Abstract
In this study, a series of azobenzothiazole dyes 4 were synthesized via diazotization of substituted benzothiazole derivatives followed by azo coupling with acetaminophen. The chemical structures of all synthesized compounds were confirmed using analytical data and spectroscopic techniques, including UV-visible, IR, mass spectra, and 1H- and 13C-NMR. The in situ formed diazobenzothiazole ions regiospecifically react with acetaminophen derivatives in the Hollemann-guided electrophilic aromatic substitution mechanism. The regio-orientations were established, on the one hand, by a rigorous interpretation of 1H-NMR spectra and, on the other hand, by the characteristic fragmentation patterns observed on the electrospray mass spectra. In the cases of 4a and 4b, multisubstitutions occurred. The antimicrobial activity of compound 4, along with all the starting materials, was investigated on Pseudomonas aeruginosa PA01, Staphylococcus aureus 18, Escherichia coli 64R, and S. aureus ATCC 25923. The results showed that this skeletal framework exhibited marked potency as antibacterial agents. The most active antibacterial agent against both targeted organisms was compound 4a′.
1 Introduction
In most of our societies, pain and discomfort are often treated with analgesics drugs [1]. Analgesics are also widely used to treat dysphoric moods and sleep disturbances [2]. It is now established that there is a link between rates of the use of pain relievers and certain psychiatric illnesses such as depressive symptoms, alcohol, nicotine, and caffeine consumption [3]. However, the most common side effects associated with the consumption of analgesic drugs are gastrointestinal disorders [4]. Inhibition of prostaglandin formation in the stomach by most pain-relieving drugs can lead to inflammation, injury, and a stomach ulcer [5]. One of the advantages of acetaminophen is that it does not cause gastrointestinal problems like most other nonsteroidal anti-inflammatory drugs [1,6], and this is due to acetaminophen’s low affinity for cyclooxygenase (COX). However, like most drugs, acetaminophen has several side effects, the most important of which is liver damage, often even at therapeutic doses [7,8]. Acetaminophen, a nonsteroidal anti-inflammatory drug, could follow some transformations like binding it to the benzothiazole ring to improve its nephrotoxicity. Benzothiazoles are aromatic heterocycles known for their anti-inflammatory [9,10,11], antibacterial [12], antifungal [13], antiviral [14], and antidiabetic [15] activities. To continue our search to find a better combination of pharmacophores within diazo molecules for pharmaceutical applications [16,17,18,19,20], we prepared a series of diazobenzothiazole ions, which were copulated with acetaminophen.
2 Results and discussion
2.1 Chemistry
The synthetic strategies adopted for the synthesis of the target compounds are depicted in Scheme 1. The structures of 4 were established based on their elemental analyses and spectral data.
Sequence of reactions leading to compounds 4 synthesis.
Diazotisation of 2-aminobenzothiazole 1 in strong acids yields diazonium salts 2, which undergo coupling reactions with acetaminophen 3 (Scheme 1).
The electronic transition of UV-visible spectra in methanol gave rise to wavelength (λ max) ranging from 272 to 515 nm. The first wavelength (λ max) for all the compounds was found between 272 and 276 nm as a result of π → π* transition of the compounds, indicating the presence of C═C atypical to benzene nucleus. The other wavelength of the benzenoid region (i.e., between 436 and 486 nm) was dole out as a result of n → π* transition and extended conjugation contributed by the C═C and the conjugative linkage performed by the N═N group. An incomparably strong bathochromic shift occurred in compound 4d that resulted in the wavelength at far visible region of light at λ max of 515 nm (log ε = 3.26) was due to the presence of an auxochrome (–Cl) in the skeletal framework of compound 4d, which improved the color deepening attribute by delocalization of the lone pair of electron present on the chlorine atom [21,22].
The infrared spectra of synthesized dyes 4 showed between 3,300 and 3,200 cm−1 a complex broad absorption band that may be assigned to the combined stretching bands of the phenolic O–H group and H2O molecule. The infrared spectra of compounds 4 also showed absorption bands due to the stretching vibrations of C═C of aromatic and Ar C–H bending vibration at 1,599–1,525 cm−1 and 889–631 cm−1, respectively. The FT-IR spectra also showed a band at 1,496–1,405 cm–1 assigned to the N═N group of the azo dyes and a band at 1,260–1,256 cm–1 assigned to the C–S of benzothiazole molecule [23].
The reaction of the diazonium salt solution 2a with 3 gave the two coupling products: 4a and 4a′ (Scheme 1). Compound 4a was obtained as brown powder melting between 262 and 264°C and crystallizing with seven H2O molecules. The presence of two characteristic doublets at δ H = 7.11 (d, J = 8.8 Hz, H-5′) and δ H = 7.49 (d, J = 8.8 Hz, H-6′) on the 1H-NMR spectrum of compound 4a suggests that the coupling reaction took place at the 2′ and 3′ position of paracetamol ring system in agreement with recent findings [16]. On the 1H-NMR spectrum, besides the set of five multiplets appearing between 8.49 and 7.03 ppm attributable to the ten aromatic protons, two broad D2O-exchangeable signals were observed around 10.00 and 2.50 ppm and assigned to the H2O and OH protons, respectively.
