Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency
Abstract
1. Introduction
2. Materials and Methods
2.1. Reagents
2.2. Chromatographic Procedure
2.3. Theoretical Lipophilicity, ADMET Parameters and Target Prediction
3. Results
4. Discussion
- Dimers 1a–4a RM0 = −89.395b − 0.4208 (r = 0.9952);
- Dimers 1b–4b RM0 = −106.55b − 1.1075 (r = 0.9957);
- Dimers 1c–4c RM0 = −93.8444b − 0.5607 (r = 0.9912);
- Dimers 1d–4d RM0 = −96.341b − 0.5183607 (r = 0.9933).
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | LogPcalcd. | |||||||
---|---|---|---|---|---|---|---|---|
iLOGP | XLOGP3 | WLOGP | MLOGP | SILICOS-IT | LogP (ChemDraw) | LogP (Mol Inspiration) | LogP (VCCLAB Alogps) | |
1a | 3.42 | 5.62 | 5.81 | 4.07 | 4.67 | 6.22 | 5.76 | 4.98 |
1b | 3.30 | 5.62 | 5.81 | 4.07 | 4.67 | 6.22 | 5.79 | 5.01 |
1c | 3.76 | 5.62 | 5.81 | 4.07 | 4.67 | 6.22 | 5.81 | 5.03 |
1d | 3.22 | 4.62 | 5.20 | 3.07 | 4.10 | 5.73 | 4.71 | 4.47 |
2a | 3.62 | 4.95 | 5.81 | 4.07 | 4.67 | 4.73 | 5.37 | 4.74 |
2b | 3.34 | 4.95 | 5.81 | 4.07 | 4.67 | 4.73 | 5.39 | 4.76 |
2c | 3.85 | 4.95 | 5.81 | 4.07 | 4.67 | 4.73 | 5.42 | 4.80 |
2d | 3.67 | 3.95 | 5.20 | 3.07 | 4.10 | 4.24 | 4.32 | 4.24 |
3a | 3.33 | 4.29 | 5.81 | 3.26 | 4.67 | 3.24 | 4.98 | 4.20 |
3b | 3.70 | 4.29 | 5.81 | 3.26 | 4.67 | 3.24 | 5.00 | 4.25 |
3c | 3.29 | 4.29 | 5.81 | 3.26 | 4.67 | 3.24 | 5.03 | 4.26 |
3d | 3.30 | 3.29 | 5.20 | 2.26 | 4.10 | 2.75 | 3.93 | 3.84 |
4a | 3.31 | 4.95 | 5.81 | 3.26 | 4.67 | 4.73 | 5.37 | 4.77 |
4b | 3.28 | 4.95 | 5.81 | 3.26 | 4.67 | 4.73 | 5.39 | 4.81 |
4c | 3.26 | 4.95 | 5.81 | 3.26 | 4.67 | 4.73 | 5.42 | 4.84 |
4d | 3.22 | 3.95 | 5.20 | 2.26 | 4.10 | 4.24 | 4.32 | 4.24 |
No. | −b | RM0 | r |
---|---|---|---|
1a | 0.045 | 3.5760 | 0.9973 |
1b | 0.0426 | 3.3468 | 0.9806 |
1c | 0.0432 | 3.4546 | 0.9979 |
1d | 0.0300 | 2.4253 | 0.9978 |
2a | 0.0409 | 3.3041 | 0.9983 |
2b | 0.0385 | 3.1117 | 0.9850 |
2c | 0.0418 | 3.4411 | 0.9972 |
2d | 0.0327 | 2.6375 | 0.9941 |
3a | 0.0217 | 1.6016 | 0.9856 |
3b | 0.0274 | 1.7742 | 0.9674 |
3c | 0.0252 | 1.9040 | 0.9850 |
3d | 0.0139 | 0.8993 | 0.9562 |
4a | 0.0274 | 1.9033 | 0.9933 |
4b | 0.0243 | 1.4866 | 0.9621 |
4c | 0.0296 | 2.0767 | 0.9983 |
4d | 0.0209 | 1.3580 | 0.9765 |
Parameters | I | II | III | IV | V |
---|---|---|---|---|---|
LogPlit. | 0.64 [28] | 1.21 [29] | 1.58 [29] | 2.43 [29] | 4.45 [28] |
RM0 | 0.5858 | 0.9275 | 1.5099 | 2.1803 | 2.6378 |
−b | 0.0168 | 0.0181 | 0.0225 | 0.0288 | 0.0346 |
r | 0.9954 | 0.9936 | 0.9920 | 0.9960 | 0.9930 |
No. | 1a | 1b | 1c | 1d | 2a | 2b | 2c | 2d | 3a | 3b | 3c | 3d | 4a | 4b | 4c | 4d |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
logPTLC | 3.06 | 2.86 | 2.95 | 2.09 | 2.82 | 2.66 | 2.94 | 2.27 | 1.39 | 1.54 | 1.68 | 0.81 | 1.65 | 1.30 | 1.80 | 1.21 |
No. | Molecular Mass (g/mol) | H-Bond Acceptors | H-Bond Donors | Rotatable Bonds | Molar Refractivity | TPSA [Å2] | P-gp Substrate | Lipinski’s Rules | Ghose’s Rules | Veber’s Rules | Muegge’s Rules |
---|---|---|---|---|---|---|---|---|---|---|---|
1a | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | − |
1b | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | − |
1c | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | − |
1d | 505.62 | 5 | 0 | 4 | 147.40 | 121.53 | + | + | − | + | + |
2a | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
2b | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
2c | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
2d | 505.62 | 5 | 0 | 4 | 147.40 | 121.53 | + | + | − | + | + |
3a | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
3b | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
3c | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
3d | 505.62 | 5 | 0 | 4 | 147.40 | 121.53 | + | + | − | + | + |
4a | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
4b | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
