Mariam Omaraa,
Mohamed Hagras*b,
Mohamed M. Elsebaie
b,
Nader S. Abutalebcd,
Hanzada T. Nour El-Din
e,
Maria O. Mekhail
f,
Ahmed S. Attiaeg,
Mohamed N. Seleemch,
Marwa T. Sarga and
Abdelrahman S. Mayhoubbi
aDepartment of Pharmaceutical Organic Chemistry, College of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
bDepartment of Pharmaceutical Organic Chemistry, College of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. E-mail: m.hagrs@azhar.edu.eg
cDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
dDepartment of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
eDepartment of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
fPharmD-Clinical Pharmacy Undergraduate Program, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
gDepartment of Microbiology and Immunology, School of Pharmacy, Newgiza University, Giza, Egypt
hCenter for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
iNanoscience Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
First published on 6th July 2023
Antimicrobial resistance has become a concern as a worldwide threat. A novel scaffold of phenylthiazoles was recently evaluated against multidrug-resistant Staphylococci to control the emergence and spread of antimicrobial resistance, showing good results. Several structural modifications are needed based on the structure–activity relationships (SARs) of this new antibiotic class. Previous studies revealed the existence of two key structural features essential for the antibacterial activity, the guanidine head and lipophilic tail. In this study, a new series of twenty-three phenylthiazole derivatives were synthesized utilizing the Suzuki coupling reaction to explore the lipophilic part. The in vitro antibacterial activity was evaluated against a range of clinical isolates. The three most promising compounds, 7d, 15d and 17d, with potent MIC values against MRSA USA300 were selected for further antimicrobial evaluation. The tested compounds exhibited potent results against the tested MSSA, MRSA, and VRSA strains (concentration: 0.5 to 4 μg mL−1). Compound 15d inhibited MRSA USA400 at a concentration of 0.5 μg mL−1 (one-fold more potent than vancomycin) and showed low MIC values against ten clinical isolates, including linezolid-resistant strain MRSA NRS119 and three vancomycin-resistant isolates VRSA 9/10/12. Moreover, compound 15d retained its potent antibacterial activity using the in vivo model by the burden reduction of MRSA USA300 in skin-infected mice. The tested compounds also showed good toxicity profiles and were found to be highly tolerable to Caco-2 cells at concentrations of up to 16 μg mL−1, with 100% of the cells remaining viable.
Previously, a novel antibacterial scaffold was discovered by our research group containing n-butylphenylthiazole (I) (Fig. 1). It showed a MIC value of 4.8 μg mL−1 against MRSA and was considered as a lead compound for further development. The lead I has two essential features: a lipophilic moiety (blue color, Fig. 1) and a cationic moiety (red color, Fig. 1). During the optimization of the lead compound, the replacement of the n-butyl group with a phenyl ring (II) decreased the MIC value to 2.4 μg mL−1 (Fig. 1).17 Meanwhile, rigidification by acetylene linked to a heteroaromatic system (III) afforded an improvement of the antibacterial activity (MIC = 2 μg mL−1).18 In this study, we aim to further advance the lead developments based on the previous results by utilizing two new lead optimization strategies: scaffold simplification and bioisosteric replacement techniques to develop novel and potent derivatives. Furthermore, we aim to investigate the structure–activity relationship of novel phenylthiazoles using the Suzuki–Miyaura coupling reaction (Fig. 1).19–24
Our compounds exhibited potent antibacterial activity against the tested MSSA, MRSA, and VRSA strains, inhibiting their growth at concentrations ranging from 0.5 to 4 μg mL−1. Notably, they maintained their potency against linezolid-resistant and vancomycin-resistant staphylococcal strains. Compound 15d displayed the most potent activity against the tested strains, inhibiting their growth at concentrations ranging from 0.5 to 1 μg mL−1 (Table 3). Interestingly, the compounds maintained their potency against linezolid-resistant and vancomycin-resistant staphylococcal strains, suggesting that they do not share the same resistance mechanism with linezolid or vancomycin.
