Butylated Hydroxytoluene Analogs: Synthesis and Evaluation of Their Multipotent Antioxidant Activities
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Single Crystal X-ray Crystallography of Compounds 3 and 4
3 | 4 | ||
---|---|---|---|
Bond lengths | |||
S(2)-C(18) | 1.6714(15) | S(2)-C(17) | 1.728(6) |
O(2)-C(17) | 1.2417(18) | S(2)-C(18) | 1.749(6) |
N(1)-C(17) | 1.3201(18) | O(1)-C(1) | 1.376(6) |
N(1)-N(2) | 1.3757(17) | N(1)-C(17) | 1.293(7) |
N(2)-C(18) | 1.3490(18) | N(1)-N(2) | 1.395(6) |
N(3)-C(18) | 1.3563(19) | N(2)-C(18) | 1.296(6) |
N(3)-C(19) | 1.4108(18) | N(3)-C(18) | 1.365(7) |
Bond angles | |||
C(16)-S(1)-C(15) | 100.77(7) | C(16)-S(1)-C(15) | 100.4(3) |
C(18)-N(2)-N(1) | 120.45(13) | C(18)-N(3)-C(19) | 130.8(5) |
N(2)-C(18)-S(2) | 121.18(11) | C(4)-C(15)-S(1) | 113.1(4) |
N(3)-C(18)-S(2) | 128.05(11) | C(17)-C(16)-S(1) | 112.1(4) |
D-H···A | H···A [Å] | D···A [Å] | D-H···A [°] |
---|---|---|---|
3 | |||
N(3)-H(3N)...O(2) #1 | 2.040 (15) | 2.8570 (16) | 158.1 (17) |
N(2)-H(2N)...O(2) #1 | 2.019 (16) | 2.7927 (17) | 150.4 (17) |
4 | |||
N(3)-H(3N)...N(2) #2 | 2.05 (2) | 2.910 (7) | 169 (5) |
3 | 4 | |
---|---|---|
Empirical formula | C24 H32 F N3 O2 S2 | C24 H30 F N3 O S2 |
Formula weight | 477.65 | 459.63 |
Crystal system | Triclinic | Monoclinic |
Space group | P-1 | C 2/c |
Unit cell dimensions | ||
a [Å] | 9.3441 (5) | 28.911 (11) |
b [Å] | 11.1548 (6) | 5.731 (2) |
c [Å] | 11.7683 (6) | 28.430 (11) |
α [°] | 91.189 (2) | |
β [°] | 93.388 (2) | 99.330 (5) |
γ [°] | 93.224 (2) | |
Volume [Å3] | 1,222.19 (11) | 4,648 (3) |
Z | 2 | 8 |
Independent reflections | 5,587 [Rint = 0.0428] | 4,202 [Rint = 0.2119] |
Observed reflections [I > 2σ(I)] | 4,988 | 1,848 |
Final R indices [I > 2σ(I)] | R1 = 0.0405, wR2 = 0.1135 | R1 = 0.0690, wR2 = 0.1340 |
R indices (all data) | R1 = 0.0448, wR2 =0.1160 | R1 = 0.1792, wR2 = 0.1820 |
2.3. Computational Evaluation of Biological Activity
Mode of biological activity | 1 | 3 | 4 | 5 | BHT | |||||
---|---|---|---|---|---|---|---|---|---|---|
Pa | Pi | Pa | Pi | Pa | Pi | Pa | Pi | pa | Pi | |
Lipid peroxidase inhibitor | 0.652 | 0.006 | 0.436 | 0.027 | 0.485 | 0.019 | 0.639 | 0.007 | 0.843 | 0.003 |
Antioxidant | 0.712 | 0.004 | 0.385 | 0.035 | 0.420 | 0.028 | 0.529 | 0.015 | 0.845 | 0.003 |
Free radical scavenger | 0.807 | 0.004 | 0.585 | 0.025 | 0.554 | 0.031 | 0.506 | 0.042 | 0.797 | 0.004 |
Antiinflammatory | 0.659 | 0.017 | 0.375 | 0.136 | 0.649 | 0.018 | 0.479 | 0.065 | 0.804 | 0.005 |
2.4. Molecular Properties and Drug-Likeness