Further supporting evidences were obtained from the elemental analysis and the electrospray mass spectra, which confirmed the molecular mass to be 599, with relevant ion fragments at m/z = 598 (M+˙ – H), 581 (M+˙ – H2O), 565 (M+˙ – H2O – CH4), 539 (M+˙ – CH3CONH2 – H), 508 (M+˙ – H – 5H2O), 507 (M+˙ – 2H2O – 2N2), 465 (M+˙ – C7H5NS), and 313 (M+˙ – H2O – 2C7H4NS). The ion fragment at m/z = 479 (M+˙ – 2N2 – 2S), 461 (M+˙ – 2N2 – 2S – H2O), 404 (M+˙ – 2N2 – 2S – H2O – CH3CON), and 327 (M+˙ – 2N2 – 2S – 2C6H4) was assigned as in Scheme 2, confirming the aforementioned structural hypothesis.
Significant HRESI-MS fragmentation patterns of compound 4a.
The azo-structures 4a′, which was a byproduct from the reaction of diazobenzothiazole 1a with acetaminophen, was reported earlier by other authors (but without water crystallites) resulting from the oxidation of 2-aminobenzothiazole 1a by sodium hypochlorite [24,25]. Compound 4a′ was obtained as a dark red powder; its elemental analysis and HREIMS experiments enabled us to establish its gross formula to be C14H14N4O3S2, showing that the coupling product crystallized with three molecules of H2O. These results agreed with the IR experiment, which exhibited a large band in the higher frequency region around 3,273 cm−1 due to the hydroxyl groups of H2O.
The electrospray mass spectra showed the molecular ion peak at m/z 350 corresponding to (M+˙ – H). The following characteristic ion fragments were rationalized as follows at m/z = 335 (M+˙ – NH), 316 (M+˙ – H2S), 299 (M+˙ – H2O – HS), 273 (M+˙ – H – C6H4), and 204 (M+˙ – 3H2O – N2 –2S). The ion fragments at m/z = 215 (M+˙ – NH3 – C7H2S), 159 (M+˙ – NH3 – 3H2O – C7H4S), and 86 (M+˙ – NH3 – 3H2O – C13H5S) were assigned as in Scheme 3, confirming the aforementioned structural hypothesis.
Significant HRESI-MS fragmentation patterns of compound 4a′.
We also studied the surface H2O exchange behaviors of compounds 4a′ by primary alcohols using electrospray ionization mass spectrometry (ESI-MS) [26,27]. Methanol was used as a model primary alcohol for the analysis. As clearly proven by peaks at m/z = 328, 300, 176, and 148 surface of azobenzothiazole dye 4a′ is fully exchanged by methanol within 1 min to give various peaks (M+˙ – 3H2O + MeOH), (M+˙ – 3H2O – N2 + ′MeOH), (M+˙ – 3H2O – 2C6H4 + MeOH), and (M+˙ – 3H2O – 2C6H4 – N2 + MeOH), respectively.
The 1H-NMR spectrum of compound 4a′ exhibits in the range 8.15–7.55 ppm a series of signals corresponding to the eight aromatic protons. The 13C (1H)-NMR experiment exhibited exactly seven signals, among which a downfield signal at 198.6 ppm is assigned to C-2 and C-2′ carbon of benzothiazole.
The reaction of diazotized 2b with 3 gave the coupling products 4b and 4b′ (Scheme 1). It should be pointed out that compound 4b′ was formed in the same manner as compound 4a′. This compound resulting from the in situ deaminated [28,29] intermediate product 2b′ probably underwent coupling with the diazobenzothiazole ion 2b to yield compound 4b′ (Scheme 4).
Reaction sequence to compounds 4b′.
Compound 4b′ was obtained as brown powder with a melting point of 182–184°C. The elemental analysis and the electrospray mass spectra experiments were used to establish the gross formula as C18H22N4O11S4, showing that the coupling product crystallized with two molecules of H2SO4 and one molecule of H2O. These results were confirmed by the IR experiment, which exhibited a large band in the higher frequency region around 3,275 cm−1, resulting from the combined stretching frequencies of the hydroxyl groups of H2SO4 and H2O.
The HRESI-MS showed the molecular ion (M+ + H) peak at m/z 599. The following characteristic ion fragments were rationalized as follows at m/z = 583 (M+˙ – CH3), 569 (M+˙ – CH3CH2), 549 (M+˙ + H – H2O – S), 535 (M+˙ – H2O – C2H5O), 410 (M+˙ – H2SO4 – 2C2H5O), 400 (M+˙ – 2H2SO4 – H2), 357 (M+ + H˙ – H2O – 2H2SO4 – N2), and 283 (M+˙ + H – 2H2SO4 – C8H8O).
The 1H-NMR spectrum of compound 4b′ shows two signals at δ 1.23 and 4.13, and three multiplets at δ 8.01, 7.91, and δ 7.09, respectively, attributable to the protons CH3 and CH2 of the ethoxy group and protons’ sets (H-4 and H-4′), (H-7 and H-7′), and (H-5 and H-5′) of the benzothiazole.
