A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Anti-Candida Activity Assay
2.3. Molecular Docking
2.4. In Silico ADMET Evaluation
3. Materials and Methods
3.1. General Information
3.2. Chemistry
3.2.1. Synthesis of 4-methyl-2-(4-(2-methylthiazol-4-yl)phenyl)thiazole-5-carbohydrazide (4)
3.2.2. General Procedure for the Synthesis of 1,4-phenylene-bisthiazole acyl-hydrazones 5a–i
3.3. Anti-Candida Activity Assay
3.4. Molecular Docking
3.5. In Silico ADMET Evaluation
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 5a–i are available from the authors. |
Compound | C. albicans ATCC 10231 | C. albicans ATCC 18804 | C. krusei ATCC 6258 | C. parapsilosis ATCC 22019 |
---|---|---|---|---|
5a | 31.25 | 31.25 | 62.5 | 62.5 |
5b | 31.25 | 31.25 | 62.5 | 62.5 |
5c | 31.25 | 31.25 | 31.25 | 31.25 |
5d | 15.62 | 15.62 | 15.62 | 15.62 |
5e | 31.25 | 31.25 | 31.25 | 31.25 |
5f | 15.62 | 15.62 | 15.62 | 15.62 |
5g | 31.25 | 31.25 | 15.62 | 7.81 |
5h | 31.25 | 31.25 | 15.62 | 15.62 |
5i | 31.25 | 31.25 | 31.25 | 31.25 |
Fluconazole | 15.62 | 15.62 | 15.62 | 7.81 |
Drug-free | Growth in all concentrations | |||
Broth control | No growth |
Compound | C. albicans ATCC 10231 | C. albicans ATCC 18804 | C. krusei ATCC 6258 | C. parapsilosis ATCC 22019 |
---|---|---|---|---|
5a | 62.5 | 62.5 | 125 | 125 |
5b | 62.5 | 62.5 | 125 | 125 |
5c | 62.5 | 62.5 | 62.5 | 62.5 |
5d | 31.25 | 31.25 | 31.25 | 31.25 |
5e | 62.5 | 62.5 | 62.5 | 62.5 |
5f | 31.25 | 31.25 | 31.25 | 31.25 |
5g | 62.5 | 62.5 | 31.25 | 15.62 |
5h | 62.5 | 62.5 | 31.25 | 31.25 |
5i | 62.5 | 62.5 | 62.5 | 62.5 |
Fluconazole | 31.25 | 31.25 | 31.25 | 15.62 |
Drug-free | Growth in all concentrations | |||
Broth control | No growth |
Compound | Best Binding Conformation | 2Å Cluster of the Best Binding Conformation | Number of Other Clusters | ||||
---|---|---|---|---|---|---|---|
ΔG (kcal/mol) | Ki (nM) | NoC 1 | Average ΔG (kcal/mol) | Standard Deviation | |||
ΔG (kcal/mol) | RMSD 2 of Cartesian Coordinates | ||||||
5a | −11.86 | 2.03 | 74 | −11.68 | 0.39 | 0.44 | 8 |
5b | −11.92 | 1.83 | 66 | −11.82 | 0.38 | 0.43 | 5 |
5c | −11.87 | 1.99 | 65 | −11.66 | 0.24 | 0.56 | 6 |
5d | −12.16 | 1.22 | 81 | −11.91 | 0.30 | 0.39 | 4 |
5e | −11.97 | 1.68 | 70 | −11.89 | 0.30 | 0.48 | 7 |
5f | −11.46 | 3.98 | 77 | −11.29 | 0.14 | 0.25 | 3 |
5g | −11.98 | 1.65 | 68 | −11.82 | 0.32 | 0.48 | 3 |
5h | −12.36 | 0.87 | 76 | −12.17 | 0.26 | 0.31 | 6 |
5i | −11.85 | 2.06 | 65 | −11.52 | 0.36 | 0.45 | 8 |
Compound | MW 1 (Da) | Rob 2 | HBA 3 | HBD 4 | MR 5 | TPSA 6 | mLogP 7 | Lipinski Violations |
---|---|---|---|---|---|---|---|---|
5a | 448.56 | 7 | 5 | 1 | 126.25 | 132.95 | 2.25 | 0 |
5b | 448.56 | 7 | 5 | 1 | 126.25 | 132.95 | 2.25 | 0 |
5c | 448.56 | 7 | 5 | 1 | 126.25 | 132.95 | 2.25 | 0 |
5d | 434.53 | 6 | 5 | 2 | 121.78 | 143.95 | 2.04 | 0 |
5e | 434.53 | 6 | 5 | 2 | 121.78 | 143.95 | 2.04 | 0 |
5f | 436.52 | 6 | 5 | 1 | 119.72 | 123.72 | 2.96 | 0 |
5g | 452.98 | 6 | 4 | 1 | 124.77 | 123.72 | 3.06 | 0 |
5h | 487.42 | 6 | 4 | 1 | 129.78 | 123.72 | 3.54 | 0 |
5i | 424.56 | 6 | 4 | 1 | 117.64 | 151.96 | 2.17 | 0 |
Compound | logS 1 | %Abs 2 | BBBP 3 | Pgp 4 Substrate | CYP2D6 Inhibitor |
---|---|---|---|---|---|
5a | −7.86 | 63.13 | No | No | No |
5b | −7.86 | 63.13 | No | No | No |
5c | −7.86 | 63.13 | No | No | No |
5d | −7.76 | 59.33 | No | No | No |
5e | −7.76 | 59.33 | No | No | No |
5f | −7.8 | 66.31 | No | No | No |
5g | −8.35 | 66.31 | No | No | No |
5h | −9.01 | 66.31 | No | No | No |
5i | −8.31 | 56.57 | No | No | No |
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Borcea, A.-M.; Marc, G.; Ionuț, I.; Vodnar, D.C.; Vlase, L.; Gligor, F.; Pricopie, A.; Pîrnău, A.; Tiperciuc, B.; Oniga, O. A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies. Molecules 2019, 24, 184. https://doi.org/10.3390/molecules24010184
Borcea A-M, Marc G, Ionuț I, Vodnar DC, Vlase L, Gligor F, Pricopie A, Pîrnău A, Tiperciuc B, Oniga O. A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies. Molecules. 2019; 24(1):184. https://doi.org/10.3390/molecules24010184
Chicago/Turabian StyleBorcea, Anca-Maria, Gabriel Marc, Ioana Ionuț, Dan C. Vodnar, Laurian Vlase, Felicia Gligor, Andreea Pricopie, Adrian Pîrnău, Brîndușa Tiperciuc, and Ovidiu Oniga. 2019. "A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies" Molecules 24, no. 1: 184. https://doi.org/10.3390/molecules24010184