Bacterial isolates | Compounds/control antibiotics | ||||
---|---|---|---|---|---|
7d | 15d | 17d | Linezolid | Vancomycin | |
MSSA ATCC 6538 | 2 | 1 | 4 | 1 | 0.5 |
MSSA NRS 107 | 4 | 1 | 4 | 0.5 | 1 |
MRSA NRS 119 | 4 | 1 | 4 | 64 | 2 |
MRSA USA 400 | 2 | 0.5 | 2 | 2 | 1 |
MRSA USA 500 | 4 | 1 | 4 | 1 | 2 |
MRSA USA 700 | 2 | 1 | 4 | 1 | 1 |
VRSA 9 | 2 | 0.5 | 4 | 1 | >64 |
VRSA 10 | 2 | 1 | 4 | 2 | 64 |
VRSA 12 | 4 | 1 | 4 | 1 | >64 |
S. epidermidis NRS 101 | 2 | 0.5 | 2 | 1 | 1 |
Bacterial isolates | Compounds/control antibiotics | ||||
---|---|---|---|---|---|
7d | 15d | 17d | Linezolid | Vancomycin | |
S. pneumoniae ATCC 51916 | 4 | 1 | 4 | 1 | 2 |
S. pneumoniae ATCC 700677 | 4 | 1 | 4 | 1 | 1 |
E. faecalis ATCC 51299 | 4 | 2 | 4 | 1 | 64 |
E. faecium ATCC 700221 | 2 | 1 | 2 | 1 | >64 |
L. monocytogenes ATCC 19111 | 4 | 1 | 8 | 1 | 1 |
C. difficile ATCC BAA 1870 | 4 | 2 | 2 | NT | 1 |
Among the tested compounds, compound 15d displayed the most potent activity among the tested compounds with MIC values ranging from 1 μg mL−1 to 2 μg mL−1. Compounds 7d and 17d also exhibited strong activity, inhibiting the bacterial strains at MICs ranging from 2 to 8 μg mL−1. Importantly, our compounds maintained their potency against vancomycin-resistant enterococcal strains, suggesting that they are not subjected to the same resistance mechanism as vancomycin.
Bacterial burdens in the skin lesions were estimated, and it was observed that compound 15d resulted in a decrease in the MRSA burden in the mice skin lesions by almost one log10 cycle, which was not significant compared to the FA treatment that generated around three log10 reduction as compared to the vehicle-treated mice (Fig. 5B). However, compound 15d demonstrated weaker activity than FA in controlling the systemic dissemination of S. aureus, as evidenced by the low reduction in the bacterial burden detected in the spleens of infected mice compared to the vehicle-treated group (Fig. 5C). These results suggest that while compound 15d shows promising potential in controlling S. aureus skin infection, its efficacy in controlling systemic dissemination is weaker than that of FA.
B. In situ: In a 75 mL sealed tube with 15 mL EtOH, compound 2a (350 mg, 1.39 mmol, 1 eq.), tetrahydroxydiboron (373.94 mg, 4.17 mmol, 3 eq.), XPhos-PdG2 (11 mg, 14 μmol, 0.01 eq.), XPhos (13.23 mg, 28 μmol, 0.02 eq.), and NaOAc (342 mg, 4.17 mmol, 3 eq.) were added respectively under N2 flushing. The reaction mixture was then heated to 80 °C until the solution changed into a red color, and a precipitation was formed, indicating that the boronic acid derivative was formed and confirmed by TLC. Then, a solution of K2CO3 (577 mg, 4.17 mmol, 3 eq.) in 5 mL distilled water was added to the reaction mixture, followed by the addition of the second halide (2.8 mmol, 2 eq.). The reaction mixture was further heated to 80 °C for 15 h. After cooling to room temperature, the reaction mixture was passed through Celite, followed by ethyl acetate (2 × 50 mL) and dried over anhydrous magnesium sulphate. The organic materials were then concentrated under reduced pressure. The crude materials were purified via silica gel flash column chromatography using hexane–ethyl acetate (7:
3).
1-(2-(4-Isobutylphenyl)-4-methylthiazol-5-yl)ethan-1-one (3c): Following the general procedure (method A), compound 3c was obtained as a light-brown oil (240 mg, 86%). 1H NMR (DMSO-d6) δ: 8.01 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 2.71 (s, 3H), 2.62 (s, 3H), 2.52 (d, J = 7.2 Hz, 2H), 1.93–1.83 (m, 1H), 0.90 (d, J = 8.2 Hz, 6H); 13C NMR (DMSO-d6); δ 200.6, 148.5, 142.3, 137.0, 135.2, 129.7, 126.6, 117.2, 44.8, 30.1, 25.2, 22.6, 17.5; MS (m/z); 273.
1-(2-(4-Cyclopropylphenyl)-4-methylthiazol-5-yl)ethan-1-one (4c): Following the general procedure (method A), compound 4c was obtained as a light-brown oil (226 mg, 86%). 1H NMR (DMSO-d6) δ: 7.98 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 1.99–194 (m, 1H), 1.01–0.97 (m, 2H), 0.75–0.72 (m, 2H); 13C NMR (DMSO-d6); δ 196.0, 153.4, 146.0, 137.0, 136.1, 135.1, 126.03, 117.0, 25.2, 17.5, 15.4, 10.1; MS (m/z); 257.
1-(4-Methyl-2-(4′-methyl-[1,1′-biphenyl]-4-yl)-thiazol-5-yl)ethan-1-one (5c): Following the general procedure (method A), compound 5c was obtained as a yellow oil (293 mg, 93%). 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 2.61 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H); MS (m/z); 307.
1-(4-Methyl-2-(3′-methyl-[1,1′-biphenyl]-4-yl)thiazol-5-yl)ethan-1-one (6c): Following the general procedure (method A), compound 6c was obtained as a light brown oil (246 mg, 78%). 1H NMR (DMSO-d6) δ: 8.20 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 2.67 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H); MS (m/z); 307.