Compound 4b was obtained as red powder melting at 197–199°C and crystallizing with six H2O molecules. Further supporting evidence was obtained from the elemental analysis and the HREIMS, which confirmed the molecular mass to be 1,490, with relevant ion fragments at m/z = 1,453 (M+˙ – H–2H2O), 1,428 (M+˙ – HO – C2H5O), 1,404 (M+˙ – 3H2O – S), 1,379 (M+˙ – 3H2O – CH3CON), 1,353 (M+ – H˙ – 6H2O – N2), 1,323 (M+˙ – 6H2O – CH3CONH2), 1,293 (M+˙ – HO – 4C2H5O), and 1,238 (M+˙ – 4H2O – 4C2H5O).
The 13C-NMR spectrum of compound 4b exhibited 59 carbon signals instead of 62 as required by the molecular formula. That could be explained by overlapping the signals of three methyl substituents of the ethoxy group at δ C 19.9 ppm and carbon C-2″ and C-2vi at δ C 178.3 ppm due to their magnetic and chemical equivalence. The assignment of 1H- and 13C(1H)-NMR data for compound 4b was done by comparison with the simulated values (Table 1).
Comparison of 1H- and 13C(1H)-NMR data of 4b with the simulated values
 |
||||
|---|---|---|---|---|
| δ H in ppm (multiplicity, J in Hz) | δ C in ppm | |||
| N° (H, C) | Simulated values | Experimental values | Simulated values | Experimental values |
| 2, 2″, 2″′, 2iv, 2v, 2vi | 166.4; 166.4; 160.4; 160.4; 160.4; 160.4 | 178.3; 178.3; 174.5; 173.7; 173.4; 173.2 | ||
| 3a, 3a″, 3a″′, 3aiv, 3av, 3avi | 151.1; 151.1; 151.1; 151.1; 150.9; 150.9 | 152.0; 152.0; 151.0; 150.1; 157.2; 156.9 | ||
| 4a, 4a″, 4a″′, 4aiv, 4av, 4avi | 136.5; 136.1; 131.8; 131.8; 131.8; 131.8; | 137.4; 137.3; 130.4; 128.7; 128.0; 127.8 | ||
| 4, 4″, 4″′, 4iv, 4v, 4vi | 8.36 (d, 1H, J = 0.4, H-4), 7.50 (dd, 1H, J = 7.8 and 0.4, H-4″), 7.53 (dd, 1H, J = 7.7 and 0.4, H-4″′), 7.51 (dd, 1H, J = 7.8 and 0.4, H-4iv), 8.34 (d, 1H, J = 0.4, H-4v), 7.49 (dd, 1H, J = 7.8 and 0.4, H-4vi), | 7.58 (s, 1H, H-4), 7.65 (d, 2H, J = 8.8, H-4″ and H-4vi), 7.91 (d, 1H, J = 9.2, H-4″′), 8.11 (d, 1H, J = 2.8, H-4iv), 7.61 (s, 1H, H-4v) | 110.0; 110.0; 105.5; 105.5; 105.5; 105.5; | 111.7; 111.4; 110.8; 110.2; 105.9; 109.9 |
| 5, 5″, 5″′, 5iv, 5v, 5vi | 6.99 (dd, 1H, J = 7.8 and 1.4, H-5″), 7.15 (dd, 1H, J = 7.7 and 1.4, H-5″′), 7.12 (dd, 1H, J = 7.8 and 1.4, H-5iv), 6.98 (dd, 1H, J = 7.8 and 1.4, H-5vi) | 7.09 (dd, 2H, J = 8.8, H-5″ and H-5vi), 7.16 (dd, 2H, J = 9.2 and 2.8, H-5″′ and H-5iv) | 155.8; 155.8; 155.8; 155.8; 145.8; 145.8 | 163.6; 163.3; 161.8; 161.7; 161.4; 158.5 |
| 6, 6″, 6″′, 6iv, 6v, 6vi | 115.5; 115.5; 115.5; 115.5; 133.6; 133.6 | 122.1; 121.7; 121.4; 123.5; 141.1; 140.9 | ||
| 7, 7″, 7″′, 7iv, 7v, 7vi | 7.43 (d, 1H, J = 0.4, H-7), 7.37 (dd, 1H, J = 1.4 and 0.4, H-7″), 7.55 (dd, 1H, J = 1.4 and 0.4, H-7″′), 7.52 (dd, 1H, J = 1.4 and 0.4, H-7iv), 7.38 (d, 1H, J = 0.4, H-7v), 7.36 (dd, 1H, J = 1.4 and 0.4, H-7vi) | 8.00 (s, 1H, H-7), 7.68 (d, 1H, J = 3.6, H-7″), 7.71 (d, 1H, J = 2, H-7″′), 7.15 (d, 1H, J = 2.4, H-7iv), 8.02 (s, 1H, H-7v), 7.62 (d, 1H, J = 6.4, H-7vi) | 124.3; 124.3; 103.4; 103.4; 118.1; 118.1 | 123.9; 123.8; 120.9; 120.7; 117.2; 113.4 |
| 1′ | 130.7 | 133.1 | ||
| 2′ | 147.9 | 143.6 | ||
| 3′ | 140.5 | 141.8 | ||
| 4′ | 140.5 | 141.5 | ||
| 5′ | 135.5 | 136.9 | ||
| 6′ | 130.7 | 130.4 | ||
| CO | 168.7 | 199.1 | ||
| CH 3 CO | 2.15 (s, 3H) | 2.52 (s, 3H) | 24.0 | 29.0 |
| OCH 2 CH3 | 4.49; 4.47; 4.34; 4.30; 4.54; 4.62 | 4.18; 4.16; 4.14; 4.12; 4.11; 4.10 | 63.7 | 74.9; 71.1; 70.7; 69.1; 69.0; 68.9 |
| OCH2 CH 3 | 1.29; 1.29; 1.29; 1.29; 1.32; 1.31 | 1.58; 1.40; 1.38; 1.36; 1.35 | 14.7 | 20.0; 19.9; 19.8; 19.7 |
| NH | 10.66 | |||
| OH | 3.27 | |||
Based on the comparison of the full width at half maximum (FWHM) of protons H-7, H-7vi, H-7, and H-7 of compounds 4a, 4b, 4c, and 4d (1.80 kHz for 4a, 0.99 kHz for 4b, 1.31 kHz for 4c, and 0.50 kHz for 4d), respectively, it could be concluded that there is a stronger π–π stacking interaction between molecules in 4a sample than in 4c, 4b, and 4d samples. Stronger π–π stacking interaction between molecules will lead to stronger 1H–1H dipolar couplings as well as the increase of anisotropic bulk magnetic susceptibility (ABMS), both of which will lead to the broadening of aromatic proton peaks [30].
