A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Silico Predictions
2.2.1. Physicochemical Properties
2.2.2. Pharmacokinetic/ADME and Drug Likeness Properties
2.3. Biological Study
2.3.1. Anticancer Activity
2.3.2. The Effects of ILs on cell Apoptosis
3. Experimental Section
3.1. Chemical Characterization and Synthesis
3.1.1. General Procedure for the Quaternization of Imidazoles
3.1.2. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium bromide (6).
3.1.3. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,2-dimethyl-1H-imidazol-3-ium bromide (7).
3.1.4. 1-Methyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium bromide (8).
3.1.5. 1,2-Dimethyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium bromide (9).
3.1.6. 1-Methyl-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium bromide (10).
3.1.7. 1,2-Dimethyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium bromide (11).
3.2. General Procedure for the Metathesis Reaction
3.2.1. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium hexafluorophosphate (12).
3.2.2. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium tetrafluoroborate (13).
3.2.3. 3-(2-Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1-methyl-1H-imidazol-3-ium 2,2,2-trifluoroacetate (14).
3.2.4. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,2-dimethyl-1H-imidazol-3-ium hexafluorophosphate (15).
3.2.5. 3-(2-(Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,2-dimethyl-1H-imidazol-3-ium tetrafluoroborate (16).
3.2.6. 3-(2-Benzo[d]thiazol-2-ylamino)-2-oxoethyl)-1,2-dimethyl-1H-imidazol-3-ium 2,2,2-trifluoroacetate (17).
3.2.7. 1-Methyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium hexafluorophosphate (18).
3.2.8. 1-Methyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium tetrafluoroborate (19).
3.2.9. 1-Methyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium 2,2,2-tri-fluoroacetate (20).
3.2.10. 1,2-Dimethyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium hexafluorophosphate (21).
3.2.11. 1,2-Dimethyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium tetrafluoroborate (22).
3.2.12. 1,2-Dimethyl-3-(2-((6-methylbenzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium 2,2,2-trifluoroacetate (23).
3.2.13. 1-Methyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium hexafluorophosphate (24).
3.2.14. 1-Methyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium tetrafluoroborate (25).
3.2.15. 1-Methyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium 2,2,2-trifluoroacetate (26).
3.2.16. 1,2-Dimethyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium hexafluorophosphate (27).
3.2.17. 1,2-Dimethyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3- ium tetrafluoroborate (28).
3.2.18. -1,2-Dimethyl-3-(2-((6-(methylsulfonyl)benzo[d]thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazol-3-ium 2,2,2-trifluoroacetate (29).
3.3. Method of Computation: In Silico Study
3.4. Biological Study
3.4.1. Anticancer Activity
Cell Line and Culture Conditions
In Vitro Cytotoxicity
Flow Cytometry Analysis:
4. Conclusions
Supplementary Materials
Author Contributions
Conflicts of Interest
Abbreviations
ILs | Ionic Liquids |
ADME | Absorption, Distribution, Metabolism and Excretion |
DCM | Dichloromethane |
