Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Assessment of Cytotoxic Activity against LPS-Activated RAW264.7 Cells
2.3. In Vitro Evaluation of the Anti-Inflammatory Activity against LPS-Activated RAW264.7 Cells by Assessing NO Production
2.4. Assessment of IL-1β Expression (Western Blot Analysis)
2.5. Assessment of IL-6 and TNF-α Expression
2.6. Assessment of Binding Affinity toward COX-1 and COX-2
3. Materials and Methods
3.1. General Description of Instrumentation and Reagents
3.2. Synthetic Procedures and Analytical Data
3.2.1. Synthesis of 3-[1-(2-Hydroxyphenylethylidene) amino]-2-thioxoimidazolidin-4-one (2)
3.2.2. Synthesis of 1-[2-(4-Chlorophenyl)-2-oxoethyl]-3-[1-(2-hydroxyphenylethylidene) amino]-2-thioxoimidazolidin-4-one (3)
3.2.3. Synthesis of 1-[2-(4-Chlorophenyl)-2-(acetoxy) ethen-1-yl]-3-[1-(2-acetoxyphenyl ethylidene) amino]-2-thioxoimidazolidin-4-one (4)
3.2.4. Synthesis of 3-[1-(2-Hydroxy-5-(phenyl diazinyl) phenyl ethylidene)-amino]-2-thioxoimidazolidin-4-ones (5)
3.2.5. Synthesis of 1-[2-(4-Chlorophenyl)-2-oxoethyl]-3-[1-(2-hydroxy-5-(phenyl diazenyl) phenyl) ethylidene) amino]-2-thioxoimidazolidin-4-one (6)
3.2.6. Synthesis of Methyl-3{3-[1-(2-hydroxy-5-(phenyldiazenyl) phenyl) ethylidene) amino]-4-oxo-2-thioxoimidazolidin-1-yl} propanoate (7)
3.2.7. Synthesis of Methyl 3-{3 [1-(2-acetoxy)-5-(phenyldiazenyl)phenyl) ethylidene)amino)-4-oxo-2-thioxoimidazolidin-1-yl} Propanoate (8)
3.3. Cell Line and Culture
3.4. Assessment of Cytotoxicity against LPS-Activated RAW264.7 Cell Line Using MTT Assay
3.5. Assessment of the Anti-Inflammatory Activity against LPS-Activated RAW264.7 Cell Line by Estimating NO Production
3.6. Assessment of the Expression of IL-1β by Western Blot Analysis
3.7. Assessment of the Expression of IL-6 and TNF-α Cytokines by Real-Time PCR
3.8. In Silico Molecular Docking Analysis
3.9. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Protein (PDB Code) | Compound | Hydrophilic Interactions | Distance (A) | Hydrophobic Interactions | S (kcal/mol) |
---|---|---|---|---|---|
COX-1 (3kk6) | 5 | Ser530 | 2.78 | Val116, Val349, Leu352, Trp387, Ile517, Phe318, Ala527, Met522, Ile523, Leu531 | −8.36 |
7 | Ser353 Arg120 | 3.23 2.94 | Leu93, Val116, Leu359, Ile345, Phe381, Trp387, Leu384, Leu352, Val349, Lez534, Leu531, Ala527, Met522, Phe518, Ile523 | −9.54 | |
COX-2 (3ln1) | 5 | Ser516 Ser516 Val509 | 2.96 3.34 3.59 | Val335, Leu338, Phe367, Trp373, Ala502, Ile503, Phe504, Met508, Ala513, Leu517 | −9.96 |
7 | Ser516 Ser516 Val509 Arg106 | 1.97 2.75 3.88 3.46 | Val102, Leu345, Val335, Leu370, Trp373, Leu338, Phe367, Met508, Ala513, Ala502, Ile503, Phe504, Leu517 | −11.17 |
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Khirallah, S.M.; Ramadan, H.M.M.; Shawky, A.; Qahl, S.H.; Baty, R.S.; Alqadri, N.; Alsuhaibani, A.M.; Jaremko, M.; Emwas, A.-H.; Saied, E.M. Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments. Molecules 2022, 27, 6271. https://doi.org/10.3390/molecules27196271
Khirallah SM, Ramadan HMM, Shawky A, Qahl SH, Baty RS, Alqadri N, Alsuhaibani AM, Jaremko M, Emwas A-H, Saied EM. Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments. Molecules. 2022; 27(19):6271. https://doi.org/10.3390/molecules27196271
Chicago/Turabian StyleKhirallah, Salma M., Heba M. M. Ramadan, Ahmed Shawky, Safa H. Qahl, Roua S. Baty, Nada Alqadri, Amnah Mohammed Alsuhaibani, Mariusz Jaremko, Abdul-Hamid Emwas, and Essa M. Saied. 2022. "Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments" Molecules 27, no. 19: 6271. https://doi.org/10.3390/molecules27196271