We also calculated the values of the full width at half maximum (FWHM) of protons H-7 for compounds 4a′ and 4b′. The full width at half maximum of 4a′, which is of the order of 0.89 kHz, is greater than that of 4b′, which is of the order of 0.50 kHz.
The structures of compounds 4c and 4d were assigned based on their analytical and spectral data by following similar reasoning as earlier.
3 Antimicrobial activity
Benzothiazole 1, acetaminophen 3, and azo products 4 exhibited different degrees of antibacterial activities against the tested bacteria (Table 2).
Antimicrobial activity (MIC and MMC in µg/mL) of synthesized compounds as well as reference antimicrobial drugs
| Compounds | Inhibition parameters | Pseudomonas aeruginosa PA01 | Staphylococcus aureus 18 | Escherichia coli 64R | Staphylococcus aureus ATCC 25923 |
|---|---|---|---|---|---|
| 1a | MIC | 128 | >256 | >256 | >256 |
| MMC | >256 | — | — | — | |
| MMC/MIC | — | — | — | — | |
| 1b | MIC | 64 | 128 | 64 | 64 |
| MMC | >256 | >256 | >256 | >256 | |
| MMC/MIC | — | — | — | — | |
| 1c | MIC | 128 | >256 | >256 | >256 |
| MMC | >256 | — | — | — | |
| MMC/MIC | — | — | — | — | |
| 1d | MIC | >256 | >256 | >256 | >256 |
| MMC | — | — | — | — | |
| MMC/MIC | — | — | — | — | |
| 3 | MIC | >256 | >256 | >256 | >256 |
| MMC | — | — | — | — | |
| MMC/MIC | — | — | — | — | |
| 4a | MIC | 16 | 32 | 32 | 16 |
| MMC | 64 | 128 | 128 | 64 | |
| MMC/MIC | 4 | 4 | 4 | 4 | |
| 4b | MIC | 8 | 64 | 32 | 16 |
| MMC | 32 | 128 | 128 | 64 | |
| MMC/MIC | 4 | 2 | 4 | 4 | |
| 4c | MIC | 8 | 64 | 32 | 32 |
| MMC | 64 | >256 | >256 | >256 | |
| MMC/MIC | 8 | — | — | — | |
| 4d | MIC | 16 | 64 | 32 | 32 |
| MMC | >256 | >256 | >256 | >256 | |
| MMC/MIC | — | — | — | — | |
| 4a′ | MIC | 4 | 16 | 8 | 4 |
| MMC | 32 | 128 | 64 | 32 | |
| MMC/MIC | 8 | 8 | 8 | 8 | |
| 4b′ | MIC | 16 | 64 | 32 | 32 |
| MMC | >256 | >256 | >256 | >256 | |
| MMC/MIC | — | — | — | — | |
| Ciprofloxacin | MIC | 32 | 16 | 16 | 8 |
| MMC | 64 | 32 | 16 | 8 | |
| MMC/MIC | 2 | 2 | 1 | 1 |
—: not determined; MIC: minimum inhibitory concentration; MBC: minimum bactericidal concentration.
