Document Details
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Document Type |
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Thesis |
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Document Title |
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Antifungal Activities and Toxicities of Certain Quinoxaline Derivatives in Experimental Animals النشاط المضاد للفطريات و السمية لمركبات معينة من الكينوكسالين في حيوانات التجارب |
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Subject |
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Faculty of medicine |
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Document Language |
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Arabic |
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Abstract |
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Background: Fungal infections are a well-known threat to human health. Quinoxaline derivatives are a precursor of interest with potential effects against fungal pathogens. The aim of this thesis is to evaluate the antifungal activity, pharmacokinetic properties and toxicity of certain quinoxaline derivatives at preclinical sitting.
Methodology: Quinoxaline derivatives (n=39) were assessed for antifungal activities (in vitro) against clinically important fungal pathogens (n=20). At the same time, the pharmacokinetics (in vitro) and toxicities (in vitro and in vivo) of QUI-2 (a known antifungal quinoxaline derivative) were assessed.
Results: QUI-9, QUI-16, QUI-17, and QUI-18 showed antifungal activities. QUI-17 demonstrates the highest activity with minimum inhibitory concentrations and minimum fungicidal concentrations at 0.25 to 4 µg/ml. QUI-2 had desirable pharmacokinetics: with aqueous solubility exceeding the upper limit of 100 µM, apparent permeability of 49.2±3.96
10-6 cm/s, efflux ratio of 1.02, distribution coefficient of 1.78, unbound fraction of 0.19±0.017%, recovery in plasma of 82%, estimated half-life in plasma of 17.8 hr, estimated hepatic clearance of 51.9±5.48 µl/min/mg protein, estimated half-life in hepatocyte of 26.7 min, CYP1A2 inhibition at IC50 = 17.3±2.64 µM, and no inhibition toward human pregnane X receptor. QUI-2 showed a desirable in vitro safety with no effect on the hERG potassium cardiac channel, no impact on the nuclear size, mitochondrial mass/membrane potential, DNA structure, phospholipidosis, glutathione, or adenosine triphosphate content of the human primary renal proximal tubule epithelial cells at concentration ≤100 µM, and a non-significant reduction in the adenosine triphosphate content of the hepatocellular carcinoma cells. QUI-2 showed desirable in vivo safety. No mortality was recorded. There was an increase in platelet counts and white blood cell counts by 99.8% and 188.8%, respectively. Kidney histology revealed enlargement of renal corpuscles. Spleen histology revealed depletion of the lymphoid. Testis histology revealed hyperplasia of testosterone-secreting cells. Heart histology revealed coronaries and capillaries dilatation.
Conclusion: QUI-17 showed a promising antifungal activity and worth further development. QUI-2 showed very attractive pharmacokinetics and safety except for thrombocytosis, leucocytosis, and some histological changes that need further investigation.
Key words: Antifungal, Pharmacokinetics, Preclinical, Quinoxaline, and Toxicity. |
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Supervisor |
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Dr. Ahmed Shaker Ali |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1444 AH
2022 AD |
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Co-Supervisor |
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Dr. Abdelbagi Alfadil Mousa |
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Added Date |
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Monday, February 27, 2023 |
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Researchers
| حمود عبدالله ال سمحان | Alsamhan, Hamoud Abdullah | Researcher | Doctorate | |
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