Pyrimidine Schiff Bases: Synthesis, Structural Characterization and Recent Studies on Biological Activities
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. X-ray Structural Studies
2.3. Biological Activity Analysis
2.3.1. Neutral Red Uptake Assay
2.3.2. Flow Cytometry Analysis
2.3.3. Cell Morphology
2.3.4. Genotoxicity Assay
2.3.5. Antimicrobial Activity Assay
2.4. In Silico Studies
2.4.1. ADME Prediction Analysis
2.4.2. Molecular Docking Analysis
3. Materials and Methods
3.1. Chemistry
General Procedure for Preparation of Schiff Bases (4a–d)
- N-(4-fluorophenyl)-5-{[(4-fluorophenyl)imino]methyl}-6-methyl-2-phenylpyrimidin-4-amine (4a). Product characterization: yield 0.30 g, 75.00%; yellow solid; melting point 178 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 2.83 (3H, s, CH3), 7.10–8.50 (13H, m, aromatic), 8.92 (1H, s, CH), 12.55 (1H, broad, NH). 13C NMR (151 MHz, CDCl3): δ (ppm) 162.58, 160.94′ (CAr-F), 160.19, 158.57′ (CAr-F), 158.27 (CH=N), 156.69 (2C), 146.64, 135.08, 131.36 (2C), 128.96, 128.65 (4C), 123.59, 123.54, 122.70, 122.65, 116.54, 116.39, 115.76, 115.61, 107.23 (CAr), 22.86 (CH3). 19F NMR 471 MHz) δ (ppm) −62.71 (C-CF3), −115.80 (CAr-F). HR-ESI-MS [M + H]+: found m/z: 401.1560, calcd. m/z: 401.1572 [mass error: 2.99 ppm]. FT–IR (ATR, selected lines): ν (cm−1) 1614 (C=N).
- 5-{[(3-chlorophenyl)imino]methyl}-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine (4b). Product characterization: yield 0.12 g, 28.85%; yellow solid; melting point 193 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 2.81 (3H, s, CH3), 7.10–8.49 (13H, m, aromatic), 8.91 (1H, s, CH), 12.38 (1H, broad, NH). 13C NMR (151 MHz, CDCl3): δ (ppm) 160.25, 158.64′ (CAr-F), 158.32 (CH=N), 157.93 (2C), 151.83, 135.28, 131.46, 130.66 (2C), 129.00 (2C), 128.66 (2C), 126.76, 123.71, 123.66, 121.40, 119.70 (2C), 115.77, 115.62, 107.10 (CAr), 22.07 (CH3). 19F NMR (471 MHz): δ (ppm) −117.54 (CAr-F). HR-ESI-MS [M + H]+: found m/z: 417.1261, calcd. m/z: 417.1277 [mass error: 3.84 ppm]. FT–IR (ATR, selected lines): ν (cm−1) 1610 (C=N).
- N-(4-fluorophenyl)-6-methyl-2-phenyl-5-{[(2-methoxyphenyl)imino]methyl}pyrimidin-4-amine (4c). Product characterization: yield 0.15 g, 36.41%; yellow solid; melting point 167–169 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 2.81 (3H, s, CH3), 3.94 (3H, s, CH3), 7.05–8.50 (13H, m, aromatic), 9.05 (1H, s, CH), 13.21 (1H, broad, NH). 13C NMR (151 MHz, CDCl3): δ (ppm) 172.43 (CH=N), 166.45 (CAr), 160.59, 158.97′ (CAr-F), 159.00 (2C), 153.50, 137.18, 134.02, 131.99 (2C), 129.38 (2C), 128.69 (2C), 124.30, 124.24 (2C), 121.37, 118.85, 115.80, 115.65, 112.01, 108.56 (CAr), 55.96 (O-CH3), 21.57 (CH3). 19F NMR (471 MHz): δ (ppm) −117.62 (CAr-F). HR-ESI-MS [M + H]+: found m/z: 413.1760, calcd. m/z 413.1772 [mass error: 2.90 ppm]. FT–IR (ATR, selected lines): ν (cm−1) 1634 (C=N).
- 5-[{[4-chloro-3-(trifluoromethyl)phenyl]imino}methyl]-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine (4d). Product characterization: yield 0.24 g, 51.65%; yellow solid; melting point 210 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) 2.81 (3H, s, CH3), 7.10–8.48 (12H, m, aromatic), 8.91 (1H, s, CH), 12.17 (1H, broad, NH). 13C NMR (151 MHz, CDCl3): δ (ppm) 172.42 (CH=N), 166.44 (CAr), 160.59, 158.99′ (CAr-F), 158.69, 158.35, 149.38, 134.04, 132.73, 131.58, 129.92–129.30 (q, CAr-CF3), 129.38, 129.06 (2C), 128.68 (2C), 125.22, 124.29, 124.23, 123.91, 123.86′ (CAr-Cl), 123.60, 121.79′ (CF3), 120.71, 120.67′, 115.82, 115.68, 106.98, 21.56 (CH3). 19F NMR (471 MHz): δ (ppm) −62.67 (CF3), −117.53 (CAr-F). HR-ESI-MS [M + H]+: found m/z: 485.1150, calcd. m/z 485.1151 [mass error: 0.21 ppm]. FT–IR (ATR, selected lines): ν (cm−1) 1646 (C=N).
