12–5.16 (m, 1H, NCH2), 6.45–6.51 (m, 2H, Ar), 6.56 (s, 1H, Ar) 7.56–7.65 (m, 2H, Hquino), 7.80–7.82 (m, 1H, Hquino), 7.90–7.92 (m, 1H, Hquino), 8.89–8.94 (m, 2H, Hquino).
13C-NMR (101 MHz, D2O): δ 37.20 (CH2), 37.56 (SCH), 55.43 (OCH3), 55.53 (OCH3), 62.18 (CH2N), 111.22, 112.45, 121.79, 121.92, 125.95, 126.85, 128.63, 129.49, 130.72, 132.92, 133.20, 146.92, 147.55, 148.92, 149.03.
Anal. Calcd for C20H20NClO2S: C 64.25, H 5.39, N 3.75, Cl 9.48, S 8.58. Found: C 63.73, H 5.21, N 4.01, Cl 10.01, S 8.99.

3.4. Synthesis of Compounds 11–14 from Styrene Derivatives and 1H-Indene

3-Phenyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (11). A solution of sulfuryl chloride (0.042 g, 0.31 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.100 g, 0.31 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of styrene (0.065 g, 0.62 mmol) in methylene chloride (5 mL) was added dropwise, and the reaction mixture was stirred for 24 h at room temperature. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.18 g, 97% yield) in the form of a light-yellow oil.
1H-NMR (400 MHz, D2O): δ 3.78 (dd, J = 14.3, 3.5 Hz, 1H, SCH2), 3.98 (dd, J = 14.3, 3.0 Hz, 1H, SCH2), 6.79–6.83 (m, 1H, NCH), 6.89–6.96 (m, 2H, Ar), 7.36–7.44 (m, 3H, Ar), 7.91–7.95 (m, 1H, Hquino), 8.08–8.13 (m, 2H, Hquino), 8.23–8.25 (m, 1H, Hquino), 9.21–9.27 (m, 2H, Hquino).
13C-NMR (101 MHz, D2O): δ 29.77 (SCH2), 69.32 (NCH), 121.99, 125.76, 126.34, 128.05, 129.14, 129.23, 129.32, 129.45, 133.91, 134.12, 136.95, 149.62, 150.31.
Anal. Calcd for C17H14ClNS: C 68.10, H 4.71, Cl 11.82, N 4.67, S 10.70. Found: C 67.81, H 4.53, Cl 12.01, N 4.48, S 10.48.
7aH,8H,12bH-Indeno[1′,2′:5,6][1,4]thiazino[2,3,4-ij]quinolin-13-ium chloride (12). A solution of sulfuryl chloride (0.071 g, 0.53 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.169 g, 0.53 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of 1H-indene (0.140 g, 1.06 mmol) in methylene chloride (10 mL) was added dropwise, and the reaction mixture was stirred for 65 h at room temperature. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.266 g, 80% yield) in the form of a yellow powder, mp 158–160 °C.
1H-NMR (400 MHz, D2O): δ 3.07 (d, J = 16.8 Hz, 1H, CH2), 3.61 (d, J = 16.8 Hz, 1H, CH2), 4.52 (d, J = 4.2 Hz, 1H, SCH), 6.71 (s, 1H, NCH), 6.77–6.79 (m, 1H, Ar), 7.13–7.17 (m, 1H, Ar), 7.33–7.36 (m, 1H, Ar), 7.45–7.46 (m, 1H, Ar), 7.68–7.72 (m, 1H, Hquino), 7.81–7.83 (m, 1H, Hquino), 8.04–8.06 (m, 1H, Hquino), 8.19–8.22 (m, 1H, Hquino), 9.20–9.22 (m, 1H, Hquino), 9.43–9.44 (m, 1H, Hquino).
13C-NMR (101 MHz, D2O): δ 36.27 (CH2), 39.61 (SCH), 72.47 (NCH), 121.6, 122.27, 125.14, 126.38, 127.22, 127.33, 129.12, 129.49, 131.04, 132.50, 138.22, 138.68, 138.71, 149.35, 149.81.
Anal. Calcd for C18H14NClS: C 69.33, H 4.53, N 4.49, Cl 11.37, S 10.28. Found: C 69.46, H 4.68, N 4.63, Cl 11.81, S 10.56.
3-(4-Methylphenyl)-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (13). A solution of sulfuryl chloride (0.097 g, 0.71 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.230 g, 0.71 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of 4-methylstyrene (0.168 g, 1.42 mmol) in methylene chloride (10 mL) was added dropwise, and the reaction mixture wasstirred for 24 h at room temperature. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was dried in vacuum, giving the product (0.445 g, quantitative yield) in the form of a yellow powder, mp 73–75 °C.
1H-NMR (400 MHz, D2O): δ 2.21 (s, 3H, CH3), 3.67 (dd, J = 14.2, 3.2 Hz, 1H, SCH2), 3.89 (dd, J = 14.2, 2.4 Hz, 1H, SCH2), 6.72 (m, 3H, NCH, Ar), 7.10 (d, J = 8.0 Hz, 2H, Ar), 7.84–7.88 (m, 1H, Hquino), 7.98–8.00 (m, 1H, Hquino), 8.04–8.08 (m, 1H, Hquino), 8.19–8.21 (m, 1H, Hquino), 9.15–9.16 (m, 1H, Hquino), 9.22–9.24 (m, 1H, Hquino).
13C-NMR (101 MHz, D2O): δ 20.11 (CH3), 29.67 (SCH2), 69.05 (NCH), 121.93, 125.57, 125.97, 127.93, 129.38, 129.41, 129.57, 131.37, 133.73, 133.90, 139.64, 149.48, 150.16.
Anal. Calcd for C18H16NClS: C 68.89, H 5.14, N 4.46, Cl 11.30, S 10.22. Found: C 69.00, H 5.21, N 4.54, Cl 11.56, S 10.68.
3-Methyl-3-phenyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium chloride (14). A solution of sulfuryl chloride (0.108 g, 0.8 mmol) in methylene chloride (10 mL) was added dropwise to a solution of di(8-quinolinyl) disulfide (0.256 g, 0.8 mmol) in methylene chloride (10 mL), and the mixture was stirred for 10 min at room temperature. A solution of α-methylstyrene (0.189 g, 1.6 mmol) in methylene chloride (10 mL) was added dropwise, and the reaction mixture was stirred for 24 h at room temperature. The mixture was filtered, and the solvent was removed by rotary evaporator. The residue was washed with cold hexane and dried in vacuum, giving the product (0.436 g, 87% yield) in the form of a yellow oil.
1H-NMR (400 MHz, D2O): δ 1.58 (s, 3H, CH3), 3.57 (d, J = 14.6, 1H, SCH2), 3.78 (d, J = 14.6 1H, SCH2), 6.58–6.64 (m, 1H, Ar), 6.66–6.72 (m, 2H, Ar), 7.00–7.05 (m, 2H, Ar), 7.77–7.62 (m, 1H, Hquino), 7.98–8.03 (m, 1H, Hquino), 8.07–8.13 (m, 1H, Hquino), 8.21–8.25 (m, 1H, Hquino), 8.90–8.94 (m, 1H, Hquino), 9.00–9.04 (m, 1H, Hquino).
13C-NMR (101 MHz, D2O): δ 28.80 (CH3), 50.91 (SCH2), 74.85 (NCH), 122.00, 124.79, 126.84, 127.22, 127.86, 129.28, 129.41, 130.14, 136.99, 141.46, 143.67, 144.20, 148.31.
Anal. Calcd for C18H16NClS: C 68.89, H 5.14, N 4.46, Cl 11.30, S 10.22. Found: C 69.12, H 4.99, N 4.27, Cl 11.19, S 9.96.

