Page 126 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences PI3K-α inhibitors for cancer immunotherapy

Figure 10. Field-based QSAR visualization of Gaussian descriptors for PLS factor 3.

A B a significant dipole moment or polarity. In addition, the
C-F bond is relatively short, enacted by its partial ionic
character, which also affects the strengths of other bonds,
rendering other parts of the drug harder to degrade. 89,90
Hence, the drug persists longer, exerting a prolonged effect
on the targeted disease or condition. We anticipate this
phenomenon to hold true for T85.
Improving the lipophilicity of the intended drug
was another design consideration in line with drug
Figure 11. T85 (B) from the structural modification of Candidate 1
(reference hit compound [A]). The nomenclature of (A) and its SMILES development protocols. For effective passive transportation
notation is 3-[6-amino-5-(2-methyl-1,3-oxazol-5-yl)pyridin-3-yl]-N-{[3- across the cell membrane, the drug must readily traverse
(hydroxymethyl)oxetan-3-yl]methyl}-4-methylbenzene-1-sulfonamide the lipid membrane without any hindrance. Therefore,
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and Cc1ncc(o1)-c1cc(cnc1N)-c1cc(ccc1C)S(=O)(=O)NCC1(CO)COC1, for a better drug compound, moderate lipophilicity is
respectively, while the nomenclature of T85 (B) and its SMILES notation
is: 6’-amino-5’-(2-fluoro-1,3-oxazol-5-yl)-N-{[3-(hydroxymethyl)oxetan- necessary. Fluorination is often a better option due to its
3-yl]methyl}-3-methyl-[2,3’-bipyridine]-6-sulfonamide and Cc1ccc(nc1- high lipophilicity, which increases drug absorption. 87,91
c1cnc(N)c(c1)-c1cnc(F)o1)S(=O)(=O)NCC1(CO)COC1, respectively. In light of the reported findings, the deliberate inclusion
of fluorine during the design of T85 can productively
The concept of incorporating a fluorine atom in the influence its intrinsic potency and membrane permeability,
compound was to furnish T85 with unconventional and thereby fostering effective metabolic pathways and
distinctive properties. Although fluorine addition is not a pharmacokinetic properties against human PI3K-α.
panacea, its presence in the drug molecule is intended to Moreover, the addition of fluorine to a molecule to inhibit
improve the drug’s biological activity, affecting both the a protein kinase involves modulating the binding affinity
pharmacokinetics and dynamic properties, ultimately and selectivity of the drug to its target receptor by altering
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aiding in saving lives. For example, the production of the electronic and steric properties of the molecule,
fluorine-associated novel therapeutic drugs approved influencing the conformation and solubility of the drug.
by the FDA in 2021 was utilized for controlling the The asymmetrical combination of pyridines – bipyridine
COVID-19 pandemic and treating various diseases. 87,88 – in the design of T85 is believed to confer various
The low metabolic stability of drugs is one of the critical advantages, such as enhanced binding affinity, selectivity,
problems in drug development. However, this could easily stability, and drug solubility. This modification can also
be circumvented by blocking the metabolically labile sites alter the electronic and steric properties of the molecule,
with fluorine substituents. Moreover, the carbon-fluorine facilitating interactions with different molecules through
(C-F) bond is one of the strongest single bonds due to non-covalent interactions and potentially resulting in the
the high electronegativity of fluorine, giving the bond formation of supramolecular structures with interesting

Volume 7 Issue 2 (2024) 16 doi: 10.36922/itps.2340