Synthesis and Structure–Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General Procedure for the Synthesis of Nitriles 1–3
6-(Pyrrolidin-1-Yl)Picolinonitrile (1)
6-(Piperidin-1-Yl)Picolinonitrile (2)
6-Phenoxypicolinonitrile (3)
2.1.2. General Procedure for the Synthesis of Thiosemicarbazones 4–9
Method A (4, 6)
Method B (7)
Method C (5, 8, 9)
N’-(Morpholine-4-Carbonothioyl)-6-(Pyrrolidin-1-Yl)Picolinohydrazonamide (4)
6-(Pyrrolidin-1-Yl)-N’-(Pyrrolidine-1-Carbonothioyl)Picolinohydrazonamide (5)
N’-(Morpholine-4-Carbonothioyl)-6-(Piperidin-1-Yl)Picolinohydrazonamide (6)
6-(Piperidin-1-Yl)-N’-(Pyrrolidine-1-Carbonothioyl)Picolinohydrazonamide (7)
N’-(Morpholine-4-Carbonothioyl)-6-Phenoxypicolinohydrazonamide (8)
6-Phenoxy-N’-(Pyrrolidine-1-Carbonothioyl)Picolinohydrazonamide (9)
2.2. Tuberculostatic Activity Assay
2.3. In Vitro Antibacterial Activity Assay
2.4. Cytotoxic Activity Assay
2.5. X-ray Study
2.6. Absorption, Distribution, Metabolism, and Excretion (ADME)
3. Results and Discussion
3.1. Chemistry
3.2. Tuberculostatic Activity
3.3. Antimicrobial Activity
3.4. Cytotoxic Activity
3.5. X-ray Study
3.6. ADME Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | MIC [µg/mL] | |
---|---|---|
H37Rv | Spec. 210 | |
4 | 16 | 4 |
5 | 2 | 1 |
6 | 8 | 1 |
7 | 2 | 0.5 |
8 | 8 | 4 |
9 | 8 | 4 |
INH | 0.125 | 8 |
Chemicals Microorganism | 4 | 5 | 6 | 7 | 8 | 9 | CIP | VAN | FCZ |
---|---|---|---|---|---|---|---|---|---|
MIC [µg/mL] | |||||||||
Gram-positive bacteria | |||||||||
S. aureus ATCC 25923 | 3.9 | 0.49 | 1.95 | 0.49 | 250 | 0.98 | 0.49 | 0.98 | - |
S. epidermidis ATCC 12228 | 1.95 | 0.49 | 0.98 | 0.49 | 31.3 | 0.49 | 0.49 | 0.98 | - |
M. luteus ATCC 10240 | 7.8 | 0.49 | 0.98 | 1.95 | 125 | 0.49 | 0.98 | 0.12 | - |
B. subtilis ATCC 6633 | 7.8 | 0.49 | 7.8 | 1.95 | >1000 | 0.49 | 0.03 | 0.24 | - |
B. cereus ATCC 10876 | 7.8 | 7.8 | 7.8 | 1.95 | >1000 | 3.9 | 0.12 | 0.98 | - |
Gram-negative bacteria | |||||||||
E. coli ATCC 25922 | >1000 | >1000 | >1000 | >1000 | >1000 | 1000 | - | 0.004 | - |
P. mirabilis ATCC 12453 | >1000 | >1000 | >1000 | >1000 | >1000 | >1000 | - | 0.03 | - |
K. pneumoniae ATCC 13883 | >1000 | >1000 | >1000 | >1000 | >1000 | >1000 | - | 0.06 | - |
P. aeruginosa ATCC 9027 | >1000 | >1000 | >1000 | >1000 | >1000 | 1000 | - | 0.49 | - |
Yeasts | |||||||||
C. albicans ATCC 102231 | 250 | 250 | 1000 | 15.6 | >1000 | 1000 | - | - | 0.98 |
C. parapsilosis ATCC 22019 | >1000 | 1000 | 1000 | 7.8 | >1000 | 1000 | - | - | 1.95 |
Compound | IC50-HaCaT [µg/mL] | SI IC50-HaCaT/MIC-MT | |
