Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens
Abstract
:1. Introduction
2. Results
2.1. Synthesis
2.2. Characterization of Absorption, Distribution, Metabolism, and Excretion (ADME) Properties
2.3. Antimicrobial Activity of Compounds 1–9
2.4. The Cytotoxicity Evaluation of Compounds 1–9
2.5. The Compounds 2a–c Demonstrates Bactericidal Activity on Staphylococcus Aureus with Genetically Defined Resistance Mechanisms
2.6. The Activity of the Compounds 2a–c on the Staphylococcus Aureus Biofilm Integrity
3. Materials and Methods
3.1. Synthesis
- 3-(1-(4-(phenylamino)phenyl)thioureido)propanoic acid (1). A solution of thioxo tetrahydro pyrimidinone [35] (0.1 mol, 29.7 g) in aqueous 10% sodium hydroxide (200 mL) was boiled, then left to cool down to room temperature, filtered off, and the obtained filtrate was acidified with acetic acid to pH 6. The formed precipitate was filtered off, washed with water, and dried to give the title compound 1 (white solid, yield 20.2 g (64%), m.p. 195 °C (decomp.).
- General procedure for the preparation of thiazoles2a–c. A suspension of compound 1 (2.2 mmol) in aqueous 5% sodium carbonate solution (10 mL) was dissolved in methanol (6 mL), and the appropriate acetophenone (2.7 mmol) was added. The mixture was refluxed for 2 h (a, b) or 4 h (c), the cooled down and acidified with diluted (30%) acetic acid to pH 6. The formed precipitate was filtered off, washed with water and recrystallized from propan-2-ol to give the title compounds 2a (white solid, yield 0.65 g, 68%, m. p. 124–125 °C), 2b (white solid, yield 0.87 g, 88%, m. p. 130–132 °C), and 2c (white solid, yield 0.87 g, 80%, m.p. 120–122 °C).
- 3-((4-(4-Fluorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanoic acid(2a). 1H-NMR (400 MHz, DMSO-d6): δ = 2.62 (t, J = 7.4 Hz, 2H, CH2CO), 4.11 (t, J = 7.4 Hz, 2H, NCH2), 6.88 (t, J = 7.3, 1H, HAr), 7.08–7.17 (m, 5H, SCH, HAr), 7.22–7.30 (m, 4H, HAr), 7.44 (d, J = 8.5 Hz, 2H, HAr), 7.88 (d, J = 8.5 Hz, 2H, HAr), 8.39 (s, 1H, NH) ppm.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanoic acid(2b).1H-NMR (400 MHz, DMSO-d6): δ = 2.62 (t, J = 7.4 Hz, 2H, CH2CO), 4.11 (t, J = 7.4 Hz, 2H, NCH2), 6.88 (t, J = 7.3, 1H, HAr), 7.05–7.16 (m, 5H, SCH, HAr), 7.16–7.39 (m, 4H, HAr), 7.44 (d, J = 8.5 Hz, 2H, HAr), 7.88 (d, J = 8.5 Hz, 2H, HAr), 8.39 (s, 1H, NH) ppm.
- 3-((4-(4-Bromophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanoic acid(2c). 1H-NMR (400 MHz, DMSO-d6): δ = 2.44, 2.57 (2t, J = 7.8, 7.6 Hz, 2H, CH2CO), 4.09 (t, J = 7.6 Hz, 2H, NCH2), 6.75–7.34 (m, 10H, SCH, HAr), 7.58 (d, J = 8.2 Hz, 4H, HAr), 7.81 (d, J = 8.2 Hz, 4H, HAr), 8.33, 8.36 (2s, 1H, NH) ppm.