TPSA | Topological Polar Surface Area |
ABS | Absorption |
HBA | Number of hydrogen bond acceptor |
HBD | Number of hydrogen bond donor |
GI | Gastro intestinal |
P-gp | P-glycoprotein |
BBB | Blood-brain barrier |
HIA | Human gastrointestinal absorption |
RO5 | Rule-of-five |
ROS | Reactive oxygen species |
HRMS | High resolution mass spectroscopy |
TMS | Tetramethylsilane |
DMSO | Dimethylsufoxide |
S | Singlet |
D | Doublet |
T | Triplet |
M | Multiplet |
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Comp.No. | Fraction Csp3 a | No. of Rotatable Bonds | HBA b | HBD c | iLogP d | Molar Refractivity | Log S e | TPSA f | In-Silico % Absorption |
---|---|---|---|---|---|---|---|---|---|
6 | 0.15 | 4 | 2 | 1 | −5.18 | 85.22 | S | 79.04 | 81.75 |
7 | 0.21 | 4 | 2 | 1 | −2.34 | 90.19 | S | 79.04 | 81.75 |
8 | 0.21 | 4 | 2 | 1 | −4.45 | 90.19 | S | 79.04 | 81.75 |
9 | 0.27 | 4 | 2 | 1 | −2.88 | 95.16 | MS | 79.04 | 81.75 |
10 | 0.21 | 5 | 4 | 1 | −5.71 | 98.32 | S | 121.56 | 67.06 |
11 | 0.27 | 5 | 4 | 1 | −4.77 | 103.28 | MS | 121.56 | 67.06 |
12 | 0.15 | 4 | 8 | 1 | 0 | 89.86 | S | 92.63 | 77.04 |
13 | 0.15 | 4 | 6 | 1 | 0 | 86.48 | S | 79.04 | 81.75 |
14 | 0.2 | 5 | 7 | 1 | −4.3 | 88.05 | S | 119.17 | 67.89 |
15 | 0.21 | 4 | 8 | 1 | 0 | 94.83 | S | 92.63 | 77.04 |
16 | 0.21 | 4 | 6 | 1 | 0 | 91.45 | S | 79.04 | 81.75 |
17 | 0.25 | 5 | 7 | 1 | −3.36 | 93.01 | S | 119.17 | 67.89 |
18 | 0.21 | 4 | 8 | 1 | 0 | 94.83 | S | 92.63 | 77.04 |
19 | 0.21 | 4 | 6 | 1 | 0 | 91.45 | S | 79.04 | 81.75 |
20 | 0.25 | 5 | 7 | 1 | −3.57 | 93.01 | S | 119.17 | 67.89 |
21 | 0.27 | 4 | 8 | 1 | 0 | 99.8 | MS | 92.63 | 77.04 |
22 | 0.27 | 4 | 6 | 1 | 0 | 96.41 | MS | 79.04 | 81.75 |
23 | 0.29 | 5 | 7 | 1 | −4.17 | 97.98 | MS | 119.17 | 67.89 |
24 | 0.21 | 5 | 10 | 1 | 0 | 102.96 | S | 135.15 | 62.37 |
25 | 0.21 | 5 | 8 | 1 | 0 | 99.58 | S | 121.56 | 67.06 |
26 | 0.25 | 6 | 9 | 1 | −5.2 | 101.14 | S | 161.69 | 53.22 |
27 | 0.27 | 5 | 10 | 1 | 0 | 107.92 | MS | 135.15 | 62.37 |
28 | 0.27 | 5 | 8 | 1 | 0 | 104.54 | MS | 121.56 | 67.06 |
29 | 0.29 | 6 | 9 | 1 | −4.83 | 106.11 | MS | 161.69 | 53.22 |
Comp. No | Pharmacokinetic/ADME Properties | ||||||||
---|---|---|---|---|---|---|---|---|---|
GI Abs a | BBB Permeant b | P-Gpsubstrate c | CYP1A2 Inhibitor d | CYP2C19 Inhibitor e | CYP2C9 Inhibitor f | CYP2D6 Inhibitor g | CYP3A4 Inhibitor h | Log Kp i | |
6 | High | No | Yes | No | No | No | No | No | −6.39 |
7 | High | No | Yes | No | No | No | No | No | −6.19 |
8 | High | No | Yes | No | No | No | No | No | −6.22 |
9 | High | No | Yes | No | No | No | No | No | −6.02 |
10 | High | No | Yes | No | No | No | No | No | −7.4 |
11 | High | No | Yes | No | No | No | No | No | −7.21 |
12 | Low | No | No | No | Yes | No | No | Yes | −5.19 |
13 | Low | No | No | No | Yes | No | No | Yes | −4.99 |
14 | High | No | No | No | No | No | No | No | −5.54 |
15 | High | No | No | No | No | No | No | No | −5.34 |
16 | High | No | Yes | No | No | No | No | No | −6.64 |
17 | High | No | Yes | No | No | No | No | No | −6.44 |
18 | Low | No | No | No | Yes | No | No | Yes | −5.02 |
19 | High | No | No | No | No | No | No | No | −5.37 |
20 | High | No | Yes | No | No | No | No | No | −6.46 |
21 | Low | No | Yes | No | Yes | No | No | Yes | −4.82 |