---|---|---|---|
MTT | SULF | SULF | |
4 | >50 | >50 | >3.13 |
5 | >50 | >50 | >25 |
6 | 9.49 | >50 | >6.25 |
7 | >50 | >50 | >25 |
8 | 0.57 | 50 | 6.25 |
9 | 0.06 | 1.31 | 0.16 |
4 | 5 | 6 | |
---|---|---|---|
Crystal data | |||
Chemical formula | C15.50H23.44N6O1.22S | C15H22N6S | C32H48.22N12O2.11S2 |
Mr | 345.46 | 318.44 | 698.94 |
Crystal system | Triagonal | Monoclinic | Triagonal |
Space group | P21/n | ||
a, b, c (Å) | 23.2044 (3), 23.2044 (3), 17.2241 (2) | 10.2776 (2), 11.0270 (2), 14.7731 (3) | 23.47158 (15), 23.47158 (15), 34.2380 (3) |
α, β, γ (°) | 90, 90, 120 | 90, 107.077 (2), 90 | 90, 90, 120 |
V (Å3) | 8031.7 (2) | 1600.44 (6) | 16335.2 (3) |
Z | 18 | 4 | 18 |
μ (mm−1) | 1.75 | 1.84 | 1.72 |
Crystal size (mm) | 0.47 × 0.19 × 0.14 | 0.74 × 0.40 × 0.06 | 0.6 × 0.4 × 0.2 |
Tmin, Tmax | 0.587, 1.000 | 0.418, 1.000 | 0.740, 1.000 |
Data collection | |||
No. of measured, independent and observed [I > 2σ(I)] reflections | 35,469, 3757, 3509 | 22,970, 3306, 3021 | 65,950, 7458, 6866 |
Rint | 0.037 | 0.056 | 0.078 |
(sin θ/λ)max (Å−1) | 0.637 | 0.636 | 0.637 |
Refinement | |||
R[F2 > 2σ(F2)], wR(F2), S | 0.037, 0.094, 1.07 | 0.039, 0.108, 1.04 | 0.038, 0.100, 1.05 |
No. of reflections | 3757 | 3306 | 7458 |
No. of parameters | 227 | 208 | 501 |
Δmax, Δmin (e Å−3) | 0.57, −0.34 | 0.61, −0.37 | 0.33, −0.35 |
7 | 8 | 9 | |
---|---|---|---|
Crystal data | |||
Chemical formula | C16H24N6S | C17H23O4S | C17H19N5OS |
Mr | 332.47 | 393.46 | 341.43 |
Crystal system | Triclinic | Orthorhombic | Monoclinic |
Space group | Pccn | P21/c | |
a, b, c (Å) | 8.46333 (10), 15.03304 (15), 27.4526 (2) | 38.0250 (5), 12.37094 (19), 7.92165 (12) | 5.0283 (1), 22.5544 (3), 14.5985 (2) |
α, β, γ (°) | 98.1961 (8), 90.2187 (8), 100.2120 (9) | 90, 90, 90 | 90, 97.451 (1), 90 |
V (Å3) | 3400.82 (6) | 3726.39 (9) | 1641.64 (5) |
Z | 8 | 8 | 4 |
μ (mm−1) | 1.76 | 1.85 | 1.87 |
Crystal size (mm) | 0.45 × 0.22 × 0.18 | 0.54 × 0.25 × 0.20 | 0.5 × 0.2 × 0.1 |
Tmin, Tmax | 0.338, 1.000 | 0.752, 1.000 | 0.526, 1.000 |
Data collection | |||
No. of measured, independent and observed [I > 2σ(I)] reflections | 106,334, 14,102, 12,685 | 14,227, 3766, 3545 | 23,458, 3365, 3150 |
Rint | 0.079 | 0.023 | 0.058 |
(sin θ/λ)max (Å−1) | 0.636 | 0.636 | 0.637 |
Refinement | |||
R[F2 > 2σ(F2)], wR(F2), S | 0.047, 0.131, 1.04 | 0.037, 0.091, 1.05 | 0.040, 0.111, 1.06 |
No. of reflections | 14,102 | 3766 | 3365 |
No. of parameters | 864 | 252 | 229 |