- Methyl 3-((4-(4-chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanoate(3). To a boiling solution of compound 2b (11.1 mmol, 5 g) in methanol (100 mL), a catalytic amount of sulfuric acid (0.6 mL) was added, and the reaction mixture was refluxed for 5 h. Then the volatile fractions were evaporated under reduced pressure, the residue was poured with aqueous 5% sodium carbonate solution (150 mL) and boiled. After cooling, the formed precipitate was filtered off, washed with water and recrystallized from the mixture of methanol and water (1:1) to give the title compound 4 (white solid, yield 4.12 g, 80%, m.p. 73–74 °C).
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanehydrazide(4). To a solution of ester 3 (20 mmol, 7.12 g) in propan-2-ol (150 mL), hydrazine monohydrate (60 mmol, 3 g) was added dropwise and the mixture was heated at reflux for 18 h. After completion of the reaction the mixture was cooled down and diluted with water (100 mL). The obtained precipitate was filtered off, washed with water, and recrystallized from propan-2-ol to give the title compound 4 (yellow solid, yield 7.52 g, 73%, m.p. 104–105 °C).
- General procedure for the preparation of hydrazones5a–i. To a boiling solution of hydrazide 4 (5 mmol, 2.32 g) in propan-2-ol (35 mL) the corresponding aromatic aldehyde (6 mmol) and a catalytic amount of acetic acid (0.4 mL) were added, and the mixture was heated at reflux for 2 h after, cooled down, the formed solid was filtered off, washed with propan-2-ol, diethyl ether, and recrystallized from propan-2-ol to give the appropriate title compound 5.
- N-benzylidene-3-((4-(4-chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanehydrazide(5a). White solid, yield 2.24 g, 81%, m.p. 162–164 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N′-(4-fluorobenzylidene)propanehydrazide (5b). White solid, yield 2.39 g, 84%, m.p. 178–180 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N′-(4-chlorobenzylidene)propanehydrazide (5c). White solid, yield 2.58 g, 88%, m.p. 201–203 °C.
- N′-(4-bromobenzylidene)-3-((4-(4-chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanehydrazide (5d) White solid, yield 2.78 g, 88%, m.p. 182–184 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)-N′-(4-nitrobenzylidene)-(4-(phenylamino)phenyl)amino)propanehydrazide (5e). White solid, yield 2.36 g, 79%, m.p. 205–207 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)-N′-(4-(dimethylamino)benzylidene)-(4-(phenylamino)phenyl)amino)propanehydrazide (5f). White solid, yield 2.38 g, 80%, m.p. 191–193 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)-N′-(4-methylbenzylidene)-(4-(phenylamino)phenyl)amino)propanehydrazide (5g). White solid, yield 2.69 g, 95%, m.p. 176–178 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N’-(thiophen-2-ylmethylene)propanehydrazide (5h). White solid, yield 1.90 g, 68%, m.p. 178–180 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N’-((5-nitrothiophen-2-yl)methylene)propanehydrazide (5i). White solid, yield 2.20 g, 73%, m.p. 186–188 °C.
- General procedure for the preparation of hydrazones5j, k. A mixture of hydrazide 4 (5 mmol, 2.32 g) and the corresponding ketone (acetone or 2-butanone) (35 mL) was heated at reflux for 5 h. After completion of the reaction, the mixture was cooled down, diluted with water (35 mL), and left in refrigerator for 24 h. Then the formed precipitate was filtered off, washed with acetone, diethyl ether and recrystallized from acetone to give the title compound 5j. Product 5k was separated from the reaction mixture by evaporating the volatile fractions under reduced pressure, diluting the residue with diethyl ether, filtering the obtained solid, and recrystallizing it from 2-butanone to give the title compound 5k.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N’-(propan-2-ylidene)propanehydrazide (5j). White solid, yield 2.07 g, 82%, m.p. 76–78 °C.
- N’-(butan-2-ylidene)-3-((4-(4-chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanehydrazide (5k). White solid, yield 1.76 g, 68%, m.p. 79–81 °C.