1-(2-(3′-Methoxy-[1,1′-biphenyl]-4-yl)-4-methylthiazol-5-yl)ethan-1-one (7c): Following the general procedure (method B), compound 7c was obtained as a yellow oil (193 mg, 43%). 1H NMR (DMSO-d6) δ: 8.08 (d, J = 8 Hz, 2H), 7.85 (d, J = 8 Hz, 2H), 7.74 (t, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.27 (s, 1H), 7.01 (d, J = 8 Hz, 1H), 3.85 (s, 3H), 2.73 (s, 3H), 2.58 (s, 3H); 13C NMR (DMSO-d6); δ: 192.1, 168.5, 160.3, 158.7, 143.2, 140.8, 132.6, 131.7, 130.6, 128.1, 127.5, 119.5, 114.3, 112.6, 55.6, 30.6, 18.6; MS (m/z); 323.
1-(2-(2′-Methoxy-[1,1′-biphenyl]-4-yl)-4-methylthiazol-5-yl)ethan-1-one (8c): Following the general procedure (method B), compound 8c was obtained as a buff oil (188 mg, 42%). 1H NMR (DMSO-d6) δ: 8.03 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H), 7.41–7.36 (m, 2H), 7.16 (t, J = 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 3.79 (s, 3H), 2.72 (s, 3H), 2.57 (s, 3H); 13C NMR (DMSO-d6); δ: 191.8, 168.8, 158.6, 156.6, 141.7, 132.5, 131.0, 130.7, 130.6, 130.0, 129.0, 126.7, 121.3, 112.3, 55.0, 30.8, 18.6; MS (m/z); 323.
Methyl 4′-(5-acetyl-4-methylthiazol-2-yl)-[1,1′-biphenyl]-2-carboxylate (9c): Following the general procedure (method B), compound 9c was obtained as a yellow oil (293 mg, 60%). 1H NMR (DMSO-d6) δ: 8.05 (d, J = 8 Hz, 2H), 7.82 (d, J = 8 Hz, 1H), 7.69 (t, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 7.50 (d, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz, 2H), 3.64 (s, 3H), 2.73 (s, 3H), 2.58 (s, 3H); 13C NMR (DMSO-d6); δ: 191.1, 168.6, 158.7, 144.0, 140.7, 132.6, 131.5, 130.9, 130.0, 129.6, 128.5, 126.9, 128.5, 126.9, 52.5, 30.9, 18.6; MS (m/z); 351.
1-(4-Methyl-2-(4-(naphthalen-2-yl)phenyl)-thiazol-5-yl)ethan-1-one (10c): Following the general procedure (method A), compound 10c was obtained as a yellow oil (302 mg, 86%). 1H NMR (DMSO-d6) δ: 8.30 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.90 (s, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.58 (t, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 2.69 (s, 3H), 2.26 (s, 3H); MS (m/z); 343.
1-(2-(4-Benzofuran-2-yl)phenyl)-4-methylthiazol-5-yl)ethan-1-one (11c): Following the general procedure (method A), compound 14c was obtained as a yellow oil (280 mg, 82%). 1H NMR (DMSO-d6) δ: 8.26 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 2.67 (s, 3H), 2.25 (s, 3H); MS (m/z); 333.
1-(2-(4-Benzo[b]thiophen-2-yl)phenyl)-4-methylthiazol-5-yl)ethan-1-one (12c): Following the general procedure (method A), compound 12c was obtained as a yellow oil (290 mg, 81%). 1H NMR (DMSO-d6) δ: 8.23 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 2.67 (s, 3H), 2.25 (s, 3H); MS (m/z); 349.
1-(2-(4-Furan-2-yl)phenyl)-5-methylthiazol-5-yl)ethan-1-one (13c): Following the general procedure (method A), compound 13c was obtained as a yellow oil (250 mg, 86%). 1H NMR (DMSO-d6) δ: 8.01 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4 Hz, 1H), 2.71 (s, 3H), 2.56 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.3, 158.7, 142.9, 136.8, 132.4, 131.3, 129.3, 127.7, 127.5, 126.4, 125.4, 30.8, 18.6; MS (m/z); 283.
1-(2-(4-Furan-3-yl)phenyl)-5-methylthiazol-5-yl)ethan-1-one (14c): Following the general procedure (method A), compound 14c was obtained as a pale-yellow oil (244 mg, 84%). 1H NMR (DMSO-d6) δ: 8.29 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 6.4 Hz, 1H), 2.59 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.6, 158.7, 140.7, 138.2, 132.3, 131.5, 129.8, 127.9, 127.5, 125.5, 122.9, 30.8, 18.6; MS (m/z); 283.
1-(4-Methyl-2-(4-(thiophen-2-yl)phenyl)thiazol-5-yl)ethan-1-one (15c): Following the general procedure (method B), compound 15c was obtained as a yellow oil (263 mg, 63%). 1H NMR (DMSO-d6) δ: 8.01 (d, J = 8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 7.66–7.64 (m, 2H), 7.20–7.18 (m, 1H), 2.70 (s, 3H), 2.56 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.3, 158.7, 142.5, 136.8, 132.4, 131.3, 129.3, 127.7, 127.5, 126.4, 125.4, 30.8, 18.6; MS (m/z); 299.