Compounds 1d and 3 did not show any antibacterial activity on all the tested microorganisms. Compounds 1a and 1c were active only against Pseudomonas aeruginosa PA01. Optimization of compound 1a by substitution of the benzene part of the benzothiazole ring at position 5 with a hydrophobic group (5-ethoxy-) resulted in improved antibacterial activities of compound 1b against P. aeruginosa, E. coli, and S. aureus compared with the 5-methoxy group (compound 1c) or to unsubstituted benzothiazole (compound 1a). Similar to our finding, a previous study has demonstrated that derivatives with 5-chloro, 5-propyl, 5-ethoxy, 5-bromo, and 5-trifluoromethyl groups at position 5 of the benzothiazole ring improved antibacterial activities against S. aureus, while the polar 5-OH substituent showed drastically decreased activity [31]. Benzothiazole 1b and reaction product 4 displayed antibacterial activities against all the tested bacteria. The antibacterial activities of reaction products are sometimes equal to or greater than those of ciprofloxacin used as a reference antibiotic. Overall, compound 4a′ was the most active, followed in a decreasing order by compounds 4b, 4a, 4c, 4d, 4b′, and 1b. Differences in the antibacterial activities of compounds 4 may be due to the nature of the substituents on the phenyl ring of the benzothiazole backbone. The lowest MIC value (4 μg/mL) corresponding to the greatest antibacterial activity was obtained with compound 4a′ against P. aeruginosa PA01 and Staphylococcus aureus ATCC 25923, while the lowest value of MBC (32 μg/mL) was recorded with compound 4a′ against P. aeruginosa PA01 and S. aureus ATCC 25923 as well as with compound 4b against P. aeruginosa PA01. The highest MBC value (128 μg/mL) was recorded with 4a and 4b against S. aureus 18 and Escherichia coli 64 R and with 4a′ on S. aureus 18. S. aureus 18 and E. coli 64 R were the most resistant bacteria, whereas P. aeruginosa PA01 and S. aureus ATCC 25923 were the most sensitive organisms. Compounds 1b, 4c, 4d, 4a′, and 4b′ (MBC/CMI >4) showed bacteriostatic activities on the sensitive bacteria, while compounds 4a and 4b showed bactericidal effects on all the tested bacteria. Several benzothiazole-based compounds have shown promising activities against several Gram-positive and Gram-negative bacteria and also against Mycobacterium tuberculosis [31]. It was found that their modes of antibacterial action are due to the inhibition of enzymes that are important for essential processes in the bacterial cells, such as cell wall synthesis, cell division, and DNA replication, or are important for different biosynthetic pathways of essential compounds in bacterial cells, such as the biosynthesis of histidine and biotin [32]. Therefore, we assume that the modes of antibacterial action of our compounds might be similar to those of analogous compounds already described in the literature.
4 Conclusion
This investigation proposes a useful method for the synthesis of heterocyclic azo dyes incorporating moieties of acetaminophen, which is an analgesic pharmacophore. Compounds 4 exhibited good antibacterial activity against all bacterial strains due to the presence of benzothiazole backbone and N═N group in the same molecular structural frame. A more extensive study is needed to confirm the preliminary results and to assess anti-inflammatory activity of this series of compounds.
5 Experimental
5.1 General information
Melting points were determined on a Buchii melting point apparatus. The thin layer chromatography (TLCs) was carried out on Eastman Chromatogram Silica Gel Sheets (13,181; 6,060) with fluorescent indicators. A mixture of hexane and ethyl acetate (4:6) was used as the eluent and iodine was used for the visualization of the chromatograms. The IR spectra were measured with a Fourier transform infrared spectrometer JASCO FT/IR-4100 and a Perkin Elmer FT-IR 2000 spectrometer. The UV spectra were recorded with a Beckman U-640 Spectrophotometer using samples’ solutions of concentration 5 × 10−5 mol/L. Combustion analyses were carried out with a Euro EA CHNSO analyzer from Hekatech Company, and the results were found to be in good agreement (±0.3%) with the calculated values. Positive ion electrospray mass spectra were recorded on a Waters Xevo TQD tandem quadrupole mass spectrometry system running in an MS scan mode, and 1 min of acquired spectra was combined and centroided. 1H-NMR spectra were recorded in DMSO-d 6 with a 400 MHz spectrometer RMN Bruker Advance 400. 13C-NMR spectra were recorded in DMSO-d 6 with a 100 MHz spectrometer RMN Bruker Advance 400. Tetramethylsilane (TMS) was used as the internal reference. Simulated 1H- and 13C(1H)-NMR-spectra were performed using http://www.nmrdb.org/spectral simulation software.
5.2 Preparation of the reagents and starting materials
All the reagents mentioned in this study were purchased from Aldrich and Fluka and were used without further purification.
5.3 Preparation of diazonium salt solution
In a similar manner as described earlier [20], dried sodium nitrite (0.69 g, 10 mmol) was slowly added over a period of 30 min to concentrated sulfuric acid (10 mL) with occasional stirring. The solution was cooled to 0–5°C. Compound 1 was dissolved in DMSO (10 mL) and cooled to 0–5°C. The nitrosyl sulfuric acid solution was added to the solution of 1, and the temperature was maintained between 0 and 5°C. The clear diazonium salt solution thus obtained consisting of the in situ-formed intermediate 2 was used immediately in the coupling reactions.
5.4 General procedure for the preparation of the coupling products 4a–d
Acetaminophen (1.51 g, 10 mmol) 3 was dissolved in DMSO (10 mL) and then cooled in an ice bath at 0–5°C. The previously prepared diazonium solution of 2 was added dropwise over 1 h, and then 15 mL of sodium acetate solution (10%) was added to the mixture. The pH of the mixtures ranged from 9 to 11. The solid precipitate was collected on a filter and crystallized from methanol to give the title compound.