- 3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-1-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-one (6). To a solution of hydrazide 4 (5 mmol, 2.32 g) in propan-2-ol (35 mL), 2,4-pentanedione (10 mmol, 1 g) and hydrochloric acid (2 drops) were added dropwise and the mixture was refluxed for 9 h, then cooled down, and the formed precipitate was filtered off washed with propan-2-ol and recrystallized from propan-2-ol to give the title compound 7 (white solid, 1.95 g, 74%, m.p. 105–106 °C).
- 2-(3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)-N-(2,5-dimethyl-1H-pyrrol-1-yl)propanamide (7). To a solution of hydrazide 4 (5 mmol, 2.32 g) in propan-2-ol (45 mL) 2,5-hexanedione (9 mmol, 1.03 g) and acetic acid (dropwise, 0.75 mL) were added and the mixture was refluxed for 3 h, then cooled down and diluted with water (30 mL). The formed crystalline solid was filtered off, washed with water and recrystallized from propan-2-ol to give the title compound 7 (white solid, 2.17 g, 80%, m.p. 146–147 °C).
- 2-(3-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)propanoyl)-N-phenylhydrazine-1-carbothioamide (8). To a solution of hydrazide 4 (5 mmol, 2.32 g) solution in methanol (100 mL), a solution of phenyl isothiocyanate (5 mmol, 0.6 mL) in methanol (5 mL) was added dropwise and the mixture was refluxed for 2 h. After completion of the reaction, the mixture was cooled down and diluted with water (80 mL). The formed solid was filtered off, washed with water, and recrystallized from propan-2-ol to give the title compound 8 (white solid, 2.79 g, 93%, m.p. 116–118 °C).
- 5-(2-((4-(4-Chlorophenyl)thiazol-2-yl)(4-(phenylamino)phenyl)amino)ethyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (9). A mixture of compound 8 (5 mmol, 3 g) and aqueous 4 % NaOH solution (150 mL) was heated at reflux for 3 h, then cooled down and acidified with acetic acid to pH 6. The formed precipitate was filtered off, washed with water and recrystallized from propan-2-ol to give the title compound 9 (white solid, 2.41 g, 83%, m.p. 119–121 °C).
3.2. In Silico ADME Prediction
3.3. Microbial Strains and Culture Conditions
3.4. Minimal Inhibitory Concentration (MIC) Determination
3.5. Evaluation of Cytotoxicity in Vero Cells
3.6. In Vitro Time-Kill Study
3.7. Biofilm Formation Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | MW | No of Heavy Atoms | No of Aromatic Heavy Atoms | Fraction Csp3 | Rotatable Bonds | H-Bond Acceptors | H-Bond Donors | Molar Refractivity | TPSA |
---|---|---|---|---|---|---|---|---|---|
1 | 315.39 | 22 | 12 | 0.12 | 7 | 2 | 3 | 92.08 | 110.68 |
2a | 433.5 | 31 | 23 | 0.08 | 8 | 4 | 2 | 122.88 | 93.7 |
2b | 449.95 | 31 | 23 | 0.08 | 8 | 3 | 2 | 127.93 | 93.7 |
2c | 494.4 | 31 | 23 | 0.08 | 8 | 3 | 2 | 130.62 | 93.7 |
3 | 463.98 | 32 | 23 | 0.12 | 9 | 3 | 1 | 132.25 | 82.7 |
4 | 463.98 | 32 | 23 | 0.08 | 9 | 3 | 3 | 131.87 | 111.52 |
5a | 552.09 | 39 | 29 | 0.06 | 11 | 3 | 2 | 162.14 | 97.86 |
5b | 570.08 | 40 | 29 | 0.06 | 11 | 4 | 2 | 162.1 | 97.86 |
5c | 586.53 | 40 | 29 | 0.06 | 11 | 3 | 2 | 167.15 | 97.86 |
5d | 630.99 | 40 | 29 | 0.06 | 11 | 3 | 2 | 169.84 | 97.86 |
5e | 597.09 | 42 | 29 | 0.06 | 12 | 5 | 2 | 170.97 | 143.68 |
5f | 595.16 | 42 | 29 | 0.12 | 12 | 3 | 2 | 176.35 | 101.1 |