22 | High | No | No | No | No | No | No | No | −5.17 |
23 | High | No | Yes | No | No | No | No | No | −6.26 |
24 | Low | No | No | No | No | No | No | Yes | −6.21 |
25 | Low | No | No | No | No | No | No | No | −6.56 |
26 | Low | No | Yes | No | No | No | No | No | −7.66 |
27 | Low | No | No | No | No | No | No | Yes | −6.01 |
28 | Low | No | No | No | No | No | No | No | −6.36 |
29 | Low | No | Yes | No | No | No | No | No | −7.46 |
Comp. No. | Lipinski Violations | Ghose Violations | Veber Violations | Egan Violations | Muegge Violations | Bioavailability Score |
---|---|---|---|---|---|---|
6 | 0 | 1 | 0 | 0 | 0 | 0.55 |
7 | 0 | 1 | 0 | 0 | 0 | 0.55 |
8 | 0 | 1 | 0 | 0 | 0 | 0.55 |
9 | 0 | 1 | 0 | 0 | 0 | 0.55 |
10 | 0 | 1 | 0 | 0 | 0 | 0.55 |
11 | 0 | 1 | 0 | 0 | 0 | 0.55 |
12 | 0 | 1 | 0 | 1 | 1 | 0.55 |
13 | 0 | 0 | 0 | 0 | 0 | 0.55 |
14 | 0 | 0 | 0 | 0 | 0 | 0.55 |
15 | 0 | 1 | 0 | 1 | 1 | 0.55 |
16 | 0 | 0 | 0 | 0 | 0 | 0.55 |
17 | 0 | 0 | 0 | 0 | 0 | 0.55 |
18 | 0 | 1 | 0 | 1 | 1 | 0.55 |
19 | 0 | 0 | 0 | 0 | 0 | 0.55 |
20 | 0 | 0 | 0 | 0 | 0 | 0.55 |
21 | 0 | 1 | 0 | 1 | 1 | 0.55 |
22 | 0 | 0 | 0 | 0 | 0 | 0.55 |
23 | 0 | 0 | 0 | 0 | 0 | 0.55 |
24 | 0 | 2 | 0 | 2 | 0 | 0.55 |
25 | 0 | 0 | 0 | 0 | 0 | 0.55 |
26 | 0 | 0 | 1 | 1 | 1 | 0.55 |
27 | 1 | 2 | 0 | 2 | 0 | 0.55 |
28 | 0 | 0 | 0 | 0 | 0 | 0.55 |
29 | 0 | 0 | 1 | 1 | 1 | 0.55 |
Comp. N | HCT | Caco-2 | T47D | MCF-7 |
---|---|---|---|---|
6 | >500 | >500 | >500 | >500 |
7 | >500 | >500 | >500 | >500 |
8 | 143 ± 5 | 122 ± 3 | 162 ± 6 | 153 ± 8 |
9 | 210 ± 8 | 189 ± 7 | 230 ± 11 | 194 ± 6 |
10 | 246 ± 12 | 229 ± 8 | 237 ± 12 | 241 ± 7 |
11 | 187 ± 8 | 178 ± 11 | 198 ± 7 | 193 ± 6 |
12 | >500 | >500 | >500 | >500 |
13 | >500 | >500 | >500 | >500 |
14 | >500 | >500 | >500 | >500 |
15 | >500 | >500 | >500 | >500 |
16 | >500 | >500 | >500 | >500 |
17 | >500 | >500 | >500 | >500 |
18 | 183 ± 7 | 179 ± 5 | 188 ± 9 | 177 ± 4 |
19 | 132 ± 9 | 112 ± 5 | 139 ± 7 | 125 ± 6 |
20 | 190 ± 11 | 181 ± 9 | 187 ± 9 | 188 ± 6 |
21 | 168 ± 7 | 156 ± 3 | 167 ± 8 | 143 ± 7 |
22 | 98 ± 9 | 88 ± 4 | 115 ± 5 | 89 ± 3 |
23 | 149 ± 6 | 137 ± 5 | 154 ± 7 | 155 ± 4 |
24 | 246 ± 9 | 260 ± 11 | 293 ± 5 | 287 ± 10 |
25 | 211 ± 5 | 199 ± 4 | 200 ± 8 | 205 ± 6 |
26 | 210 ± 9 | 219 ± 3 | 213 ± 7 | 218 ± 4 |
27 | 239 ± 11 | 248 ± 8 | 241 ± 9 | 251 ± 7 |
28 | 186 ± 7 | 179 ± 7 | 178 ± 4 | 168 ± 6 |
29 | 174 ± 10 | 169 ± 7 | 167 ± 8 | 171 ± 9 |
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Al-blewi, F.; Rezki, N.; Naqvi, A.; Qutb Uddin, H.; Al-Sodies, S.; Messali, M.; Aouad, M.R.; Bardaweel, S. A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids. Int. J. Mol. Sci. 2019, 20, 2865. https://doi.org/10.3390/ijms20122865
Al-blewi F, Rezki N, Naqvi A, Qutb Uddin H, Al-Sodies S, Messali M, Aouad MR, Bardaweel S. A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids. International Journal of Molecular Sciences. 2019; 20(12):2865. https://doi.org/10.3390/ijms20122865
Chicago/Turabian StyleAl-blewi, Fawzia, Nadjet Rezki, Arshi Naqvi, Husna Qutb Uddin, Salsabeel Al-Sodies, Mouslim Messali, Mohamed Reda Aouad, and Sanaa Bardaweel. 2019. "A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids" International Journal of Molecular Sciences 20, no. 12: 2865. https://doi.org/10.3390/ijms20122865