Antifungal agents: An introduction, classification, mechanism, uses, with its effects.

Antifungal drugs (agents)

Fungus-in-The-laboratory
Fungus in the laboratory

Antifungal agents (drugs) are the drugs that selectively eliminate fungal pathogens through a host with the least toxicity to the host cells. These are the substances that inhibit the spread of fungi either by killing fungal cells or spores or preventing their growth. These are killed fungi or inhibits their growth. Those kill fungi are called fungicidal while those are only inhibiting their growth are called fungistatic.

Introduction of antifungal

Generally, the infectious diseases caused by fungi are called mycoses. They are often chronic in nature.  Mycotic infections are may involve only in the skin cutaneous mycoses extending into the epidermis or may cause subcutaneous or systemic infections.  Human-fungi-parasitic relationship results in mycotic illnesses.

Fungal infections included causative organisms-

SUPERFICIAL MYCOSIS  DEEP MYCOSIS
-DermatophytesAspergillus
EpidermophytonBlastomyces
TrichophytonCryptococcus
MicrosporumCoccidioides
-CandidaCandida
-Malassezia FurfurHistoplasma
 Mucormycosis
 Sporotrichosis

History of antifungal

The discovery of first antifungal antibiotics is discovered in 1939 when Oxford et al. reported the isolation of the first antifungal antibiotic, Griseofulvin. It inhibits the growth of various species of Epidermophyton, Microsporum, and Trichophyton. Cycloheximide was discovered by Whiffen et al. in 1946 in streptomycin- yielding culture of Streptomyces griseus.

Amphotericin B, a polyene macrolide which is standard for the treatment of the most serve invasive fungal infections, was discovered in the 1950s.

The development of imidazole’s in the mid-1970s and triazoles in the 1980s has been an advancement. Terbinafine is a novel antifungal. The group of potent semisynthetic antifungal antibiotics, the Echinocandins are the latest addition.

Classification of antifungal

-Antibiotics

Polyenes– Amphotericin B (AMB), Nystatin, Hamycin

Echinocandins– Caspofungin, Micafungin, Anidulafungin

Heterocyclic benzofuran– Griseofulvin

-Antimetabolite– Flucytosine (5-FC)

Azoles

Imidazoles- (Topical) Clotrimazole, Econazole, Miconazole, Oxiconazole

Systemic– Ketoconazole

Triazoles– Fluconazole, Voriconazole, Posaconazole

Systemic-Itraconazole

-Allylamine– Terbinafine

-Other topical agents-

Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox, Butenafine

You may read- antimicrobial agents.

Mechanism of antifungal-

Mechanism-of-anti-fungal-agents
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Resistance of antifungal-

Resistance-of-Anti-fungal-Agents
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DRUGS USED TO TREAT FUNGAL INFECTIONS

Most of the fungal drugs are opportunistic like- superficial mycosis, deep mycosis, etc., hence they are common in diabetes mellitus, cancer, AIDs, pregnancy, in patients on board-spectrum antimicrobial agents and on immunosuppressant therapy such as the prolonged course of corticosteroids, anticancer drugs, etc.

POLYENE ANTIBIOTICS

The name polyene is derived from its highly double-bonded structure. The fungal cell membrane contains a sterol which resembles cholesterol and is called ‘ergosterol’.

Mechanism-of-Polyene-antibiotics

Amphotericin B-

It is a naturally occurring polyene antifungal agent, which is produced by Streptomyces nodosus. In spite of toxic potential, it remains the drug of choice for the treatment of several life-threatening mycoses. It is a bord-spectrum either fungicidal or fungistatic.

It is mainly effective against a wide spectrum of fungi, including Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, and many strains of Aspergillus.

Mechanism of action- Amphotericin B binds with ergosterol in the plasma membranes present in fungal cells. There, it forming pores that require hydrophobic interactions between the lipophilic segment of the polyene antifungal and the sterol.

The pores disrupt the function of the membrane, allowing electrolytes particularly potassium and small molecules to leak from the cell, resulting in cell death.