5g | 566.12 | 40 | 29 | 0.09 | 11 | 3 | 2 | 167.11 | 97.86 |
5h | 558.12 | 38 | 28 | 0.07 | 11 | 3 | 2 | 160.02 | 126.1 |
5i | 603.11 | 41 | 28 | 0.07 | 12 | 5 | 2 | 168.84 | 171.92 |
5j | 504.05 | 35 | 23 | 0.15 | 10 | 3 | 2 | 147.27 | 97.86 |
5k | 518.07 | 36 | 23 | 0.18 | 11 | 3 | 2 | 152.08 | 97.86 |
6 | 528.07 | 37 | 28 | 0.14 | 9 | 3 | 1 | 153.08 | 91.29 |
7 | 542.09 | 38 | 28 | 0.13 | 10 | 2 | 2 | 158.85 | 90.43 |
8 | 599.17 | 41 | 29 | 0.06 | 13 | 2 | 4 | 173.39 | 141.65 |
9 | 581.15 | 40 | 34 | 0.06 | 9 | 2 | 2 | 168.15 | 122.1 |
Comp-ound | Log Kp (cm/s) | GI Absorption | BBB Permeant | P-Gp Substrate | Inhibition of Cytochrome P450 System | ||||
---|---|---|---|---|---|---|---|---|---|
CYP1A2 | CYP2C19 | CYP2C9 | CYP2D6 | CYP3A4 | |||||
1 | −6.56 | High | No | No | No | No | Yes | No | No |
2a | −4.85 | Low | No | No | No | Yes | Yes | Yes | Yes |
2b | −4.57 | Low | No | No | No | Yes | Yes | Yes | Yes |
2c | −4.8 | Low | No | No | No | Yes | Yes | Yes | Yes |
3 | −4.43 | Low | No | Yes | No | Yes | Yes | Yes | Yes |
4 | −5.37 | Low | No | No | Yes | Yes | Yes | Yes | Yes |
5a | −4.21 | Low | No | No | No | Yes | No | Yes | Yes |
5b | −4.25 | Low | No | No | No | Yes | No | Yes | Yes |
5c | −3.98 | Low | No | No | No | Yes | No | Yes | Yes |
5d | −4.21 | Low | No | No | No | Yes | No | Yes | Yes |
5e | −4.61 | Low | No | No | No | Yes | No | No | Yes |
5f | −4.39 | Low | No | No | No | Yes | No | Yes | Yes |
5g | −4.04 | Low | No | No | No | Yes | No | Yes | Yes |
5h | −4.24 | Low | No | No | No | No | Yes | Yes | Yes |
5i | −4.4 | Low | No | No | No | Yes | No | No | Yes |
5j | −4.94 | Low | No | Yes | No | Yes | Yes | Yes | Yes |
5k | −4.7 | Low | No | Yes | No | Yes | Yes | Yes | Yes |
6 | −4.25 | Low | No | No | No | Yes | Yes | No | Yes |
7 | −4.22 | Low | No | No | No | Yes | No | Yes | Yes |
8 | −4.6 | Low | No | No | No | Yes | No | No | Yes |
9 | −4.14 | Low | No | No | No | No | No | No | Yes |
Compound | Gram-Positive | Gram-Negative | |||||||
---|---|---|---|---|---|---|---|---|---|
S. a MRSA | S. a MSSA | S. a VRSA | E. fec | E. fae VREF | E. raffi | K. pn NDM-1 | S. m R | P. ae AmpC | |
1 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
2a | 2 | 2 | 2 | 32 | 32 | 64< | 64< | 64< | 64< |
2b | 1 | 1 | 2 | 64< | 64< | 64< | 64< | 64< | 64< |
2c | 64 | 32 | 32 | 32 | 32 | 64 | 64< | 64< | 64< |
3 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
4 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5a | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5b | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5c | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5d | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5e | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5f | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5g | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5h | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5i | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5j | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5k | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
6 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
7 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
8 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
9 | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