1-(4-Methyl-2-(4-(thiophen-3-yl)phenyl)thiazol-5-yl)ethan-1-one (16c): Following the general procedure (method B), compound 16c was obtained as a yellow oil (210 mg, 50%). 1H NMR (DMSO-d6) δ: 8.02 (d, J = 8 Hz, 2H), 7.98 (s, 1H), 7.86 (d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 2.7 (s, 3H), 2.55 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.4, 158.5, 140.7, 136.2, 132.5, 132.3, 131.1, 127.9, 127.2, 126.5, 122.9, 30.8, 18.6; MS (m/z); 299.
1-(4-Methyl-2-(4-(5-methylthiophen-3-yl)phenyl)thiazol-5-yl)ethan-1-one (17c): Following the general procedure (method B), compound 17c was obtained as a brown oil (180 mg, 41%). 1H NMR (DMSO-d6) δ: 8.01 (d, J = 8 Hz, 2H), 7.82 (d, J = 8 Hz, 2H), 7.77 (s, 1H), 7.33 (s, 1H), 2.71 (s, 3H), 2.57 (s, 3H), 2.39 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.6, 158.7, 141.0, 140.3, 138.4, 132.3, 130.9, 127.5, 126.9, 124.8, 120.8, 30.9, 18.6, 15.5; MS (m/z); 313.
1-(2-(4-(4,5-Dimethylthiophen-3-yl)phenyl)-4-methylthiazol-5-yl)ethan-1-one (18c): Following the general procedure (method B), compound 18c was obtained as a yellow oil (305 mg, 67%). 1H NMR (DMSO-d6) δ: 8.03 (d, J = 8 Hz, 2H), 7.52 (d, J = 8 Hz, 2H), 7.32 (s, 1H), 2.72 (s, 3H), 2.57 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H); 13C NMR (DMSO-d6); δ 191.0, 168.4, 158.5, 142.3, 140.5, 134.3, 132.5, 131.4, 131.0, 129.5, 127.0, 120.4, 30.8, 18.5, 13.9, 13.4; MS (m/z); 327.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N-methylthiophene-2-sulfonamide (19c): Following the general procedure (method B), compound 19c was obtained as a yellow oil (130 mg, 23%); 1H NMR (DMSO-d6) δ: 8.06 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.79 (brs, 1H), 7.72 (d, J = 4 Hz, 1H), 7.62 (d, J = 4 Hz, 1H), 2.71 (s, 3H), 2.57 (s, 3H), 2.56 (s, 3H); 13C NMR (DMSO-d6) δ: 191.1, 167.9, 158.7, 148.0, 140.1, 135.2, 133.2, 132.9, 132.7, 127.8, 127.1, 125.6, 30.9, 29.3, 18.6; MS (m/z) 392.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N-ethylthiophene-2-sulfonamide (20c): Following the general procedure (method B), compound 20c was obtained as a yellow oil (150 mg, 27%); 1H NMR (DMSO-d6) δ: 8.06 (d, J = 8.4 Hz, 2H), 7.90 (brs, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 4 Hz, 1H), 7.61 (d, J = 4 Hz, 1H), 2.94 (m, 2H), 2.73 (s, 3H), 2.58 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6) δ: 191.1, 167.9, 158.7, 147.8, 141.5, 135.2, 132.96, 132.90, 132.6, 127.8, 127.1, 125.6, 38.3, 30.9, 18.6, 15.1; MS (m/z) 406.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N-isopropylthiophene-2-sulfonamide (21c): Following the general procedure (method B), compound 21c was obtained as a yellow oil (160 mg, 28%); 1H NMR (DMSO-d6) δ: 8.07 (d, J = 8.4 Hz, 2H), 7.95 (brs, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 4 Hz, 1H), 7.61 (d, J = 4 Hz, 1H), 3.46 (m, 1H), 2.72 (s, 3H), 2.58 (s, 3H), 1.07 (m, 6H); 13C NMR (DMSO-d6) δ: 191.1, 167.9, 158.7, 147.6, 142.9, 135.3, 132.89, 132.80, 132.6, 127.8, 127.0, 125.5, 46.2, 30.9, 23.6, 19.0; MS (m/z) 421.