Molecular formula-C47H73NO17

Molecular Weight-924.1g/mol

IUPAC Name- 33-(4-amino-3,5-dihydroxy-6-methyloxan-2-yl)oxy-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid

Structure-
Structure-of-Amphotericin-B

Properties and use-

It occurs as a white crystalline powder. It is soluble in water. It is administered by slow intravenous infusion. It gets metabolized in the liver. It is amphoteric, forming soluble salts in both basic and acidic environments, and due to extensive unsaturation, it is unstable, primarily used as antifungal agents.

-Used in the treatment of various types of fungal infection.

Nystatin

Nystatin is a polyene antifungal drug to which many mold and yeast are sensitive, including Candida spp. It is an antifungal substance produced by the growth of streptomyces noursei. It has some toxicity associated with it when given intravenously, but it is not absorbed across intact skin or mucous membranes. It is a polyene macrolide antibiotic that is effective against a large number of fungi and yeasts.

Mechanism of action-Nystatin exerts its fungal activity by binding to sterols in the fungal cell membrane. As a result of this binding, the membrane is not able to function as a selective barrier hence potassium and other cellular constituents are lost. This led to the death of fungal cells.

Molecular formula- C47H75NO17

Molecular Weight-926.1g/mol

IUPAC Name- (1S,15S,16R,17R,18S,19E,21E,25E,27E,29E,31E)-33-[(2S,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,25,27,29,31-hexaene-36-carboxylic acid  

Structure-
Structure-of-Nystatin

Properties and use-

It occurs as a light-yellow powder. It is soluble in water but insoluble in ether. It does not metabolize in the liver and is excreted unchanged in faces.

-Used in the treatment of fungal infections of the oral cavity caused by Candida Albicans.

-Used in the treatment of various types of fungal infections.

-Used in the treatment of intestinal mycosis due to candida.

Hamycin

It was developed in India by Hindustan Antibiotics. It is isolated from S.pimprina. It is similar to nystatin. Mechanism of action- It binds to ergosterol, a major component of the fungal cell membrane. When it is present in sufficient concentrations, it forms pores in the membrane that lead to K+ leakage, acidification, and death of the fungal cell.

Molecular formula- C58H86N2O19

Molecular Weight- 1115.3g/mol

IUPAC Name- 19E,21E,23E,25E,27E,29E,31E)-33-[(2S,3R,4R,5R,6S)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-17-[7-(4-aminophenyl)-5-hydroxy-7-oxoheptan-2-yl]-1,3,5,7,9,11,13,37-octahydroxy-18-methyl-15-oxo-16,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid  

Structure-
Structure-of-Hamycin

Properties and use-

It is an antibiotic effective against candida albicans. It is a fungal drug. It is soluble in water.

-Used topically for oral, cutaneous and virginal candidiasis.

Echinocandins-

These are a new class of potent semisynthetic antifungal antibiotics with a complex cyclic lipopeptide structure, which stand out due to their low toxicity compared to amphotericin B. It interferes with the synthesis of the fungal cell wall by inhibiting the synthesis of β (1,3)-D-glucan, that leading to lysis and cell death.

It has potent activity against Aspergillus and most Candida species, including those species resistant to azoles. However, they have minimal activity against other fungi.

Structure-
Structure-of-Echinocandins

Caspofungin Acetate

It is a semisynthetic antifungal agent effective against Candida and Aspergillus. It acts by inhibiting the synthesis of glucans in the fungal cell walls. It is not effective orally and is administered by I.V. infusion, metabolized in the liver, and metabolites are excreted in faces and urine.

Molecular formula- C56H96N10O19

Molecular Weight- 1213.4g/mol

IUPAC Name-aceticacid;N[(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S)-21-(2aminoethylamino)-3-[(1R)-3-amino-1-hydroxypropyl]-6[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-15-[(1R)-1-hydroxyethyl]-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-10,12-dimethyltetradecanamide  

Structure-
Structure-of-Caspofungin-Acetate

Micafungin-

 It is similar to caspofungin and administered for treatment of invasive candidiasis, also for prophylaxis of invasive candidiasis and in-patient undergoing stem cell transplantation.