Vancomycin | 2 | 0.5 | 64< | 0.5 | 32 | 32 | n.a | n.a | n.a |
Daptomycin | 0.5< | 0.5< | 0.5 | 1 | 2 | 2 | n.a | n.a | n.a |
Meropenem | 4 | 1 | 4 | n.a | n.a | n.a | 32 | 16 | 16 |
Compound | A. fumigatus Azole Resistance Phenotype | ||
---|---|---|---|
L98H, TR34 | F495I, L98H, S297T, TR34 | Wt | |
1 | 64< | 64< | 64< |
2a | 32 | 32 | 64< |
2b | 32 | 32 | 64< |
2c | 64 | 64< | 64 |
3 | 64< | 64< | 64< |
4 | 64< | 64< | 64< |
5a | 64< | 64< | 64< |
5b | 64< | 64< | 64< |
5c | 64< | 64< | 64< |
5d | 64< | 64< | 64< |
5e | 64< | 64< | 64< |
5f | 64< | 64< | 64< |
5g | 64< | 64< | 64< |
5h | 64< | 64< | 64< |
5i | 64< | 64< | 64< |
5j | 64< | 64< | 64< |
5k | 64< | 64< | 64< |
6 | 64< | 64< | 64< |
7 | 64< | 64< | 64< |
8 | 64< | 64< | 64< |
9 | 64< | 64< | 64< |
Voriconazole | 8 | 1 | 0.5 |
Itraconazole | 2 | 16< | 1 |
Compound | C. auris 381 | C. auris 382 | C. auris 383 | C. auris 384 | C. duobushaemulonii 394 | C. krusei 397 | C. albicans 1214 |
---|---|---|---|---|---|---|---|
1 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
2a | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
2b | 32 | 16 | 32 | 32 | 16 | 64< | 64< |
2c | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
3 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
4 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5a | 64 | 64 | 64< | 64< | 64< | 32 | 64< |
5b | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5c | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5d | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5e | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5f | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5g | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5h | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5i | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5j | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
5k | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
6 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
7 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
8 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
9 | 64< | 64< | 64< | 64< | 64< | 64< | 64< |
Fluconazole | 4 | 16 | 64< | 64< | 8 | 64 | 32 |
Itraconazole | 0.125 | 1 | 0.5 | 0.5 | 0.5 | 1 | 1 |
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Malūkaitė, D.; Grybaitė, B.; Vaickelionienė, R.; Vaickelionis, G.; Sapijanskaitė-Banevič, B.; Kavaliauskas, P.; Mickevičius, V. Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens. Molecules 2022, 27, 74. https://doi.org/10.3390/molecules27010074
Malūkaitė D, Grybaitė B, Vaickelionienė R, Vaickelionis G, Sapijanskaitė-Banevič B, Kavaliauskas P, Mickevičius V. Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens. Molecules. 2022; 27(1):74. https://doi.org/10.3390/molecules27010074
Chicago/Turabian StyleMalūkaitė, Dovilė, Birutė Grybaitė, Rita Vaickelionienė, Giedrius Vaickelionis, Birutė Sapijanskaitė-Banevič, Povilas Kavaliauskas, and Vytautas Mickevičius. 2022. "Synthesis of Novel Thiazole Derivatives Bearing β-Amino Acid and Aromatic Moieties as Promising Scaffolds for the Development of New Antibacterial and Antifungal Candidates Targeting Multidrug-Resistant Pathogens" Molecules 27, no. 1: 74. https://doi.org/10.3390/molecules27010074