Ketoconazole belongs to the azole group of antifungal drugs.
SAR (Structure-Activity relationship)
Imidazole Ring
- It coordinates with the iron atom of fungal cytochrome P450 (CYP51)
- This binding blocks the conversion of lanosterol to ergosterol.
- SAR Conclusion: Removal or modification of the Imidazole ring reduces antifungal activity.
Aromatic Chlorophenyl Ring
- It increases the potency.
- Increases Lipophilicity (Due to the hydrophobic group rich in carbon) this helps the drug reach the target site easily.
- Improves membrane penetration.
- SAR Conclusion: Presence of chlorine enhances antifungal activity.
Dioxolane Ring
- Positions Imidazole ring correctly for enzyme binding.
- SAR Conclusion: Alteration of the ring causes a reduction in binding affinity.
Piperazine Moiety
- Improves aqueous solubility (it contains six-membered ring containing two nitrogen atoms.) the nitrogen atom attracts hydrogen ions, which forms the positive charge on the molecule. The presence of a charge forms an ion-dipole interaction, which increases the solubility.
- SAR Conclusion: Modification affects bioavailability more than antifungal activity.
Conclusion: Understanding the structural activity helps the formulator to modify the drug and identify the efficiency and does make one understand the dossier of the drug.
The dioxolane ring in ketoconazole primarily:
- Binds fungal DNA
- Enhances membrane penetration directly
- Maintains proper spatial orientation of the molecule
- Increases aqueous solubility
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voters
Ketoconazole is primarily used as the following:
- Topical
- Systemic
- Both
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voters
Have you ever used ketoconazole? Which infection made you use it?
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