Molecular formula- C56H71N9O23S

Molecular Weight- 1270.3g/mol

IUPAC Name-  [5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-11,20,21,25-tetrahydroxy-15-[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[[4-[5-(4-pentoxyphenyl)-1,2-oxazol-3-yl]benzoyl]amino]-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxyphenyl] hydrogen sulfate  

Structure-
Structure-of-Micafungin

Heterocyclic benzofuran

Griseofulvin

Griseofulvin is a narrow spectrum antifungal antibiotic, which is isolated from the cultures of Penicillium griseofulvum. It is not effective topically. It has largely been superseded by other drugs. It gets metabolized in the liver.

Mechanism of action– It inhibits fungal cell mitosis and nuclear acid synthesis by binding to and interfering with the function of spindle and cytoplasmic microtubules by binding to alpha and beta-tubulin. It binds to fungal microtubules, disrupts, microtubule function, and inhibits mitosis.

Mechanism-of-Griseofulivin

Molecular formula- C17H17CIO6

Molecular Weight- 352.8g/mol

IUPAC Name- (2S,5’R)-7-chloro-3′,4,6-trimethoxy-5′-methylspiro [1-benzofuran-2,4′ cyclohex-2-ene]-1′,3-dione 

Structure-
Structure-of-Griseofulvin

Properties and use-

It occurs as a white to pale cream-colored crystalline powder, odorless or almost in ethanol, chloroform, methanol, and acetic acid. It is incompletely absorbed when administered orally.

-Used in the treatment of superficial fungal infections caused by trichophyton mentagrophytes.

-Used orally for dermatophytic infections.

-Used in the treatment of ringworm infections of the skin, hair, and nails.

Antimetabolite

Flucytosine (5-FC)-

It is a fluorinated cytosine analog that is used as an antifungal agent. It is a prodrug that is taken up by susceptible fungal cells and converted into 5-fluorouracil (5-FC) that interfering with fungal DNA synthesis by inhibiting thymidylate synthase enzyme, thus producing the fungistatic effect.

Mechanism of action– It has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil.

Mechanism-of-Flucytosine

It enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. It is extensively incorporated into fungal RNA and inhibits the synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.

Molecular formula- C4H4FN3O

Molecular Weight- 129.09g/mol

IUPAC Name- 6-amino-5-fluoro-1H-pyrimidin-2-one  

Structure-
Structure-of-Flucytosine
Source-internet

Properties and uses-

It is a white crystalline powder. It is sparingly soluble in water, and slightly soluble in ethanol. It is rapidly and virtually completely absorbed orally. Its bioavailability is 78% to 89%. It is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption.  A small portion of the dose is excreted in the faces.

-Only available antimetabolite drug having antifungal activity.

Allylamine-

Terbinafine

It is a highly lipophilic, keratinophilic fungicidal compound active against a wide range of skin pathogens. It is a synthetic allylamine antifungal. It is highly lipophilic in nature and tends to accumulate in the skin, nails, and fatty tissues.

Mechanism of action-It acts by inhibiting squalene monooxygenase. Thus, blocking the biosynthesis of ergosterol, an essential component of the fungal cell membranes. This inhibition also results in an accumulation of squalene, which is a substrate catalyzed to2,3-oxy do squalene by squalene monooxygenase.

The resultant high concentration of squalene and decreased amount of ergosterol are both thought to contribute to terbinafine antifungal activity.

Molecular formula- C21H25N

Molecular Weight- 291.4g/mol

IUPAC Name- (E)-N,6,6-trimethyl-N-(naphthalen-1-ylmethyl) hept-2-en-4-yn-1-amine  

Structure-
Structure-of-Terbinafine
Source-internet

Properties and uses– Terbinafine hydrochloride are a white powder. It is slightly soluble in water and in acetone, soluble in anhydrous ethanol, and in methanol.

-Used as an antifungal agent.

Azoles

The azoles are a group of synthetic fungistatic agents with a broad spectrum of antifungal activity. Azoles antifungals are broadly divided into imidazoles and triazoles.

Both of them are structurally related compounds, have a similar mechanism of action and antifungal spectrum. Azoles impair ergosterol synthesis by inhibiting the 1,4alpha-demethylase enzyme.

Imidazoles-

Clotrimazole

It is an antifungal antibiotic used for local application. It acts as a board spectrum antifungal drug effective against candida Trichomonas vaginalis. It acts by inhibiting the synthesis of ergosterol causing damage to the cell membrane of fungi. It is available as a clotrimazole gel for local applications.  