5. Conclusions

A new family of water-soluble [1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives in 75–100% yields have been developed based on the annulation reactions of 8-quinolinesulfenyl halides with natural products (eugenol, isoeugenol, methyl eugenol, trans-anethole) and alkenes (1-hexene, 1-heptene, styrene, 4-methylstyrene, α-methylstyrene and 1H-indene).
The annulation reactions of 8-quinolinesulfenyl halides with styrene derivatives, which contain the double bond in conjugation with the benzene ring, and terminal alkenes including allyl arenes proceed in a regioselective fashion but with the opposite regiochemistry. The annulation reactions with styrene derivatives occur with the attachment of the sulfur atom of the 8-quinolinesulfenyl electrophile at the β-position of the vinyl group, whereas the opposite regiochemistry is observed in the case of terminal alkenes and allyl arenes.
The formation of possible intermediates in the annulation reactions of 8-quinolinesulfenyl halides with styrene derivatives and terminal alkenes including allyl arenes has been discussed. Three-membered thiiranium cations are assumed as intermediates in the reactions of 8-quinolinesulfenyl halides with terminal alkenes and allyl arenes. Nucleophilic attack of the nitrogen atom of the quinoline ring occurs at the unsubstituted carbon atom of thiiranium intermediates due to the steric factor. Linear carbocations are regarded as intermediates in the reactions with styrene derivatives. In this case, linear carbocations are energetically favorable due to their stabilization by the benzene ring.
Based on the evaluation of antimicrobial activity of novel water-soluble compounds against bacteria Enterococcus durans, Bacillus subtilis and Escherichia coli, the compounds with high activity have been found. A number of the obtained compounds are superior in their activity compared to the antibiotic gentamicin.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/app11188532/s1, examples of 1H- and 13C-NMR spectra of the obtained compounds.

Author Contributions

Conceptualization and the paper preparation, V.A.P.; methodology and research experiments, R.S.I.; antibacterial activity evaluation, L.A.B.; research experiments, I.V.S.; the data curation and supervision, S.V.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors thank Baikal Analytical Center SB RAS for providing the instrumental equipment for structural investigations.

Conflicts of Interest

The authors declare no conflict of interest.