3.2. X-ray Structural Studies
3.3. Biological Activity Assays
3.3.1. Materials
3.3.2. Neutral Red Uptake Assay
3.3.3. Flow Cytometry
3.3.4. Microscopic Observations
3.3.5. Comet Assay
3.3.6. Antimicrobial Activity Assay
3.4. In Silico Analysis
3.4.1. ADME Prediction Analysis
3.4.2. Molecular Docking 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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4a | 4b | 4c | 4d | |
---|---|---|---|---|
Chemical formula | C24H18F2N4 | C24H18ClFN4 | C25H21FN4O | C25H17ClF4N4 |
Mr | 400.42 | 416.87 | 412.46 | 484.88 |
Crystal system, space group | Orthorhombic, Pna21 | Orthorhombic, P212121 | Monoclinic, C2/c | Monoclinic, P21/c |
Temperature (K) | 100 | 100 | 100 | 100 |
a, b, c (Å) | 7.168 (2), 15.447 (4), 17.123 (5) | 7.907 (2), 11.842 (3), 20.544 (4) | 39.850 (8), 5.131 (2), 44.009 (9) | 7.766 (2), 11.769 (3), 23.623 (5) |
α, β, γ (°) | 90, 90, 90 | 90, 90, 90 | 90, 115.29 (3), 90 | 90, 98.54 (3), 90 |
V (Å3) | 1895.9 (9) | 1923.6 (8) | 8136 (4) | 2135.2 (9) |
Z | 4 | 4 | 16 | 4 |
Radiation type | Cu Kα | Mo Kα | Cu Kα | Cu Kα |
µ (mm−1) | 0.81 | 0.23 | 0.74 | 2.10 |
Crystal size (mm) | 0.13 × 0.03 × 0.02 | 0.32 × 0.19 × 0.14 | 0.33 × 0.02 × 0.02 | 0.47 × 0.03 × 0.02 |
Tmin, Tmax | 0.815, 1.000 | 0.994, 1.000 | 0.812, 1.000 | 0.453, 1.000 |
No. of measured, independent, and observed [I > 2σ(I)] reflections | 9572, 3490, 3415 | 28147, 5625, 5150 | 43,588, 7927, 4121 | 13,249, 4111, 3338 |
Rint | 0.019 | 0.031 | 0.091 | 0.029 |
(sin θ/λ)max (Å−1) | 0.620 | 0.719 | 0.625 | 0.621 |
R[F2 > 2σ(F2)], wR(F2), S | 0.028, 0.070, 1.06 | 0.034, 0.082, 1.03 | 0.064, 0.187, 1.03 | 0.039, 0.107, 1.02 |
Δρmax, Δρmin (e Å−3) | 0.25, −0.14 | 0.31, −0.24 | 0.23, −0.27 | 0.25, −0.39 |
Absolute structure parameter | 0.12 (4) | 0.023 (15) | – | – |
Compounds | d(N5-C57) | <(C5-C57-N5-C51) | (N1 ÷ C5) < (C21 ÷ C26) | (N1 ÷ C5) < (C41 ÷ C46) | (N1 ÷ C5) < (C51 ÷ C56) | |
---|---|---|---|---|---|---|
4a | 1.286 (3) | −173.35 (17) | 12.2 (2) | 19.8 (2) | 14.8 (2) | |
4b | 1.289 (2) | −178.82 (17) | 7.0 (3) | 2.1 (2) | 41.8 (2) | |
4c | Molecule A | 1.284 (4) | 177.4 (3) | 8.0 (4) | 8.1 (6)/ 7.9 (6) ′ | 5.3 (4) |
Molecule B | 1.281 (4) | −177.1 (3) | 6.0 (4) | 18.8 (5)/ 26.9 (5) ″ | 7.426 (4) | |
4d | 1.282 (2) | −178.90 (14) | 4.9 (2) | 19.1 (2) | 6.4 (2) | |
III [43] | 1.288 (2) * | 176.65 (16) * | 10.3 (3) * | 15.2 (3) * | 8.6 (3) * |
Compounds | D–H∙∙∙A | d(D–H) | d(H···A) | d(D···A) | <(D–H···A) |
---|---|---|---|---|---|
4a | N4–H4···N5 | 0.95 (2) | 1.87 (2) | 2.692 (2) | 143 (2) |
C46–H46···N3 | 0.95 | 2.26 | 2.825 (3) | 117.3 | |
C56–H56···F4 i | 0.95 | 2.66 | 3.592 (3) | 168.8 | |
C61–H613···F4 i | 0.98 | 2.66 | 3.372 (2) | 129.6 | |
4b | N4–H4···N5 | 0.86 (2) | 1.93 (2) | 2.669 (2) | 143 (2) |
C45–H45···Cl5 i | 0.95 | 2.80 | 3.591 (2) | 141.2 | |
C46–H46···N3 | 0.95 | 2.35 | 2.951 (3) | 120.9 | |
C61–H611···F4 ii | 0.98 | 2.61 | 3.280 (2) | 125.5 | |
C61–H613···Cl5 iii | 0.98 | 2.92 | 3.738 (2) | 141.8 | |
4c | N4A–H4A···N5A | 0.90 (3) | 1.86 (3) | 2.678 (4) | 151 (3) |
N4B–H4B···N5B | 0.88 (4) | 1.84 (4) | 2.651 (4) | 152 (3) | |
C42A–H42A···O5A | 0.95 | 2.66 | 3.552 (12) | 156.5 | |
C42C–H42C···O5A | 0.95 | 2.73 | 3.577 (13) | 149.4 | |
C42B–H42B···O5B | 0.95 | 2.56 | 3.374 (8) | 144.4 | |
C46A–H46A···N3A | 0.95 | 2.36 | 2.935 (12) | 118.6 | |
C46C–H46C···N3A | 0.95 | 2.30 | 2.868 (12) | 118.1 | |
C46B–H46B···N3B | 0.95 | 2.52 | 3.060 (9) | 115.9 | |
C46D–H46D···N3B | 0.95 | 2.19 | 2.765 (9) | 117.8 | |