5.4.1 N-(3-(Benzo[d]thiazol-2-yldiazenyl)-2-(benzo[d]thiazol-2-yldiazenyl)-4-hydroxyphenyl) acetamide heptahydrate (4a)
Compound 4a was obtained in 31% yield as brown powder; m.p. 262–264°C (dec); 1H-NMR (DMSO-d 6, 400 MHz): δ 8.45 (d, 1H, J = 2.4, H-7″), 8.14 (dd, 1H, J = 2.8 and 8.4, H-7), 8.05 (d, 1H, J = 8.4, H-4), 7.68 (ddd, 1H, J = 2.4, 6.8 and 9.2, H-5″), 7.65 (ddd, 1H, J = 2.4, 6.4 and 8.8, H-5), 7.61 (d, 1H, J = 7.6, H-6), 7.58 (ddd, 1H, J = 8.0, 6.4 and 1.6, H-6″), 7.54 (dd, 1H, J = 8.4 and 1.2, H-4″), 7.49 (d, 1H, J = 8.8, H-6’), 7.11 (d, 1H, J = 8.8, H-5’), 2.5 (s, 3H, COCH3); 13C-NMR (DMSO-d 6, 100 MHz): δ 175.5 (CO), 168.1 (C-2 and C-2′), 153.9 (C-4′), 152.2 (C-3a and C-3a″), 138.4 (C-2′ and C-3′), 133.8 (C-4a and C-4a″), 132.1 (C-1′), 128.6 (C-6), 127.4 (C-6″), 126.9 (C-5 and C-5″), 124.2 (C-4 and C-4″), 122.9 (C-7″), 122.0 (C-7), 118.9 (C-6′), 107.8 (C-5′), 23.8 (CH3); UV-Vis λ max (DMSO) (log ε): 221 (3.82), 267 (4.05), 322 (4.03), 340 (4.05), 376 (4.06), 384 (4.05), 413(3.98), 428 (3.94), 442 (3.91), 507 (3.68) nm; IR (KBr) ν max: 3,269 (O–H), 2,916–2,847 (Ar C–H), 1,663 (C═O), 1,528 (C═C), 1,496–1,433 (N═N), 1,312 (C–S), 1,239 (C–O), 881–645 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 581 (2), 508 (2), 507 (14), 447(80), 449 (53), 342 (75), 309 (82), 281 (75), 147 (45), 133 (100), 98 (3); anal. calcd for C22H27N7O8S2: C, 45.43; H, 4.68; N, 16.86; S, 11.02. Found: C, 45.39; H, 4.68; N, 16.87; S, 11.03. Rf = 0.54.
5.4.2 1,2-Bis(benzo[d]thiazol-2-yl)diazene trihydrate (4a′)
Compound 4a′ was obtained in 11% as dark red powder; m.p. ≥360°C (dec) {Lit. m.p. 295°C, [24]}; 1H-NMR (DMSO-d 6, 400 MHz): δ 8.15 (d, 2H, J = 2.4, H-7 and H-7′), 7.62 (ddd, 2H, J = 8.8, 7.8 and 1.6, H-4 and H-4′), 7.55 (ddd, 2H, J = 7.8, 8.8 and 1.6, H-6 and H-6′), 7.66 (d, 2H, J = 2.4, H-5 and H-5′); 13C-NMR (DMSO-d 6, 100 MHz): δ 198.6 (C-2 and C-2′), 153.9 (C-4a and C-4a′), 132.1 (C-3a and C-3a′), 124.5 (C-5 and C-5’), 120.7 (C-6 and C-6′), 118.9 (C-7 and C-7′); 105.4 (C-4 and C-4′); UV-Vis λ max (DMSO) (log ε): 219 (3.83), 229 (3.82), 266 (4.01), 284 (3.97), 315 (4.02), 321 (4.02), 344 (4.07), 356 (4.09), 467 (3.78), 492 (3.72) nm; IR (KBr) ν max: 3,273 (O–H), 1,661 (C═N), 1,532 (C═C), 1,498–1,419 (N═N), 888–610 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 349 (8), 335 (3), 291 (13), 299 (6), 233 (34), 175 (41), 116 (61), 73 (74), 57 (100); anal. calcd for C14H14N4O3S2: C, 47.99; H, 4.03; N, 15.99; S, 18.30. Found: C, 47.97; H, 3.99; N, 15.97; S, 18.32. Rf = 0.69.