Δmax, Δmin (e Å−3) | 0.85, −0.54 | 0.49, −0.45 | 0.34, −0.39 |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
N4—H4A···S1 i | 0.87(2) | 2.55(2) | 3.3997(13) | 167(2) |
N4—H4B···S1 ii | 0.87(2) | 2.68(2) | 3.4601(13) | 150(2) |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
N4—H4A···S1 i | 0.89(2) | 2.45(2) | 3.3295(13) | 171.8(17) |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
N4A—H4AB···S1B | 0.88(3) | 2.48(3) | 3.3022(16) | 156(2) |
N3B—H3B···S1B | 0.83(2) | 2.35(2) | 2.8530(15) | 120(2) |
N4B—H4BA···S1A i | 0.89(3) | 2.50(3) | 3.3494(16) | 161(2) |
N4C—H4CB···S1D i | 0.90(3) | 2.48(3) | 3.3307(16) | 157(2) |
N4D—H4DA···S1C | 0.88(3) | 2.45(3) | 3.2760(17) | 156(2) |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
N4—H4B···S1 i | 0.85(2) | 2.48(2) | 3.3061(15) | 165(2) |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
N4A—H4A···S1B | 0.89(2) | 2.49(2) | 3.3485(13) | 164.3(16) |
N4A—H4B···S1A i | 0.84(2) | 2.86(2) | 3.5748(12) | 143.9(16) |
N3B—H3B···S1B | 0.871(19) | 2.349(18) | 2.8316(12) | 115.2(14) |
N4B—H4C···S1A ii | 0.86(2) | 2.59(2) | 3.4157(13) | 160.3(17) |
N4B—H4D···S1B iii | 0.81(2) | 2.58(2) | 3.3085(13) | 150.8(17) |
D—H···A | D—H | H···A | D···A | D—H···A |
---|---|---|---|---|
O1W—H1WA···O2W | 0.76(2) | 2.01(2) | 2.7698(18) | 174(2) |
O1W—H1WB···S1 i | 0.86(2) | 2.51(2) | 3.3673(13) | 177.1(18) |
O2W—H2WA···S1 ii | 0.86(2) | 2.45(2) | 3.3097(12) | 172.8(18) |
O2W—H2WB···S1 iii | 0.86(2) | 2.41(2) | 3.2556(13) | 169.1(18) |
N4—H4A···O14Aa, iv | 0.88 | 2.20 | 2.928 (4) | 139.2 |
N4—H4A···O14Bb iv | 0.88 | 2.25 | 3.001(3) | 143.8 |
N4—H4B···O1W | 0.88 | 2.08 | 2.9164(17) | 159.7 |
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Ziembicka, D.; Gobis, K.; Szczesio, M.; Olczak, A.; Augustynowicz-Kopeć, E.; Głogowska, A.; Korona-Głowniak, I.; Bojanowski, K. Synthesis and Structure–Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents. Materials 2023, 16, 448. https://doi.org/10.3390/ma16010448
Ziembicka D, Gobis K, Szczesio M, Olczak A, Augustynowicz-Kopeć E, Głogowska A, Korona-Głowniak I, Bojanowski K. Synthesis and Structure–Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents. Materials. 2023; 16(1):448. https://doi.org/10.3390/ma16010448
Chicago/Turabian StyleZiembicka, Dagmara, Katarzyna Gobis, Małgorzata Szczesio, Andrzej Olczak, Ewa Augustynowicz-Kopeć, Agnieszka Głogowska, Izabela Korona-Głowniak, and Krzysztof Bojanowski. 2023. "Synthesis and Structure–Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents" Materials 16, no. 1: 448. https://doi.org/10.3390/ma16010448