5-(4-(5-Acetyl-4-methylthiazol-2-yl)phenyl)-N-butylthiophene-2-sulfonamide (22c): Following the general procedure (method B), compound 22c was obtained as a yellow oil (175 g, 30%); 1H NMR (DMSO-d6) δ: 8.07 (d, J = 8.4 Hz, 2H), 7.92 (brs, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 4 Hz, 1H), 7.61 (d, J = 4 Hz, 1H), 2.92 (m, 2H), 2.73 (s, 3H), 2.58 (s, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6) δ: 191.1, 167.9, 158.7, 147.8, 141.5, 135.2, 132.96, 132.90, 132.6, 127.8, 127.1, 125.6, 42.9, 31.4, 30.9, 19.7, 18.6, 13.9; MS (m/z) 434.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N-(pentan-2-yl)thiophene-2-sulfonamide (23c): Following the general procedure (method B), compound 23c was obtained as a yellow oil (134 mg, 22%); 1H NMR (DMSO-d6) δ: 8.08 (d, J = 8.4 Hz, 2H), 7.89 (brs, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 4 Hz, 1H), 7.61 (d, J = 4 Hz, 1H), 3.30–3.20 (m, 1H), 2.72 (s, 3H), 2.58 (s, 3H), 1.33–1.21 (m, 4H), 0.99–0.97 (m, 3H), 0.79–0.77 (m, 3H); 13C NMR (DMSO-d6) δ: 191.3, 167.9, 158.7, 147.5, 143.2, 135.3, 132.9, 132.7, 132.6, 127.9, 127.0, 125.5, 49.8, 30.9, 21.5, 18.8, 18.6, 14.1; MS (m/z) 448.6.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N-hexylthiophene-2-sulfonamide (24c): Following the general procedure (method B), compound 24c was obtained as a yellow oil (144 mg, 22%); 1H NMR (DMSO-d6) δ: 8.06 (d, J = 8.4 Hz, 2H), 7.92 (brs, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 4 Hz, 1H), 7.60 (d, J = 4 Hz, 1H), 2.90 (q, J = 6.8 Hz, 2H), 2.72 (s, 3H), 2.58 (s, 3H), 1.45–1.38 (m, 2H), 1.28–1.16 (m, 6H), 0.83–0.80 (t, J = 6.4 Hz, 3H); 13C NMR (DMSO-d6) δ: 191.0, 167.9, 158.7, 147.8, 141.6, 135.2, 132.9, 132.6, 132.2, 127.8, 127.0, 125.5, 43.2, 31.2, 30.9, 29.2, 26.1, 22.4, 18.6, 14.3; MS (m/z) 462.11.
5-[4-(5-Acetyl-4-methylthiazol-2-yl)phenyl]-N,N-diethylthiophene-2-sulfonamide (25c): Following the general procedure (method B), compound 25c was obtained as a light yellow oil (280 mg, 46%); 1H NMR (DMSO-d6) δ: 8.06 (d, J = 8.4 Hz, 2H), 7.9 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 4 Hz, 1H), 7.69 (d, J = 4 Hz, 1H), 3.25 (q, J = 7.2 Hz, 4H), 2.72 (s, 3H), 2.58 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H); 13C NMR (DMSO-d6) δ: 192.2, 167.9, 158.7, 148.2, 139.6, 135.1, 133.3, 132.9, 132.7, 127.8, 127.1, 125.8, 42.9, 30.9, 18.6, 14.6; MS (m/z) 434.
2-(1-(2-(4-Isobutylphenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (3d): Light-brown solid (90 mg, 73%); mp 117–119 °C; 1H NMR (DMSO-d6) δ: 8.01 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.70 (brs, 2H), 5.50 (brs, 2H), 2.63 (s, 3H), 2.52 (d, J = 8.4 Hz, 2H), 2.23 (s, 3H), 1.90–1.85 (m, 1H), 0.91 (d, J = 8.4 Hz, 6H); 13C NMR (DMSO-d6); δ 160.2, 155.4, 153.4, 148.5, 137.0, 135.2, 129.7, 126.6, 117.2, 44.8, 30.1, 25.28, 22.6, 17.5; HPLC purity 95.1% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-Cyclopropylphenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (4d): Light-brown solid (87 mg, 74%); mp 121–123 °C; 1H NMR (DMSO-d6) δ: 7.98 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.71 (brs, 2H), 5.50 (brs, 2H), 2.62 (s, 3H), 2.23 (s, 3H), 1.99–1.94 (m, 1H), 1.01–0.97 (t, J = 8.4 Hz, 2H), 0.74–0.72 (t, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6); δ 160.2, 155.4, 153.4, 148.6, 145.0, 137.0, 136.1, 126.7, 126.0, 25.2, 17.5, 15.4, 10.1; HPLC purity 99% (acetonitrile-3% TEA, 1:
4).
2-(1-(4-Methyl-2-(4′-methyl-[1,1′-biphenyl]-4-yl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (5d): Beige solid (90 mg, 76%); mp 133–135 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 5.78 (brs, 2H), 5.71 (brs, 2H), 2.61 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6); δ 160.3, 155.6, 152.9, 148.5, 140.7, 137.7, 137.1, 137.0, 135.4, 130.0, 127.3, 126.8, 117.4, 25.3, 21.1, 17.5; HPLC purity 100% (acetonitrile-3% TEA, 1:
4).