5.4.3 N-(2-(6-Ethoxy-5-((6-ethoxybenzo[d]thiazol-2-yl)diazenyl)benzo[d]thiazol-2-yl)diazenyl)-3-((6-ethoxy-5-((6-ethoxybenzo[d]thiazol-2-yl)diazenyl)benzo[d]thiazol-2-yl)diazenyl)-5,6-bis((6-ethoxybenzo[d]thiazol-2-yl)diazenyl)-4-hydroxyphenyl)acetamide hexahydrate (4b)
Compound 4b was obtained in 47% yield as red powder; m.p. 197–199°C (dec); 1H-NMR (DMSO-d 6, 400 MHz): δ 8.11 (d, 1H, J = 2.8, H-4iv), 8.00 (s, 1H, H-7), 8.02 (s, 1H, H-7v), 7.91 (d, 1H, J = 9.2, H-4″′), 7.71 (d, 1H, J = 2.0, H-7″′), 7.68 (d, 1H, J = 3.6, H-7″), 7.65 (d, 2H, J = 8.8, H-4″ and H-4vi), 7.62 (d, 1H, J = 6.4, H-7vi), 7.61 (s, 1H, H-4v), 7.58 (s, 1H, H-4), 7.16 (dd, 2H, J = 9.2 and 2.8, H-5″′ and H-5iv), 7.15 (d, 1H, J = 2.4, H-7iv), 7.09 (d, 2H, J = 8.8, H-5″ and H-5vi), 4.18, 4.16, 4.14, 4.12, 4.11, 4.10, 4.08 (OCH 2 CH3); 1.58, 1.40, 1.38, 1.36, 1.35 (OCH2 CH 3 ); 2.05 (s, 3H, COCH3); 13C-NMR (DMSO-d 6, 100 MHz): δ (see Table 1); UV-Vis λ max (DMSO) (log ε): 211 (4.45), 214 (4.47), 229 (4.51), 238 (4.51), 258 (4.53), 2.69 (4.65), 279 (4.57), 309 (4.54), 364 (4.58), 378 (4.56), 416 (4.62) nm; IR (KBr) ν max: 3,281 (O–H), 2,980–2,933 (ArC–H), 1,657 (C═O), 1,599 (C═N), 1,556 (C═C), 1,488–1,456 (N═N), 1,263 (C–S), 1,211 (C–O), 899–519 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 1,492 (9), 1,453 (9), 1,428 (17), 1,404 (17), 1,379 (15), 1,353 (18), 1,323 (16), 1,293 (11), 1,238 (17), 955 (32), 728 (69), 659 (71), 549 (72), 486 (52); anal. calcd for C62H63N19O14S6: C, 49.96; H, 4.26; N, 17.85; S, 12.90. Found: C, 49.98; H, 4.28; N, 17.81; S, 12.88. Rf = 0.39.
5.4.4 2,2′-Diazene-1,2-diylbis(5-ethoxy-1,3-benzothiazole) monohydrate (4b′)
Compound 4b′ was obtained in 13% yield as a brown powder; m.p. 182–184°C (dec); 1H-NMR (DMSO-d 6, 400 MHz): δ 8.01 (d, 2H, J = 9.0, H-4 and H-4′), 7.91 (m, 2H, H-7 and H-7′), 7.09 (d, 2H, J = 8.8, H-5 and H-5′), 4.13 (s, 2H, CH 2 CH3), 1.23 (s, 3H, CH2 CH 3 ); 13C-NMR (DMSO-d 6, 100 MHz): δ 198.6 (C-2 and C-2′), 149.9 (C-6 and C-6′), 136.1 (C-3a and C-3a′), 125.2 (C-4a and C-4a′), 122.8 (C-4 and C-4′), 118.2 (C-5 and C-5′), 105.4 (C-7 and C-7′), 63.9 (CH 2 CH3), 14.6 (CH2 CH 3 ); UV-Vis: λ max (DMSO) (log ε): 216 (3.90), 258 (4.01), 271 (4.22), 279 (4.10), 291 (4.04), 314 (4.19), 322 (4.21), 332 (4.16), 352 (4.19), 359 (4.19), 384 (4.03), 429 (4.01) nm; IR (KBr) ν max 3,275 (N–H), 2,979–2,936 (ArC–H), 1,661 (C═N), 1,599 (C═C), 1,488–1,457 (N═N), 1,263 (C–S), 1,228 (C–O), 900–561 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 599 (33), 583 (2), 569 (2), 549 (2), 535 (3), 477 (3), 410 (18), 400 (13), 380 (22), 357 (28), 343 (22), 316 (70), 201 (70); anal. calcd for C18H22N4O11S4: C, 36.12; H, 3.70; N, 9.36; S, 21.42. Found: C, 36.09; H, 3.69; N, 9.34; S, 21.39. Rf = 0.378.
5.4.5 N-(4-Hydroxy-3-((6-methoxybenzo[d]thiazol-2-yl)diazenyl)phenyl)acetamide hexahydrate (4c)
Compound 4c was obtained in 51% yield as brown powder; m.p. 197–199°C (dec); 1H-NMR (DMSO-d 6, 400 MHz): δ 8.11 (d, 1H, J = 2.0, H-2′), 8.02 (d, 1H, J = 9.0, H-4), 7.70 (d, 1H, J = 2.4, H-7), 7.63 (dd, 1H, J = 8.8 and 2.4, H-6′), 7.18 (dd, 1H, J = 8.8 and 2.4, H-5), 7.09 (d, 1H, J = 8.8, H-5′), 3.89 (s, 3H, OCH3), 2.04 (s, 3H, COCH3); 13C-NMR (DMSO-d 6, 100 MHz): δ 173.1 (CO), 168.1 (C-2), 159.1 (C-6), 153.3 (C-3a), 146.8 (C-4′), 138.4 (C-1′), 135.8 (C-3′), 132.0 (C-4a), 127.9 (C-4), 125.1 (C-6′), 118.7 (C-5′), 116.6 (C-5), 108.0 (C-2′), 105.1 (C-7), 55.8 (OCH3), 23.8 (COCH 3 ); UV-Vis λ max (DMSO) (log ε): 227 (4.06), 257 (4.12), 272 (4.26), 290 (4.09), 295 (4.08), 302 (4.12), 325 (4.19), 348 (4.18), 355 (4.19), 399 (4.23), 445 (4.25), 486 (4.22) nm; IR (KBr) ν max: 3,282 (O–H and N–H), 2,941–2,834 (ArC–H), 1,658 (C═O), 1,598 (C═N), 1,555 (C═C), 1,482–1,434 (N═N), 1,264 (C–S), 1,228 (C–O), 910–510 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 448 (11), 429 (11), 409 (42), 385 (10), 316 (100), 300 (22), 281 (19), 216 (70), 202 (14), 192 (21), 150 (70); anal. calcd for C16H26N4O9S: C, 42.66; H, 5.82; N, 12.44; S, 7.12. Found: C, 42.63; H, 5.80; N, 12.41; S, 7.10. Rf = 0.30.
