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Anti fungal Agents- Pharmacy-Medicinal Chemistry

This document discusses antifungal agents and their mechanisms of action. It focuses on azole antifungal agents, which inhibit the enzyme lanosterol 14-demethylase involved in ergosterol biosynthesis. This disrupts the fungal cell membrane. Specific azoles mentioned include clotrimazole, miconazole, ketoconazole, and fluconazole. Their structures contain an imidazole or triazole ring linked to aromatic groups, which allows binding to the enzyme's heme group. Halogen substitutions, particularly chlorine, increase potency by mimicking the enzyme's natural substrate. The azoles have fungistatic or fungicidal effects depending on concentration.

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ANTIFUNGAL AGENTS Dr. Akhil Nagar RCP-IPER Shirpur
• Common fungi types invented in early years are Trichophyton schoenleinii, C. Albicans. • Collectively named as mycoses and homogeneous group of fungi, the dermatophytes. • These include ringworm, which are infections of the hair or hair follicles, The causative microbes are specialized saprophytes with the unusual ability to digest keratin. • Systemic Mycoses: Diseases caused by the systemic organisms include histoplasmosis, sporotrichosis, blastomycosis, coccidioidomycosis, cryptococcosis, and paracoccidioidomycosis. • The causative agents for these diseases are saprophytes, Fungal spores are inhaled into the lung, and a mild, cold like condition may result.
Azole Antifungal Agents • The azoles represent a class of synthetic antifungal agents that possess a unique mechanism of action. • selectivity for the infecting fungus • one can treat infections ranging from simple dermatophytoses to life-threatening, deep systemic fungal infections. • Aimed at developing more potent azoles and compounds that penetrate the blood-brain barrier more effectively. • The first members of the class were highly substituted imidazoles, such as clotrimazole and miconazole. • Structure–activity studies revealed that the imidazole ring could be replaced with a bioisosteric 1,2,4-triazole ring without adversely affecting the antifungal properties of the molecule.
• At high in vitro concentrations (micromolar), the azoles are fungicidal; at low in vitro concentrations (nanomolar), they are fungistatic. • fungicidal effect is clearly associated with damage to the cell membrane, with the loss of essential cellular components such as potassium ions and amino acids. • The fungistatic effect of the azoles at low concentration has been associated with inhibition of membrane-bound enzymes. • A cytochrome P450-class enzyme, lanosterol 14-demethylase, is the likely target for the azoles. • P450 possesses a heme moiety, The function of lanosterol 14- demethylase is to oxidatively remove a methyl group from lanosterol during ergosterol biosynthesis. MECHANISM OF ACTION
There are three general mechanisms of action for the antifungal agents: 1. Cell membrane disruption 2. Inhibition of cell division 3. Inhibition of cell wall formation. (Least)
Cell Membrane Disruption • Antifungal agents that disrupt the cell membrane do so by targeting ergosterol, either by binding to the sterol, forming pores and causing the membrane to become leaky or inhibiting ergosterol biosynthesis. • Ergosterol is similar to mammalian cholesterol, thus agents binding ergosterol may have a cytotoxic effect in the host tissue. Ergosterol has two conjugated double bonds that are lacking in mammalian sterols.
• When demethylation is inhibited, the 14-sterol accumulates in the membrane, causing destabilization. • Lanosterol 14-demethylase is also required for mammalian biosynthesis of cholesterol and the azoles are known to inhibit cholesterol biosynthesis.
• The 1,2,4-triazoles appear to cause a lower incidence of endocrine effects and hepatotoxicity than the corresponding imidazoles, possibly because of a lower affinity for the mammalian cytochrome P450 enzymes involved. • The primary mode of resistance to the triazoles and imidazoles in C. albicans is the development of mutations in ERG 11, the gene coding for C14-- sterol demethylase. • These mutations appear to protect heme in the enzyme pocket from binding to azole but allow access of the natural substrate of the enzyme, lanosterol.
Clotrimazole Econazole Butoconazole
Oxiconazole Tioconozole Miconazole 1-[2-(2,4-Dichlorophenyl)-2- [2,4-dichlorophenyl]- methoxy]ethyl]-1H-imidazole mononitrate
TerconazoleKetoconazole Fluconazole
Naftifine hydrochloride Tolnaftate 2-Naphthyl N-methyl-N-(3 tolyl)thionocarbamate[
STRUCTURE–ACTIVITY RELATIONSHIPS • The basic structural requirement for members of the azole class is a weakly basic imidazole or 1,2,4-triazole ring. • (pKa of 6.5–6.8) bonded by a nitrogen–carbon linkage to the rest of the structure. • At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of molecular oxygen and prevent oxidation of steroidal substrates by the enzyme. • The most potent antifungal azoles possess two or three aromatic rings, at least one of which is halogen substituted. • (e.g., 2,4- dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other nonpolar functional groups.
• Only 2, and/or 2,4 substitution yields effective azole compounds. • The halogen atom that yields the most potent compounds is fluorine & sulfonic acids also gives same potency. • The large nonpolar portion of these molecules mimics the nonpolar steroidal part of the substrate for lanosterol 14- demethylase, lanosterol, in shape and size. • The nonpolar functionality confers high lipophilicity to the antifungal azoles. • The free bases are typically insoluble in water but are soluble in most organic solvents, such as ethanol. • Fluconazole, which possesses two polar triazole moieties, is an exception, in that it is sufficiently water soluble to be injected intravenously as a solution of the free base.