Mechanism of action– It inhibits the biosynthesis of sterols, mainly ergosterol, which is an essential component of the fungal cell membrane, damage, and affect the permeability of the cell membrane. This results in leakage and loss of essential intracellular compounds and causes cell lysis.

Molecular formula- C22H17CIN2

Molecular Weight- 344.8g/mol

IUPAC Name- 1-[(2-chlorophenyl)-diphenyl methyl] imidazole  

Structure-
Structure-of-Cotrimazole

Properties and use-

It occurs as a white to pale yellow crystalline powder, odorless. It is slightly soluble in water, benzene, and toluene.  It is freely soluble in alcohol and slightly soluble in ether. It gets metabolized in the liver.

-Used in the treatment of tropical fungal, dermatophyte, and yeast infections.

-Used in the treatment of vulvovaginal and mucocutaneous candidiasis.

Econazole

Econazole is a broad spectrum antimycotic agent and active some action against Gram-positive bacteria. It is tropically used in the dermatomycoses also orally and parenterally. It prevents fungal organisms from producing vital substances required for growth and function.

Mechanism of action– It inhibits 14-alpha demethylase enzyme which catalyzes the conversion of lanosterol to ergosterol, an essential component of the fungal cell wall.  This results in an increase in permeability of fungal cells, leakage of cellular contents, and cell lysis.

Molecular formula- C18H15Cl3N2O

Molecular Weight- 381.7g/mol

IUPAC Name- 1-[2-[(4-chlorophenyl) methoxy]-2-(2,4-dichlorophenyl) ethyl] imidazole  

Structure-
Structure-of-Econazole

Properties and uses-

It occurs as a white powder. It is slightly soluble in water. Soluble in methanol, sparingly soluble in methylene chloride, and slightly soluble in alcohol. It gets metabolized in the liver.

-Used as a cream in the treatment of Variety of fungal skin infections such as athlete’s foot, jock itch, and ringworm.

-Used in the treatment of cutaneous candidiasis.

Miconazole-

Miconazole is generally used topically as a gel for oral and other infections of the GI tract or for skin or mucosal fungal infection. If significant systemic absorption occurs, drug interactions can present a problem.

Mechanism of action– It interacts with 14-alpha demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. It is an essential component of the fungal cell membrane as in the ergosterol, in the inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents.

It may also inhibit the transformation of yeast to mycelial forms, inhibits purine uptake, and impair triglyceride and phospholipid biosynthesis.

Molecular formula- C18H14Cl4N2O

Molecular Weight- 416.1g/mol

IUPAC Name- 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl) methoxy] ethyl] imidazole  

Structure-
Structure-of-Miconazole

Properties and use-

It occurs as a white crystalline powder. It is soluble in water. It gets metabolized in the liver.

It has good penetrating power when applied locally. It is administered intravenous infusions.

-It is a topical application in the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

-Used in the treatment of cutaneous candidiasis (moniliasis), and in the treatment of tinea versicolor.

Oxiconazole-

It is an antifungal agent that is commonly found in a topical formulation. It has fungicidal or fungistatic activity against a number of pathogenic fungi including the following dermatophytes, and yeast: T. rubrum, T. mentagrophytes, T. violaceum, E. floccosum, M. canis, M. gypseum, C. Albicans, and M. furfur.

Mechanism of action– It inhibits the synthesis of ergosterol, an essential component of the fungal cell wall. It increases in the permeability of fungal cells, leakage of cellular contents, and cell lysis. It acts to destabilize the fungi cytochrome P-450 51 enzyme.

This is vital in the cell membrane structure of the fungus. Its inhibition leads to cell lysis. It has also been shown to inhibit DNA synthesis and suppress intracellular concentrations of ATP. Like other imidazole antifungals, it can increase membrane permeability to zinc, augmenting its toxicity.

Molecular formula- C18H13Cl4N3O

Molecular Weight- 429.1g/mol

IUPAC Name- (Z)-1-(2,4-dichlorophenyl)-N-[(2,4-dichlorophenyl) methoxy]-2-imidazol-1-ylethanimine  

Structure-
Structure-of-Oxiconazole

Properties and uses-

 It occurs as a white crystalline powder. It is practically insoluble in water. It gets metabolized in the liver.

