Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds
Abstract
:1. Introduction
2. Results and Discussion
2.1. QSAR Model of Pyrimidine and Uracil Derivatives
2.2. Analysis of Molecular Descriptors
2.3. Validation and Applicability Domain
2.4. Synthesis of New Compounds
2.5. Antiproliferative Activity of Synthesized Compounds
2.6. Predicted Physicochemical, Pharmacokinetic, and Drug-Likeness Properties of Synthesized Compounds
3. Blind Validation of Model Applicability
4. Materials and Methods
4.1. Pyrimidine Derivatives
4.2. Computational Characterization of Pyrimidine Derivatives
4.3. Development of Quantitative Structure–Activity Relationships
4.3.1. Internal and External Validation of the Model
4.3.2. Blind Validation of the Model: Newly Synthesized Pyrimidine Derivatives
4.4. Availability of the Model
4.5. Chemistry
4.5.1. Synthesis
4.5.2. Elemental Analysis
4.5.3. NMR Spectra
4.5.4. Mass Spectra
4.6. In Vitro Testing of Antiproliferative Activity
4.7. ADME Predictions
5. 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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Compounds | MCF-7 | CFPAC-1 | HeLa | SW620 |
---|---|---|---|---|
40 | >100 | >100 | 80.2 | >100 |
41 | 5 | 8.77 | 4.24 | 6.17 |
42 | >100 | 81.31 | >100 | >100 |
43 | >100 | >100 | 55.67 | >100 |
Properties | Compound 40 | Compound 41 | Compound 42 | Compound 43 |
---|---|---|---|---|
Physicochemical | ||||
Mw (g/mol) | 280.06 | 225.50 | 170.60 | 216.66 |
Num. rotatable bonds | 3 | 3 | 0 | 5 |
Num. H-bond acceptors | 2 | 2 | 3 | 4 |
Num. H-bond donors | 2 | 1 | 0 | 0 |
Molar Refractivity | 55.23 | 51.43 | 41.19 | 54.39 |
TPSA (Å2) | 65.72 | 25.7 | 35.01 | 44.24 |
Log Po/w (iLOGP) | 1.41 | 2.36 | 1.89 | 2.73 |
Pharmacokinetics | ||||
GI absorption | High | High | High | High |
BBB permeant | No | Yes | Yes | Yes |
P-gp substrate | No | No | No | No |
Drug likeness | ||||
Lipinski | Yes; 0 violation | Yes; 0 violation | Yes; 0 violation | Yes; 0 violation |
Ghose | Yes | No; 1 violation: #atoms < 20 | No; 1 violation: #atoms < 20 | Yes |
Veber | Yes | Yes | Yes | Yes |
Egan | Yes | Yes | Yes | Yes |
Muegge | Yes | Yes | No; 1 violation: MW < 200 | Yes |
Bioavailability Score | 0.55 | 0.55 | 0.55 | 0.55 |
Compound | Residuals | ||
---|---|---|---|
40 | 4.1 | 5.05808 | −0.958081 |
41 | 5.37 | 5.38919 | −0.0191896 |
42 | 4 | 6.63909 | −2.63909 |
43 | 4.25 | 3.7424 | 0.507605 |
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Zukić, S.; Osmanović, A.; Harej Hrkać, A.; Kraljević Pavelić, S.; Špirtović-Halilović, S.; Veljović, E.; Roca, S.; Trifunović, S.; Završnik, D.; Maran, U. Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds. Int. J. Mol. Sci. 2024, 25, 9390. https://doi.org/10.3390/ijms25179390
Zukić S, Osmanović A, Harej Hrkać A, Kraljević Pavelić S, Špirtović-Halilović S, Veljović E, Roca S, Trifunović S, Završnik D, Maran U. Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds. International Journal of Molecular Sciences. 2024; 25(17):9390. https://doi.org/10.3390/ijms25179390
Chicago/Turabian StyleZukić, Selma, Amar Osmanović, Anja Harej Hrkać, Sandra Kraljević Pavelić, Selma Špirtović-Halilović, Elma Veljović, Sunčica Roca, Snežana Trifunović, Davorka Završnik, and Uko Maran. 2024. "Data-Driven Modelling of Substituted Pyrimidine and Uracil-Based Derivatives Validated with Newly Synthesized and Antiproliferative Evaluated Compounds" International Journal of Molecular Sciences 25, no. 17: 9390. https://doi.org/10.3390/ijms25179390