Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Anti-Proliferative Activity
2.3. Computational Studies
3. Conclusions
4. Experimental
4.1. Experimental Instrumentation
4.2. Synthesis of methyl 2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene) hydrazinecarbodithioate (3)
4.3. Synthesis of 2-((1-((1,3,4-thiadiazolylidene)hydrazono)ethyl)-3-methyl-6-phenylimidazo[2,1-b]thiazoles (6a–i)
4.4. Synthesis of bis-thiadiazoles 10, 11 and 12
4.5. Anti-Proliferative Activity Cells
4.6. Compounds
4.7. An Anti-Proliferative Assay In Vitro
4.8. Cytotoxic Test SRB
4.9. In Silico Studies
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | HepG2 IC50 ± SD[µg/mL] | BALAB/3T3 IC50 ± SD[µg/mL] |
---|---|---|
Doxorubicin | 3.56 ± 0.46 | 3.21 ± 0.32 |
3 | Nd | Nd |
6a | 63.32 ± 12.83 | 25.09 ± 12.00 |
6b | 59.20 ± 9.27 | Nd |
6c | Nd | Nd |
6d | 41.14 ± 8.32 | Nd |
6e | Nd | Nd |
6f | 57.52 ± 6.61 | Nd |
6g | 33.24 ± 8.25 | 76.72 ± 4.14 |
6h | Nd | Nd |
6j | 19.93 ± 3.28 | 35.65 ± 1.27 |
10 | 23.51 ± 4.48 | 26.24 ± 3.21 |
11 | Nd | Nd |
12 | 12.73 ± 1.36 | 8.34 ± 1.81 |
Structure | Binding Affinity (kcal·mol−1) | Docked Complex (Amino Acid–Ligand) Interactions | Distance (Å) | |
---|---|---|---|---|
Ref. | | −8.60 | H-bonds reference—TYR255 reference—TYR255 reference—CYS401 reference—PRO267 | 2.94 2.95 2.30 1.87 |
3 | | −6.90 | π-cation interactions compound 3—ARG197 compound 3—ARG197 | 6.42 6.49 |
6a | | −9.40 | H-bonds compound 6a—-SER136 | 1.97 |
6b | | −9.11 | H-bonds compound 6b—SER136 | 1.99 |
6c | | −8.17 | H-bonds compound 6c—SER136 | 2.53 |
6d | | −8.15 | H-bonds compound 6d—GLN356 | 2.10 |
6e | | −8.11 | H-bonds compound 6e—GLN356 | 2.42 |
6f | | −7.91 | H-bonds compound 6f—GLN356 | 2.71 |
6g | | −9.30 | π-π interactions compound 6g—TYR357 | 4.45 |
6h | | −8.52 | H-bonds compound 6h—SER136 | 2.90 |
6i | | −9.03 | π-π interactions compound 6i—PHE144 compound 6i—PHE401 compound 6i—PHE401 | 4.81 4.82 4.02 |
10 | | −9.52 | π-π interactions compound 10—PHE398 | 5.69 |
11 | | −9.01 | π-π interactions compound 11—TYR408 | 4.17 |
12 | | −10.30 | π-π interactions compound 12—PHE398 | 4.75 |
Blood-Brain Barrier (BBB+) | Human Intestinal Absorption (HIA+) | Caco-2 Permeability (Caco2+) | AMES Toxicity | Carcino-Genicity | |
---|---|---|---|---|---|
3 | 0.726 | 0.992 | 0.535 | Nontoxic | Non carcinogenic |
6a | 0.898 | 1 | 0.559 | Nontoxic | Non carcinogenic |
6b | 0.907 | 1 | 0.55 | Nontoxic | Non carcinogenic |
6c | 0.872 | 1 | 0.541 | Nontoxic | Non carcinogenic |
6d | 0.884 | 1 | 0.53 | Nontoxic | Non carcinogenic |
6e | 0.884 | 1 | 0.53 | Nontoxic | Non carcinogenic |
6f | 0.849 | 0.997 | 0.533 | Nontoxic | Non carcinogenic |
6g | 0.857 | 0.996 | 0.556 | Nontoxic | Non carcinogenic |
6h | 0.784 | 0.993 | 0.528 | Nontoxic | Non carcinogenic |
6i | 0.9 | 0.994 | 0.588 | Nontoxic | Non carcinogenic |
10 | 0.9 | 0.994 | 0.588 | Nontoxic | Non carcinogenic |
11 | 0.9 | 0.997 | 0.536 | Nontoxic | Non carcinogenic |
12 | 0.532 | 0.95 | 0.567 | Nontoxic | Non carcinogenic |
TPSA (A2) | HBA | HBD | n Rotatable | Volume (A3) | |
---|---|---|---|---|---|
3 | 41.70 | 4 | 1 | 5 | 319.26 |
6a | 76.93 | 7 | 0 | 5 | 434.42 |
6b | 86.17 | 8 | 0 | 6 | 443.40 |
6c | 76.93 | 7 | 0 | 5 | 431.39 |
6d | 86.17 | 8 | 0 | 7 | 443.64 |
6e | 86.17 | 8 | 0 | 7 | 460.20 |
6f | 86.17 | 8 | 0 | 7 | 461.53 |
6g | 88.96 | 8 | 1 | 6 | 485.10 |
6h | 134.78 | 10 | 1 | 7 | 508.44 |
6i | 59.86 | 6 | 0 | 5 | 453.72 |
10 | 119.72 | 10 | 0 | 10 | 823.39 |
11 | 153.68 | 10 | 0 | 10 | 751.66 |
12 | 155.01 | 10 | 0 | 12 | 854.50 |
Sample Availability: Samples of the compounds are available from the authors. | |
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Rashdan, H.R.M.; Abdelmonsef, A.H.; Shehadi, I.A.; Gomha, S.M.; Soliman, A.M.M.; Mahmoud, H.K. Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates. Molecules 2020, 25, 4997. https://doi.org/10.3390/molecules25214997
Rashdan HRM, Abdelmonsef AH, Shehadi IA, Gomha SM, Soliman AMM, Mahmoud HK. Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates. Molecules. 2020; 25(21):4997. https://doi.org/10.3390/molecules25214997
Chicago/Turabian StyleRashdan, Huda R. M., Aboubakr H. Abdelmonsef, Ihsan A. Shehadi, Sobhi M. Gomha, Abdel Mohsen M. Soliman, and Huda K. Mahmoud. 2020. "Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates" Molecules 25, no. 21: 4997. https://doi.org/10.3390/molecules25214997