2-(1-(4-Methyl-2-(3′-methyl-[1,1′-biphenyl]-4-yl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (6d): Beige solid (97 mg, 71%); mp 137–139 °C; 1H NMR (DMSO-d6) δ: 8.20 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.82 (brs, 2H), 5.71 (brs, 2H), 2.67 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H); 13C NMR (DMSO-d6); δ 160.1, 155.6, 153.0, 148.7, 140.9, 140.0, 138.1, 137.9, 137.1, 135.4, 129.3, 128.7, 127.7, 124.2, 117.4, 25.3, 21.6, 17.5; HPLC purity 99.5% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(3′-Methoxy-[1,1′-biphenyl]-4-yl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (7d): Yellow solid (80 mg, 68%) mp = 125–127 °C; 1H NMR (DMSO-d6) δ: 7.98 (d, J = 8 Hz, 2H), 7.80 (d, J = 8 Hz, 2H), 7.41 (t, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.26 (s, 1H), 6.99 (d, J = 8 Hz, 1H), 5.78 (brs, 2H), 5.67 (brs, 2H), 3.84 (s, 3H), 2.61 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6) δ: 162.7, 160.2, 160.1, 140.4, 143.1, 141.5, 141.1, 135.9, 132.8, 130.5, 127.8, 126.6, 119.4, 114.0, 112.5, 55.6, 18.7, 16.5; MS (m/z) 379; HPLC purity 93% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(2′-Methoxy-[1,1′-biphenyl]-4-yl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (8d): Yellow solid (77 mg, 65%) mp = 130–132 °C; 1H NMR (DMSO-d6) δ: 7.94 (d, J = 8 Hz, 2H), 7.60 (d, J = 8 Hz, 2H), 7.40–7.38 (m, 2H), 7.15 (d, J = 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 5.98 (brs, 4H), 3.79 (s, 3H), 2.61 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6) δ: 162.7, 159.7, 156.6, 148.8, 143.6, 140.1, 135.2, 132.1, 130.6, 130.4, 129.8, 129.3, 125.8, 121.3, 112.3, 56.0, 18.6, 16.7; MS (m/z) 379; HPLC purity 90.9% (acetonitrile-3% TEA, 1:
4).
Methyl-4′-(5-(1-(2-carbamimidoylhydrazono)ethyl)-4-methylthiazol-2-yl)-[1,1′-biphenyl]-2-carboxylate (9d): Yellow solid (75 mg, 64%) mp = 136 °C; 1H NMR (DMSO-d6) δ: 7.96 (d, J = 8 Hz, 2H), 7.80 (d, J = 8 Hz, 1H), 7.68 (t, J = 8 Hz, 1H), 7.54–7.51 (m, 2H), 7.41 (d, J = 8 Hz, 2H), 6.22 (brs, 4H), 3.63 (s, 3H), 2.61 (s, 3H), 2.35 (s, 3H); 13C NMR (DMSO-d6) δ: 173.1, 168.8, 162.6, 159.5, 149.2, 143.8, 142.4, 140.9, 132.5, 132.1, 131.1, 130.8, 129.9, 129.4, 126.0, 52.4, 18.6, 16.9; MS (m/z) 407; HPLC purity 95.7% (acetonitrile-3% TEA, 1:
4).
2-(1-(4-Methyl-2-(4-(naphthalen-2-yl)phenyl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (10d): Yellow solid (100 mg, 67%); mp 141–143 °C; 1H NMR (DMSO-d6) δ: 8.30 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.83 (t, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 5.84 (brs, 2H), 5.69 (brs, 2H), 2.69 (s, 3H), 2.26 (s, 3H); 13C NMR (DMSO-d6); δ 160.2, 155.7, 152.9, 148.7, 140.5, 138.1, 137.3, 135.5, 133.8, 132.8, 129.0, 128.7, 127.9, 126.7, 125.4, 117.5, 25.3, 17.5; HPLC purity 100% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(Benzofuran-2-yl)phenyl)-4-methyl-thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (11d): Yellow solid (90 mg, 62%); mp 136–138 °C; 1H NMR (DMSO-d6) δ: 8.26 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 5.81 (brs, 2H), 5.62 (brs, 2H), 2.67 (s, 3H), 2.25 (s, 3H); 13C NMR (DMSO-d6); δ 160.2, 155.3, 154.8, 152.5, 139.1, 137.1, 136.1, 135.7, 130.3, 129.3, 127.4, 125.2, 123.8, 121.7, 117.6, 111.6, 103.0, 25.3, 17.5; HPLC purity 98.8% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(Benzo[b]thiophen-2-yl)phenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (12d): Yellow solid (96 mg, 63%); mp 132–134 °C; 1H NMR (DMSO-d6) δ: 8.21 (s, 1H), 8.01–7.78 (m, 8H), 5.77 (brs, 2H), 5.60 (brs, 2H), 2.63 (s, 3H), 2.35 (s, 3H); 13C NMR (DMSO-d6); δ 160.2, 155.7, 152.5, 148.5, 143.2, 140.9, 139.1, 137.1, 135.7, 134.1, 127.5, 126.8, 125.3, 124.3, 120.8, 117.5, 25.3, 17.5; HPLC purity 97.6% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(Furan-2-yl)phenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (13d): Beige solid (90 mg, 71%); mp 122–124 °C; 1H NMR (DMSO-d6) δ: 7.94 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 6.2 Hz, 1H), 5.78 (brs, 2H), 5.67 (brs, 2H), 2.61 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6); δ 162.3, 160.1, 148.3, 145.0, 143.1, 140.5, 135.6, 133.8, 132.1, 126.6, 126.5, 125.7, 109.0, 18.6, 16.5; HPLC purity 96.5% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(Furan-3-yl)phenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (14d): Beige solid (84 mg, 66%); mp 120–122 °C; 1H NMR (DMSO-d6) δ: 8.30 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 6.4 Hz, 1H), 5.77 (brs, 2H), 5.66 (brs, 2H), 2.60 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6); δ 162.3, 160.1, 148.3, 145.0, 143.1, 140.5, 135.6, 133.8, 132.1, 126.6, 126.5, 125.7, 109.0, 18.6, 16.5; HPLC purity 97% (acetonitrile-3% TEA, 1:
4).
