Page 160 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
Potential of flavonoids against glioblastoma

3.5. Lipophilicity and water solubility 3.8. Toxicity assessment

The lipophilicity and water solubility of the phytochemicals The toxicity assessment for the phytochemicals was
are represented by their log P values. Compound 1 conducted using the PkCSM server, as summarized
o/w
exhibited superior lipophilicity with a consensus log P of in Table 5. The results indicated that Compound 1
o/w
1.73 compared to Compound 2’s value of 1.52. In contrast, demonstrated non-toxic characteristics across several
Compound 2 demonstrated enhanced water solubility, toxicity models, including Ames toxicity, hepatotoxicity,
as indicated by its log S value of 3.94, in comparison to hERG I and II inhibitors, and skin sensitization, where
Compound 1’s log S of 3.82 (Table 4). it remained inactive. In contrast, Compound 2 displayed
potential Ames toxicity, suggesting possible carcinogenic
3.6. Drug-likeness assessment effects.
The drug-likeness of both phytochemicals (Compounds
1 and 2) was evaluated according to Lipinski, Ghose, 3.8.1. Maximum tolerated dose and toxicity levels
Veber, and Egan rules. As outlined in Table 4, neither The maximum tolerated doses were calculated to be 0.839
phytochemical violated any of the specified rules. The log mg/kg/day for Compound 1 and 1.023 log mg/kg/day
medicinal chemistry evaluation revealed one PAINS for Compound 2. This suggests that Compound 2 is more
(Pan-Assay Interference Compound) and one Brenk alert tolerant at higher doses. In addition, Compound 2 exhibited
for both phytochemicals. Furthermore, the synthetic lower toxicity to both Minnow and Tetrahymena pyriformis,
accessibility analysis indicated that Compound 1, with a indicating a more favorable toxicity profile in aquatic
score of 3.02, is easier to synthesize than Compound 2, environments. However, the oral rat acute and chronic
which has a score of 3.28. toxicity assessments revealed that both phytochemicals
exhibited similar levels of chronic toxicity, with Compound
3.7. Pharmacokinetic evaluation 1 having a slightly lower acute toxicity (2.235 mol/kg)
The pharmacokinetic properties of both phytochemicals compared to Compound 2 (2.347 mol/kg).
were further assessed using the BOILED-EGG model,
depicted in Figure 3. Both compounds demonstrated 3.8.2. Further toxicity evaluation using StopTox
high gastrointestinal (GI) absorption potential. Notably, The toxicity of both phytochemicals was also evaluated
neither compound was identified as a substrate for through the StopTox platform, as illustrated in Table 6. The
P-glycoprotein (PGP-negative), suggesting that the results indicated that both compounds exhibited a non-toxic
pharmacological activity of both phytochemicals will
remain unaffected by PGP. Despite both phytochemicals Table 5. Toxicity prediction of bioactive flavonoids
having a bioavailability score of 0.55, this indicates (Compounds 1 and 2) across various parameters, accessed
a moderate level of oral bioavailability within the through PkCSM
physicochemical space.
Toxicity assessment Phytochemicals
Compound 1 Compound 2
Ames toxicity No Yes
Maximum tolerated dose, 0.839 1.023
human (log mg/kg/day)
hERG I inhibitor No No
hERG II inhibitor No No
Oral rat acute toxicity, LD50 2.235 2.347
(mol/kg)
Oral rat chronic toxicity, 2.052 2.035
LOAEL (log mg/kg bw/day)
Hepatotoxicity No No
Skin sensitization No No
T.Pyriformis toxicity (log µg/L) 0.361 0.302
Minnow toxicity (log mM) 0.87 1.214
Abbreviations: hERG I: Human Ether‑à‑go‑go‑Related Gene, type I;
Figure 3. Brain Or IntestinaL EstimateD permeation (BOILED-Egg) hERG II: Human Ether-à-go-go-Related Gene, type II;
representation of bioactive flavonoids (Compounds 1 and 2) of Pistacia LD: Lethal dose; LOAEL: Lowest observed adverse effect level;
chinensis T. pyriformis: Tetrahymena pyriformis.

Volume 9 Issue 1 (2025) 152 doi: 10.36922/ejmo.5768