C43B–H43B···F4B i | 0.95 | 2.03 | 2.643 (10) | 121.0 | |
C58A–H5A3···N4A ii | 0.98 | 2.77 | 3.283 (5) | 113.6 | |
C58D–H5D2···N4B ii | 0.98 | 2.66 | 3.241 (10) | 118.4 | |
C61A–H6A1···F4D iii | 0.98 | 2.61 | 3.336 (8) | 131.1 | |
C61A–H6A3···F4D iv | 0.98 | 2.59 | 3.381 (8) | 137.4 | |
4d | N4–H4···N5 | 0.87 (2) | 1.90 (2) | 2.651 (2) | 144.1 (18) |
C46–H46···N3 | 0.95 | 2.35 | 2.933 (2) | 119.3 | |
C55–H55···F52 i | 0.95 | 2.47 | 3.394 (2) | 162.8 | |
C52–H52···F4 ii | 0.95 | 2.82 | 3.280 (2) | 111.0 |
Compounds | A172 | AGS | CaCo-2 | HeLa | HepG2 |
---|---|---|---|---|---|
4b | 63.385 | 32.210 | >100 | >100 | >100 |
4c | >100 | >100 | >100 | >100 | >100 |
4d | >100 | >100 | >100 | >100 | >100 |
III [43] | 4b | N-1H-Indazol-5-yl-2-(6-methylpyridin-2-yl)quinazolin-4-amine | |
---|---|---|---|
Physiochemical properties | The compound has a molecular weight of 426.49 g/mol; number of heavy atoms and number of aromatic heavy atoms: 32 and 24, respectively; number of rotatable bonds: 7; number of H-bond acceptors and donors: 5 and 1, respectively. The value of the polar surface area (PSA) calculated using the topological polar surface area (TPSA), considering sulphur and phosphorus as polar atoms, is 59.40 Å [47] | The compound has a molecular weight of 416.88g/mol; number of heavy atoms and number of aromatic heavy atoms: 30 and 24, respectively; number of rotatable bonds: 5; number of H-bond acceptors and donors: 4 and 1, respectively. The value of the polar surface area (PSA) calculated using the topological polar surface area (TPSA), considering sulphur and phosphorus as polar atoms, is 50.17 Å | The compound has a molecular weight of 352.39 g/mol; number of heavy atoms and number of aromatic heavy atoms: 27 and 25, respectively; number of rotatable bonds: 3; number of H-bond acceptors and donors: 4 and 2 respectively. The value of the polar surface area (PSA) calculated using the topological polar surface area (TPSA), considering sulphur and phosphorus as polar atoms, is 79.38 Å |
Lipophilicity | The value partition coefficient between n-octanol and water (log Po/w) is 5.55 [48]. It is an average value of five freely available predictive models (i.e., XLOGP3 [49], WLOGP [50], MLOGP [51,52], SILICOS-IT [53], and iLOGP) [54]. | The consensus value partition coefficient between n-octanol and water (log Po/w) is 5.75. | The consensus value partition coefficient between n-octanol and water (log Po/w) is 3.63. |
Water solubility | Estimated by three predictors. The value of Log S (ESOL) [55] is −6.28, which indicates that a compound is poorly soluble. The predicted value of solubility is 2.23 × 10−4 mg/mL. The value of log S (Ali) [56] is −6.90, which classifies the compound as poorly soluble. The value of solubility is 5.37 × 10−5 mg/mL. The value of log S (SILICOS-IT) [53] is −10.45, which classifies the compound as insoluble. The predicted value of solubility is 1.53 × 10−8 mg/mL. | The value of Log S (ESOL) is −6.57, which classifies a compound as poorly soluble. The predicted value of solubility is 1.11 × 10−4 mg/mL. The value of log S (Ali) is −7.01, which also classifies the compound as poorly soluble. The value of solubility is 2.99 × 10−2 mg/mL. The value of log S (SILICOS-IT) is −10.54, which classifies the compound as insoluble. The predicted value of solubility is 1.21 × 10−8 mg/mL. | The value of Log S (ESOL) is −5.08, which classifies a compound as poorly soluble. The predicted value of solubility is 1.11 × 10−4 mg/mL. The value of log S (Ali) is −7.01, which also classifies the compound as poorly soluble. The value of solubility is 2.99 × 10−2 mg/mL. The value of log S (SILICOS-IT) is −10.54, which classifies the compound as insoluble. The predicted value of solubility is 1.21 × 10−8 mg/mL. |