2-(1-(4-Methyl-2-(4-(thiophen-2-yl)phenyl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (15d): Yellow solid (90 mg, 76%) mp = 120–122 °C; 1H NMR (DMSO-d6) δ: 7.94 (d, J = 8 Hz, 2H), 7.76 (d, J = 8 Hz, 2H), 7.63–7.60 (m, 2H), 7.19–7.17 (m, 1H), 5.79 (brs, 2H), 5.67 (brs, 2H), 2.60 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6) δ: 160.2, 158.1, 148.4, 142.9, 135.9, 133.6, 131.9, 129.2, 126.8, 126.3, 124.9, 18.6, 16.5; MS (m/z) 355; HPLC purity 96.2% (acetonitrile-3% TEA, 1:
4).
2-(1-(4-Methyl-2-(4-(thiophen-3-yl)phenyl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (16d): Yellow solid (102 mg, 88%) mp = 123–125 °C; 1H NMR (DMSO-d6) δ: 7.97 (s, 1H), 7.93 (d, J = 8 Hz, 2H), 7.83 (d, J = 8 Hz, 2H), 7.67 (d, J = 8 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 5.79 (brs, 2H), 5.67 (brs, 2H), 2.60 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6) δ: 162.2, 160.1, 148.3, 143.1, 141.0, 136.7, 135.7, 132.2, 127.8, 127.0, 126.6, 126.5, 122.2, 18.6, 16.5; MS (m/z) 355; HPLC purity 94.7% (acetonitrile-3% TEA, 1:
4).
(1-(4-Methyl-2-(4-(5-methylthiophen-3-yl)phenyl)thiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (17d): Yellow solid (105 mg, 89%) mp = 120–122 °C; 1H NMR (DMSO-d6) δ: 7.91 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.71 (s, 1H), 7.32 (s, 1H), 5.79 (brs, 2H), 5.68 (brs, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6) δ: 162.2, 160.2, 148.3, 143.0, 140.8, 140.6, 136.9, 135.7, 132.1, 126.8, 126.6, 124.8, 120.0, 18.6, 16.5, 15.5; MS (m/z) 369; HPLC purity 97% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(4,5-Dimethylthiophen-3-yl)phenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (18d): Yellow solid (106 mg, 90%) mp = 123–125 °C; 1H NMR (DMSO-d6) δ: 7.94 (d, J = 8 Hz, 2H), 7.49 (d, J = 8 Hz, 2H), 7.29 (s, 1H), 5.78 (brs, 2H), 5.69 (brs, 2H), 2.60 (s, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); 13C NMR (DMSO-d6) δ: 162.3, 160.1, 148.4, 143.1, 142.6, 138.9, 135.7, 134.1, 132.1, 131.4, 129.4, 126.2, 119.9, 18.6, 16.5, 13.9, 13.5; MS (m/z) 383; HPLC purity 98.9% (acetonitrile-3% TEA, 1:
4).
2-{1-[4-Methyl-2-(4-(5-(N-methylsulfamoyl)thiophen-2-yl)phenyl)thiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (19d): Yellow solid (80 mg, 70%) mp = 129–131 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.71 (brs, 1H), 7.68 (d, J = 4 Hz, 1H), 7.60 (d, J = 4 Hz, 1H), 5.78 (brs, 2H), 5.67 (brs, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 2.32 (s, 3H); 13C NMR (DMSO-d6) δ: 161.5, 160.2, 148.5, 148.4, 142.9, 139.6, 136.4, 133.9, 133.6, 133.2, 126.98, 126.94, 125.0, 29.3, 18.6, 16.4; MS (m/z) 448.5; HPLC purity 95.9% (acetonitrile-3% TEA, 1:
4).
2-(1-(2-(4-(5-(N-Ethylsulfamoyl)thiophen-2-yl)phenyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (20d): Yellow solid (83 mg, 73%) mp = 130–132 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.90 (brs, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 4 Hz, 1H), 7.60 (d, J = 4 Hz, 1H), 5.89 (brs, 4H), 2.98 (q, J = 6.8 Hz, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 1.06 (t, J = 6.8 Hz, 3H); 13C NMR (DMSO-d6) δ: 161.7, 159.9, 148.9, 148.3, 143.3, 140.9, 136.0, 133.8, 133.7, 132.9, 126.9, 126.6, 125.0, 38.3, 18.6, 16.6, 15.1; MS (m/z) 462.6; HPLC purity 98.9% (acetonitrile-3% TEA, 1:
4).