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Applsci 11 08532 sch001 550
Scheme 1. The annulation reactions of 8-quinolinesulfenyl chloride and bromide with cyclopentene.
Scheme 1. The annulation reactions of 8-quinolinesulfenyl chloride and bromide with cyclopentene.
Applsci 11 08532 sch001
Applsci 11 08532 sch002 550
Scheme 2. The generation of 8-quinolinesulfenyl chloride 3 and bromide 4 from di(8-quinolinyl) disulfide 2 by the action of sulfuryl chloride or bromine.
Scheme 2. The generation of 8-quinolinesulfenyl chloride 3 and bromide 4 from di(8-quinolinyl) disulfide 2 by the action of sulfuryl chloride or bromine.
Applsci 11 08532 sch002
Applsci 11 08532 sch003 550
Scheme 3. Synthesis of 2-butyl- and 2-pentyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium bromides 5 and 6 from sulfenyl bromide 4 and 1-alkenes.
Scheme 3. Synthesis of 2-butyl- and 2-pentyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium bromides 5 and 6 from sulfenyl bromide 4 and 1-alkenes.
Applsci 11 08532 sch003
Applsci 11 08532 sch004 550
Scheme 4. Synthesis of compounds 7 and 8 by the annulation reactions of sulfenyl chloride 3 with isoeugenol and eugenol.
Scheme 4. Synthesis of compounds 7 and 8 by the annulation reactions of sulfenyl chloride 3 with isoeugenol and eugenol.
Applsci 11 08532 sch004
Applsci 11 08532 sch005 550
Scheme 5. Synthesis of compounds 9 and 10 by the annulation reactions of sulfenyl chloride 3 with trans-anethole and methyl eugenol.
Scheme 5. Synthesis of compounds 9 and 10 by the annulation reactions of sulfenyl chloride 3 with trans-anethole and methyl eugenol.
Applsci 11 08532 sch005
Applsci 11 08532 sch006 550
Scheme 6. Synthesis of compounds 11 and 12 by the annulation reactions of sulfenyl chloride 3 with styrene and 1H-indene.
Scheme 6. Synthesis of compounds 11 and 12 by the annulation reactions of sulfenyl chloride 3 with styrene and 1H-indene.
Applsci 11 08532 sch006
Applsci 11 08532 sch007 550
Scheme 7. Synthesis of compounds 13 and 14 by the annulation reactions of sulfenyl chloride 3 with 4-methylstyrene and α-methylstyrene.
Scheme 7. Synthesis of compounds 13 and 14 by the annulation reactions of sulfenyl chloride 3 with 4-methylstyrene and α-methylstyrene.
Applsci 11 08532 sch007
Applsci 11 08532 sch008 550
Scheme 8. Directions of the reactions of sulfenyl chloride 3 and bromide 4 with natural products and alkenes.
Scheme 8. Directions of the reactions of sulfenyl chloride 3 and bromide 4 with natural products and alkenes.
Applsci 11 08532 sch008
Table
Table 1. The evaluation of antibacterial activity of compounds 1, 5–14.
Table 1. The evaluation of antibacterial activity of compounds 1, 5–14.
CompoundMinimum Inhibitory Concentration (μg/mL)
Enterococcus duransBacillus subtilisEscherichia coli
1 Applsci 11 08532 i00131.2>1000>1000
5 Applsci 11 08532 i002250250250
6 Applsci 11 08532 i0033.162.512.5
7 Applsci 11 08532 i004310310>1000
8 Applsci 11 08532 i0053.13.162.5
9 Applsci 11 08532 i006250125>1000
10 Applsci 11 08532 i0073.1251000
11 Applsci 11 08532 i0086.2250125
12 Applsci 11 08532 i0090.63.1250
13 Applsci 11 08532 i0106.2125250
14 Applsci 11 08532 i01162.5250125
Gentamicin 2550100
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Potapov, V.A.; Ishigeev, R.S.; Belovezhets, L.A.; Shkurchenko, I.V.; Amosova, S.V. New Water-Soluble Condensed Heterocyclic Compounds with Antimicrobial Activity Based on Annulation Reactions of 8-Quinolinesulfenyl Halides with Natural Products and Alkenes. Appl. Sci. 2021, 11, 8532. https://doi.org/10.3390/app11188532

AMA Style

Potapov VA, Ishigeev RS, Belovezhets LA, Shkurchenko IV, Amosova SV. New Water-Soluble Condensed Heterocyclic Compounds with Antimicrobial Activity Based on Annulation Reactions of 8-Quinolinesulfenyl Halides with Natural Products and Alkenes. Applied Sciences. 2021; 11(18):8532. https://doi.org/10.3390/app11188532

Chicago/Turabian Style

Potapov, Vladimir A., Roman S. Ishigeev, Lyudmila A. Belovezhets, Irina V. Shkurchenko, and Svetlana V. Amosova. 2021. "New Water-Soluble Condensed Heterocyclic Compounds with Antimicrobial Activity Based on Annulation Reactions of 8-Quinolinesulfenyl Halides with Natural Products and Alkenes" Applied Sciences 11, no. 18: 8532. https://doi.org/10.3390/app11188532

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