4c | 504.63 | 4 | 0 | 4 | 149.60 | 108.64 | + | + | − | + | + |
4d | 505.62 | 5 | 0 | 4 | 147.40 | 121.53 | + | + | − | + | + |
No. | Caco-2 Permeability (nm/s) | Skin Permeability (SP, log Kp) | BBB Permeability (C.brain/C.blood) | HIA (%) | MDCK (nm/s) | Plasma Protein Binding (PPB,%) |
---|---|---|---|---|---|---|
1a | 35.7262 | −2.60631 | 1.783 | 97.816 | 0.275 | 100 |
1b | 30.5877 | −2.62873 | 0.208 | 97.816 | 0.073 | 100 |
1c | 32.9405 | −2.63079 | 0.202 | 97.816 | 3.944 | 100 |
1d | 28.8091 | −2.91305 | 0.415 | 98.019 | 0.205 | 98 |
2a | 29.7800 | −2.91532 | 0.905 | 97.816 | 0.1395 | 96 |
2b | 26.4756 | −2.94119 | 0.224 | 97.816 | 0.0607 | 97 |
2c | 27.9283 | −2.94361 | 0.311 | 97.816 | 1.399 | 95 |
2d | 25.5742 | −3.25587 | 0.205 | 98.019 | 0.114 | 91 |
3a | 29.3153 | −3.48028 | 0.391 | 97.816 | 0.151 | 91 |
3b | 25.9114 | −3.50753 | 0.400 | 97.816 | 0.064 | 90 |
3c | 27.4437 | −3.5101 | 0.201 | 97.816 | 1.636 | 90 |
3d | 25.1325 | −3.81394 | 0.183 | 98.019 | 0.121 | 87 |
4a | 32.0035 | −3.15846 | 0.258 | 97.816 | 4.062 | 97 |
4b | 29.4980 | −3.1559 | 0.938 | 97.816 | 0.072 | 99 |
4c | 32.0035 | −3.15846 | 0.258 | 97.816 | 4.062 | 97 |
4d | 28.0612 | −3.47613 | 0.403 | 98.019 | 0.203 | 91 |
Doxorubicin | 17.7263 | −4.73786 | 0.036 | 56.841 | 1.204 | 31 |
No. of Compounds | ADMET Activities | Equation | r |
---|---|---|---|
1a,b,c,d–4a,b,c,d | Caco-2 | Caco-2 = 4.0763 RM03 − 26.748 RM02 + 54.697 RM0 − 6.1633 | 0.7288 |
1a,b,c,d–4a,b,c,d | SP | SP = 0.5685 RM03 − 3.7459 RM02 + 7.621 RM0 − 7.7475 | 0.3022 |
1a,b,c,d–4a,b,c,d | BBB | BBB = 0.4934 RM03 − 3.0831 RM02 + 5.8357 RM0 − 2.9445 | 0.6158 |
1a,b,c,d–4a,b,c,d | HIA | HIA = −0.118 RM03 + 0.7997 RM02 − 1.7015 RM0 + 99.01 | 0.6705 |
1a,b,c,d–4a,b,c,d | MDCK | MDCK = 0.7955 RM03 − 5.8698 RM02 + 13.621 RM0 − 8.7393 | 0.3143 |
1a,b,c,d–4a,b,c,d | PPB | PPB = −2.0899 RM03 − 14.54 RM02 + 34.436 RM0 + 66.883 | 0.6918 |
No. of Compound | Target Prediction | ||
---|---|---|---|
1a | Kinase | Family C G protein-coupled receptor | Phosphodiesterase |
1b | Ligand-gated ion channel | Cytochrome P450 | Phosphodiesterase |
1c | Kinase | Protease | Enzyme |
1d | Kinase | Family C G protein-coupled receptor | Phosphodiesterase |
2a | Kinase | Enzyme | Phosphodiesterase |
2b | Kinase | Histone deacetylase 1 | Phosphodiesterase |
2c | Kinase | Family C G protein-coupled receptor | Protease |
2d | Kinase | Family C G protein-coupled receptor | Phosphodiesterase |
3a | Kinase | Cytochrome P450 | Protease |
3b | Cytochrome P450 | Protease | Phosphodiesterase |
3c | Kinase | Enzyme | Protease |
3d | Reader | Family C G protein-coupled receptor | Protease |
4a | Phosphodiesterase | Family C G protein-coupled receptor | Protease |
4b | Kinase | Family A G protein-coupled receptor | Cytochrome P450 |
4c | Kinase | Family C G protein-coupled receptor | Voltage-gated ion channel |
4d | Phosphodiesterase | Bromodomain-containing protein 4,3,2 | Cytochrome P450 |
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Martula, E.; Morak-Młodawska, B.; Jeleń, M.; Okechukwu, P.N. Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency. Pharmaceutics 2024, 16, 1235. https://doi.org/10.3390/pharmaceutics16091235
Martula E, Morak-Młodawska B, Jeleń M, Okechukwu PN. Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency. Pharmaceutics. 2024; 16(9):1235. https://doi.org/10.3390/pharmaceutics16091235
Chicago/Turabian StyleMartula, Emilia, Beata Morak-Młodawska, Małgorzata Jeleń, and Patrick Nwabueze Okechukwu. 2024. "Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency" Pharmaceutics 16, no. 9: 1235. https://doi.org/10.3390/pharmaceutics16091235
APA StyleMartula, E., Morak-Młodawska, B., Jeleń, M., & Okechukwu, P. N. (2024). Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency. Pharmaceutics, 16(9), 1235. https://doi.org/10.3390/pharmaceutics16091235