Pharmacokinetics | One of the estimated predictors relates to skin permeability coefficient (Kp) [57]. The more negative Kp is, the less permeant a molecule is. The predicted Kp value of compound 3 is −4.73 cm/s, which is the predicted interaction of a molecule with cytochromes P450 [58,59]. The compound is predicted to be an inhibitor of CYP2C19, CYP2D6, and CYP3A4. | The predicted Kp value of the compound is −4.46 cm/s. The compound is predicted to be an inhibitor of CYP2C19 and CYP3A4. | The predicted Kp value of the compound is −5.56 cm/s. The compound is predicted to be an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4. |
Drug-likeness | Estimation of the chance to be an oral drug. The software programme SwissADME (http://www.swissadme.ch/, accessed on 29 December 2023) is based on five different predictors and was originally used by major pharmaceutical companies aiming to improve the quality of their chemical substances. These are the Lipinski (Pfizer) rule of five [60], Ghose (Amgen) [61], Veber (GSK) [62], Egan (Pharmacia) [63], and Muegge (Bayer) [64]. According to Lipinski and Veber, the compound is predicted to have a chance to be an oral drug, with a bioavailability score 0.55 | According to the Lipinski rule of five [60] and Veber [62], the compound is predicted to have a chance to be an oral drug. | According to the Lipinski rule of five [60], Veber [62], Egan [63], and Muegge [64], the compound is predicted to have a chance to be an oral drug. |
Medicinal chemistry | Two complementary pattern recognition methods allow for the identification of potentially problematic fragments—assay interference compounds (PAINS) [65] and Brenk Structural alert [66]. One predicted alert according to Brenk. | Compound has one predicted structural problematic fragment. | Compound has one predicted structural problematic fragments. |
Compound | Target Class | Target Name | Protein Data Bank (PDB) Accession Code |
---|---|---|---|
III [43] | Kinase | VEGFR2 in complex with a novel 4-amino-furo[2,3-d]pyrimidine | 1YWN |
4b | Kinase | VEGFR2 in complex with a novel 4-amino-furo[2,3-d]pyrimidine | 1YWN |
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Bryndal, I.; Stolarczyk, M.; Mikołajczyk, A.; Krupińska, M.; Pyra, A.; Mączyński, M.; Matera-Witkiewicz, A. Pyrimidine Schiff Bases: Synthesis, Structural Characterization and Recent Studies on Biological Activities. Int. J. Mol. Sci. 2024, 25, 2076. https://doi.org/10.3390/ijms25042076
Bryndal I, Stolarczyk M, Mikołajczyk A, Krupińska M, Pyra A, Mączyński M, Matera-Witkiewicz A. Pyrimidine Schiff Bases: Synthesis, Structural Characterization and Recent Studies on Biological Activities. International Journal of Molecular Sciences. 2024; 25(4):2076. https://doi.org/10.3390/ijms25042076
Chicago/Turabian StyleBryndal, Iwona, Marcin Stolarczyk, Aleksandra Mikołajczyk, Magdalena Krupińska, Anna Pyra, Marcin Mączyński, and Agnieszka Matera-Witkiewicz. 2024. "Pyrimidine Schiff Bases: Synthesis, Structural Characterization and Recent Studies on Biological Activities" International Journal of Molecular Sciences 25, no. 4: 2076. https://doi.org/10.3390/ijms25042076