2-{1-[2-(4-(5-(N-Isopropylsulfamoyl)thiophen-2-yl)phenyl)-4-methylthiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (21d): Yellow solid (77 mg, 68%) mp = 133–135 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.91 (brs, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 4 Hz, 1H), 7.60 (d, J = 4 Hz, 1H), 5.84 (brs, 2H), 5.73 (brs, 2H), 3.43–3.39 (m, 1H), 2.60 (s, 3H), 2.31 (s, 3H), 1.04 (d, J = 6.4 Hz, 6H); 13C NMR (DMSO-d6) δ: 161.5, 160.3, 148.5, 148.1, 142.8, 142.3, 136.4, 133.8, 133.7, 132.8, 127.2, 126.9, 124.9, 46.1, 23.6, 18.6, 16.4; MS (m/z) 476.6; HPLC purity 91% (acetonitrile-3% TEA, 1:
4).
2-{1-[2-(4-(5-(N-Butylsulfamoyl)thiophen-2-yl)phenyl)-4-methylthiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (22d): Yellow solid (79 mg, 70%) mp = 136–138 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.90 (brs, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 4 Hz, 1H), 7.60 (d, J = 4 Hz, 1H), 5.86 (brs, 4H), 2.90 (t, J = 6.4 Hz, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6) δ: 161.6, 159.9, 148.8, 148.2, 143.2, 141.0, 136.1, 133.8, 133.7, 132.9, 127.2, 126.9, 125.4, 42.9, 31.4, 19.7, 18.6, 16.6, 13.9; MS (m/z) 490; HPLC purity 95.4% (acetonitrile-3% TEA, 1:
4).
2-{1-[4-Methyl-2-(4-(5-(N-(pentan-2-yl)sulfamoyl)thiophen-2-yl)phenyl)thiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (23d): Yellow solid (83 mg, 73%) mp = 136–138 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.89 (brs, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 4 Hz, 1H), 7.59 (d, J = 4 Hz, 1H), 5.83 (brs, 4H), 3.37–3.28 (m, 1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.33–1.21 (m, 4H), 0.98–0.97 (m, 3H), 0.79–0.76 (m, 3H); 13C NMR (DMSO-d6) δ: 161.6, 160.0, 148.7, 148.0, 143.2, 142.6, 136.2, 133.8, 133.7, 132.7, 126.95, 126.92, 124.9, 49.8, 42.6, 21.5, 18.8, 18.6, 16.5, 14.1; MS (m/z) 504.6; HPLC purity 98.13% (acetonitrile-3% TEA, 1:
4).
2-{1-[2-(4-(5-(N-Hexylsulfamoyl)thiophen-2-yl)phenyl)-4-methylthiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (24d): Yellow solid (87 mg, 77%) mp = 139–141 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.88 (brs, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 4 Hz, 1H), 7.59 (d, J = 4 Hz, 1H), 5.79 (brs, 2H), 5.71 (brs, 2H), 2.89 (t, J = 8 Hz, 2H), 2.60 (s, 3H), 2.32 (s, 3H), 1.43–1.37 (m, 2H), 1.28–1.16 (m, 6H), 0.83–0.80 (m, 3H); 13C NMR (DMSO-d6) δ: 161.5, 160.2, 148.5, 148.2, 143.0, 141.0, 136.3, 133.8, 133.7, 132.9, 126.98, 126.94, 124.9, 43.2, 31.2, 29.2, 26.1, 22.4, 18.6, 16.5, 14.3; MS (m/z) 518.7; HPLC purity 97.7% (acetonitrile-3% TEA, 1:
4).
2-{1-[2-(4-(5-(N,N-Diethylsulfamoyl)thiophen-2-yl)phenyl)-4-methylthiazol-5-yl]ethylidene}hydrazine-1-carboximidamide (25d): Yellow solid (80 mg, 70%) mp = 135–137 °C; 1H NMR (DMSO-d6) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 4 Hz, 1H), 7.67 (d, J = 4 Hz, 1H), 5.78 (brs, 2H), 5.7 (brs, 2H), 3.25 (q, J = 7.2 Hz, 4H), 2.60 (s, 3H), 2.32 (s, 3H), 1.39 (t, J = 7.2 Hz, 6H); 13C NMR (DMSO-d6) δ: 161.4, 160.2, 148.7, 148.5, 143.0, 139.0, 136.4, 133.9, 133.5, 133.3, 127.0, 126.9, 125.2, 42.9, 18.6, 16.5, 14.6; MS (m/z) 490.6; HPLC purity 95.7% (acetonitrile-3% TEA, 1:
4).
Footnote |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ra02778c |
This journal is © The Royal Society of Chemistry 2023 |