Synthesis, Molecular Docking Study, and Cytotoxic Activity against MCF Cells of New Thiazole–Thiophene Scaffolds
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Cytotoxic Potential
- The 1,3-thiazole derivatives 4b and 13a (IC50 = 10.2 ± 0.7 and 11.5 ± 0.8 μM, respectively) have promising antitumor activity against the breast carcinoma cell line (MCF-7), and showed greater activities than the cisplatin reference drug (IC50 = 13.3 ± 0.61 μM);
- The 1,3-thiazole derivatives 11c and 11d have poor antitumor activity (IC50 > 38 μM), while the rest of the evaluated thiazoles have moderate activity (IC50 = 13.6–23.7 μM);
- For 1,3-thiazoles 4, 8, and 11: the introduction of an electron-donating group (eg. methyl group) into phenyl group at position 5 in the 1,3-thiazole ring enhances the antitumor activity, while the introduction of an electron-withdrawing group (chlorine) decreases the activity (4b > 4a > 4c > 4d; 8a > 8b; and 11b >11a > 11c >11d);
- For the substituent at position 5 of the 1,3-thiazoles: an acetyl group (Ac) gives higher activity than an ester group (CO2Et). 13a (IC50 = 11.5 ± 0.7 μM) > 13b (IC50 = 16.3 ± 1.4 μM).
2.3. Molecular Docking Studies
2.4. Toxicity Radar
2.5. SwissADME Studies
2.6. Pred-hERG
3. Experimental Section
3.1. Chemistry
3.1.1. Experimental Instrumentation
3.1.2. General Procedure for Synthesizing the Thiazole Derivatives 4a–d, 8a,b, 11a–d, and 13a,b
3.1.3. Alternate Synthesis of 4a and 8a
3.2. In Vitro Cytotoxic Activity
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Tested Compounds | IC50 (μM) MCF-7 | CC50 (μM) LLC-MK2 | SI Values (CC50/IC50) |
---|---|---|---|
4a | 16.3 ± 1.0 | 183.05 ± 21.31 | 11.23 |
4b | 10.2 ± 0.8 | 175.92 ± 18.24 | 17.25 |
4c | 19.7 ± 1.3 | - | - |
4d | 19.8 ± 0.9 | - | - |
8a | 13.6 ± 0.9 | 149.46 ± 15.86 | 10.99 |
8b | 23.7 ± 1.6 | - | - |
11a | 21.0 ± 0.7 | - | - |
11b | 17.9 ± 0.8 | 231.45 ± 25.03 | 12.93 |
11c | 38.2 ± 1.4 | - | - |
11d | 54.8 ± 1.6 | - | - |
13a | 11.5 ± 0.7 | 162.65 ± 19.06 | 14.14 |
13b | 16.3 ± 1.4 | 135.22 ± 9.58 | 8.29 |
Cisplatin | 13.3 ± 0.61 | 158.75 ± 4.67 | 11.93 |
Compound | Ligand | Receptor | Interaction | Distance | E (kcal/mol) |
---|---|---|---|---|---|
4a | No measurable interaction | ||||
4b | S (8) | O ARG 66 (B) | H-donor | 3.69 | −0.5 |
8a | No measurable interaction | ||||
11b | No measurable interaction | ||||
13a | No measurable interaction | ||||
13b | No measurable interaction | ||||
Carbo-Pt | No measurable interaction |
4a | 4b | 8a | 11b | 13a | 13b | |
---|---|---|---|---|---|---|
Predicted LD50 (mg/kg) | 525 | 3200 | 1000 | 1000 | 300 | 1000 |
Predicted toxicity class | 4 | 5 | 4 | 4 | 3 | 4 |
Average similarity (%) | 29.02 | 29.63 | 33.11 | 38.09 | 32.55 | 37.66 |
Prediction accuracy (%) | 12 | 12 | 23 | 23 | 23 | 23 |
Property | Pred-hERG | |
---|---|---|
4b | 13a | |
Prediction/Potency | Weak or Moderate | Weak or Moderate |
Confidence (%) | 60 | 70 |
Applicability domain (AD) | No (Value = 0.19 and limit = 0.26) | No (Value = 0.23 and limit = 0.26) |
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Gomha, S.M.; Riyadh, S.M.; Huwaimel, B.; Zayed, M.E.M.; Abdellattif, M.H. Synthesis, Molecular Docking Study, and Cytotoxic Activity against MCF Cells of New Thiazole–Thiophene Scaffolds. Molecules 2022, 27, 4639. https://doi.org/10.3390/molecules27144639
Gomha SM, Riyadh SM, Huwaimel B, Zayed MEM, Abdellattif MH. Synthesis, Molecular Docking Study, and Cytotoxic Activity against MCF Cells of New Thiazole–Thiophene Scaffolds. Molecules. 2022; 27(14):4639. https://doi.org/10.3390/molecules27144639
Chicago/Turabian StyleGomha, Sobhi M., Sayed M. Riyadh, Bader Huwaimel, Mohie E. M. Zayed, and Magda H. Abdellattif. 2022. "Synthesis, Molecular Docking Study, and Cytotoxic Activity against MCF Cells of New Thiazole–Thiophene Scaffolds" Molecules 27, no. 14: 4639. https://doi.org/10.3390/molecules27144639