5.4.6 N-(3-((6-Chlorobenzo[d]thiazol-2-yl)diazenyl)-4-hydroxyphenyl)acetamide sulfate (4d)
Compound 4d was obtained in 61% yield as brown powder; m.p. 206–208°C (dec); 1H-NMR (DMSO-d 6, 400 MHz): δ 8.20 (d, 1H, J = 2.8, H-4), 8.11 (d, 1H, J = 8.0, H-7), 7.74 (s, 1H, NH), 7.70 (m, 1H, H-8), 7.67 (m, 1H, H-6), 7.65 (s, 1H, OH), 7.55 (d, 1H, J = 8.0, H-4′), 7.51 (m, 1H, H-3′); 13C-NMR (DMSO-d 6, 100 MHz): δ 198.8 (CO), 168.3 (C-2), 154.3 (C-2′), 150.5 (C-3a), 138.6 (C-4a), 135.7 (C-5′), 131.9 (C-1′), 127.0 (C-5), 126.7 (C-6), 122.1 (C-4 and C-7), 107.7 (C-4′), 105.3 (C-3′), 84.6 (C-6′), 24.0 (COCH 3 ); UV-Vis: λ max (DMSO) (log ε): 216 (3.45), 233 (3.48), 267 (3.75), 287 (3.87), 297 (3.91), 309 (3.93), 343 (3.91), 373 (3.88), 390 (3.81), 402 (3.74), 504 (3.28), 529 (3.15), 557 (2.89) nm; IR (KBr) ν max: 3,292 (O–H), 1,664 (C═O), 1,585 (C═N), 1,525 (C═C), 1,496–1,405 (N═N), 1,256 (C–S), 1,206 (C–O), 882–507 (Ar def C═N str thiazole) cm−1; ms: (ESI+) m/z (%) 442 (1), 425 (1), 409 (8), 381(1), 357 (2), 353 (4), 316 (70), 304 (10), 289 (5), 202 (30), 174 (22), 148 (41); anal. calcd for C15H13ClN4O6S2: C, 40.50; H, 2.95; Cl, 7.97; N, 12.59; S, 14.41. Found: C, 40.52; H, 2.93; N, 12.58; S, 14.38. Rf = 0.73.
6 Biological assay
6.1 Antimicrobial evaluation
6.1.1 Tested microorganisms
The antimicrobial activity was performed against four bacterial and three fungal species. The selected microorganisms were two Gram-positive S. aureus ATCC 25923 and S. aureus 18 and two Gram-negative P. aeruginosa PA01 and E. coli 64R. These microorganisms were taken from our laboratory collection. The bacterial species were grown at 37°C and maintained on a nutrient agar (NA, Conda) slant.
6.1.2 Determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)
The antibacterial activity was performed by determining the MICs and MBCs as previously described [33]. MICs of synthesized compounds were determined by broth micro dilution. Each test sample was dissolved in dimethylsulfoxide (DMSO) to give a stock solution. This was serially diluted twofold in Mueller-Hinton broth (MHB) to obtain a concentration range of 512–0.25 μg/mL. Then, 100 µL of each sample concentration was added to respective wells (96-well micro plate) containing 90 µL of MHB and 10 µL of inoculums to give final concentration ranges of 256 to 0.125 μg/mL. The final concentration of microbial suspensions was 106 CFU/mL for bacteria. Dilution of ciprofloxacin (Sigma-Aldrich, Steinheim, Germany) was used as a positive control. Broth with 10 µL of DMSO was used as a negative control. The MIC values of samples were determined by adding 50 μL of a 0.2 mg/mL p-iodonitrotetrazolium violet solution followed by incubation at 37°C for 30 min. Viable microorganisms reduced the yellow dye to pink color. MIC values were defined as the lowest sample concentrations that prevented this change in color, indicating a complete inhibition of bacterial growth [33]. For the determination of MMC values, a portion of liquid (5 μL) from each well that showed no growth of microorganism was plated on Mueller-Hinton agar and incubated at 37°C for 24 h. The lowest concentrations that yielded no growth after this subculturing were taken as the MBC values [33]. All the tests were performed in triplicate.
Acknowledgments
J.T. is grateful to Gilbert Kirsch and Véronique Vaillant for running the NMR spectra.
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Funding information: The authors state no funding involved.
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Conflict of interest: The authors state no conflict of interest.
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Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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