2.4.1. Calculation of Drug-Likeness Properties
2.4.2. Lipophilicity
Compound | Violation of Rule of 5 (≤1) | HBA (≤10) | HBD (≤5) | Log P (≤5) | MW (≤500) | NROTB (≤10) | %ABS | PSA A2 ≤90 |
---|---|---|---|---|---|---|---|---|
1 | 0 | 4 | 2 | 4.41 | 310.452 | 6 | 88.66 | 58.93 |
3 | 1 | 4 | 4 | 6.43 | 477.658 | 10 | 82.59 | 76.54 |
4 | 1 | 5 | 2 | 6.94 | 459.643 | 8 | 89.63 | 56.14 |
5 (thione) | 1 | 4 | 2 | 6.84 | 459.643 | 7 | 92.33 | 48.30 |
5 (thiol) | 5 | 2 | 6.96 | 459.643 | 7 | 92.21 | 48.68 | |
BHT | 0 | 1 | 1 | 4.87 | 220.350 | 2 | 101.81 | 20.81 |
Vitamin E * | - | - | - | 10.44 | 430.71 | - | 98.73 | 29.74 |
Vitamin C * | - | - | - | −1.70 | 176.12 | - | 71.23 | 109.49 |
2.4.3. Violations of Lipinski’s Rule of Five
2.5. In Vitro Antioxidant Activities
2.5.1. In Vitro DPPH Free Radical Scavenging Activity
Compounds | IC50 a Values (µM/mL) ± S.E.M b and Max. inhibition % ± S.E.M | |
---|---|---|
DPPH Radical Scavenging | Lipid Peroxidation Inhibition | |
1 | 96.73 ± 1.87 (51.25 ± 0.82) | 38.84 ± 1.54 (73.99 ± 1.30) |
3 | 68.03 ± 1.27 (65.21 ± 0.55) | 56.00 ± 5.05 (74.64 ± 1.68) |
4 | > 100 c (26.09 ± 0.33) | 33.20 ± 2.91 (84.99 ± 1.37) |
5 | 85.30 ± 1.16 (65.26 ± 0.38) | 16.07 ± 3.51 (83.99 ± 1.65) |
BHT | >100 c (25.23 ± 0.17) | 36.67 ± 1.78 (79.45 ± 1.27) |
Ascorbic acid | 67.77 ± 0.17 (71.93 ± 1.61) | - |
α-TOH | - | 5.63 ± 1.09 (84.69 ± 1.23) |
2.5.2. In Vitro Lipid Peroxidation Activity
3. Experimental
3.1. General
3.2. X-ray Crystallography
3.3. Antioxidant Assays
3.3.1. DPPH Free Radical Scavenging Assay
3.3.2. Lipid Peroxidation Inhibition Assay
4. Conclusions
Acknowledgments
References and Notes
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Yehye, W.A.; Abdul Rahman, N.; A. Alhadi, A.; Khaledi, H.; Ng, S.W.; Ariffin, A. Butylated Hydroxytoluene Analogs: Synthesis and Evaluation of Their Multipotent Antioxidant Activities. Molecules 2012, 17, 7645-7665. https://doi.org/10.3390/molecules17077645
Yehye WA, Abdul Rahman N, A. Alhadi A, Khaledi H, Ng SW, Ariffin A. Butylated Hydroxytoluene Analogs: Synthesis and Evaluation of Their Multipotent Antioxidant Activities. Molecules. 2012; 17(7):7645-7665. https://doi.org/10.3390/molecules17077645
Chicago/Turabian StyleYehye, Wageeh A., Noorsaadah Abdul Rahman, Abeer A. Alhadi, Hamid Khaledi, Seik Weng Ng, and Azhar Ariffin. 2012. "Butylated Hydroxytoluene Analogs: Synthesis and Evaluation of Their Multipotent Antioxidant Activities" Molecules 17, no. 7: 7645-7665. https://doi.org/10.3390/molecules17077645