Synthesis and Modeling of Ezetimibe Analogues
Abstract
:1. Introduction
2. Results
2.1. Pharmacophore Docking Overlay
2.2. Design of the Ligands
- In position 1 of the ring, it is advisable to have an N-phenyl or N-benzyl group, although a range of other substituents are allowed.
- An oxygenated function is required at a distance of three carbons from the cycle at position 3.
- An aromatic group is required at position 4, preferably p-hydroxyl or p-methoxyphenyl. In addition, isomers with S stereochemistry at this carbon show greater activity against R.
- The 3S and 3R isomers have comparable activity without preference. That is, there is no stereochemical preference at this asymmetric center [30]. This point is relevant in the present work and it has been very well documented by J.W. Clader et al., in the article with tittle: “2-Azetidinone Cholesterol Absorption Inhibitors: Structure-Activity Relationships on the Heterocyclic Nucleus” [35].
3. 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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Ligand | R1 | R2 | R3 | Ligand | R1 | R2 | R3 |
---|---|---|---|---|---|---|---|
L1 | | H | Me | L6 | | Me | H |
L2 | | H | H | L7 | H | Me | H |
L3 | H | H | H | L8 | H | Me | Me |
L4 | H | H | Me | L9 | | H | Me |
L5 | | Me | Me | L10 | | H | H |
Ligand | Score | SC | Ar | Hy | Do | Ac | + | − |
---|---|---|---|---|---|---|---|---|
L1 | 9.039 | 4 | 1 | 0 | 1 | 3 | 0 | 0 |
L2 | 7.538 | 3 | 1 | 0 | 1 | 2 | 0 | 0 |
L3 | 7.539 | 3 | 1 | 0 | 1 | 2 | 0 | 0 |
L4 | 7.539 | 3 | 1 | 0 | 1 | 2 | 0 | 0 |
L5 | 7.532 | 4 | 1 | 0 | 0 | 3 | 0 | 0 |
L6 | 7.525 | 4 | 1 | 0 | 0 | 3 | 0 | 0 |
L7 | 6.029 | 3 | 1 | 0 | 0 | 2 | 0 | 0 |
L8 | 6.028 | 3 | 1 | 0 | 0 | 2 | 0 | 0 |
L9 | 6.017 | 3 | 1 | 0 | 0 | 2 | 0 | 0 |
L10 | 7.513 | 3 | 2 | 0 | 0 | 1 | 0 | 0 |
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Salgado, M.M.; Manchado, A.; Nieto, C.T.; Díez, D.; Garrido, N.M. Synthesis and Modeling of Ezetimibe Analogues. Molecules 2021, 26, 3107. https://doi.org/10.3390/molecules26113107
Salgado MM, Manchado A, Nieto CT, Díez D, Garrido NM. Synthesis and Modeling of Ezetimibe Analogues. Molecules. 2021; 26(11):3107. https://doi.org/10.3390/molecules26113107
Chicago/Turabian StyleSalgado, Mateo M., Alejandro Manchado, Carlos T. Nieto, David Díez, and Narciso M. Garrido. 2021. "Synthesis and Modeling of Ezetimibe Analogues" Molecules 26, no. 11: 3107. https://doi.org/10.3390/molecules26113107