-Used as a cream in the treatment of a verity of fungal skin infections such as athlete’s foot, jock itch, and ringworm.

-Used in the treatment of cutaneous candidiasis.

Ketoconazole

It was the first azole derivative that could be given orally for the treatment of systemic fungal infections. It is a board spectrum antifungal agent used or long periods high doses, especially in immunosuppressed conditions.

Mechanism of action– It interacts with 14-alpha demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability.

Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhabitation of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis.

It can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.

Molecular formula- C26H28Cl2N4O4

Molecular Weight- 531.4g/mol

IUPAC Name- 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy] phenyl] piperazin-1-yl] ethenone 

Structure-
Structure-of-Ketaconazole

Properties and uses-

Ketoconazole is a white powder. It is practically insoluble in water. It is soluble in methylene chloride, and in methanol, sparingly soluble in alcohol. It is, however, toxic, and relapse is common after apparently successful treatment It is well absorbed from the GI tract. It is inactivated in the liver and excreted in bile and in the urine.

Triazoles

Fluconazole-

Fluconazole is a bistriazole antifungal agent and structurally related to imidazole derivatives. It acts as a fungistatic. It increases fungi membranes permeability causing leakage of essential elements like amino acids, potassium. Fluconazole is well absorbed and can be given orally or intravenously, and fungicidal concentrations are also achieved in vaginal tissue, saliva, skin, and nails.

Mechanism of action– Fluconazole inhibits ergosterol biosynthesis and causes direct damage to membrane phospholipids. It acts as a fungal drug.

Molecular formula- C13H12F2N6O

Molecular Weight- 306.27g/mol

IUPAC Name- 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl) propan-2-ol  

Structure-
Structure-of-Fluconazole

Properties and uses-

It occurs as a white crystalline powder. It is slightly soluble in water but soluble in organic solvents like- chloroform, propylene glycol, etc. It gets metabolized in the liver but in a very less extent.

-Used in the treatment of tinea manuum (ringworm of the hand).

-Used in the treatment of fungal pneumonia, vulvovaginal candidiasis, and in Candida infection, dermatophyte infections.

Itraconazole–          

It is a synthetic triazole. It is administered orally as well as by the intravenous route. Gastric acidity favors the absorption of itraconazole. It has a board spectrum of activity against many including Aspergillus.

Mechanism of action- It inhibits fungal Cytochrome P-450 enzymes, resulting in a decrease in fungal ergosterol synthesis, causes cell lysis, and finally death of fungal cells.

Molecular formula- C35H38Cl2N8O4

Molecular Weight- 7005.6g/mol

IUPAC Name- 2-butan-2-yl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one 

Structure-
Structure-of-Itraconazole

Properties and use-

It occurs as a white crystalline powder. It is practically insoluble in water. It is highly bound to plasma proteins, does not cross BBB, and metabolized in the liver by cytochrome P-450 isoenzyme system.

-Used in the treatment of fungal infections in immune-compromised and non-immune compromised patients.

-Used in the treatment of another fungal infection like- aspergillosis, blastomycosis, coccidioidomycosis, and histoplasmosis.

Voriconazole-

It inhibits cytochrome enzymes. It is contradicted in pregnancy. It is administered orally or intravenously. It is used for the treatment of invasive aspergillosis and disseminated Candida infections.

Molecular formula-C16H14F3N5O

Molecular Weight- 349.31g/mol

IUPAC Name- (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl) butan-2-ol  

Structure-
Structure-of-Voriconazole

Posaconazole-

It is an azole, has a broad spectrum of activity against many fungi including aspergillus and agents causing mucormycosis. It is administered orally; fatty food increases its bioavailability. It may come in a formulation of cream, powder, spray, or liquid aerosol.

Molecular formula- C37H42F2N8O4

Molecular Weight- 700.8g/mol

IUPAC Name-  4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one  

Structure-
Structure-of-Posaconazole
Source-internet

Other tropical agents-

Tolnaftate

It is a synthetic over-the-counter (OTC) antifungal drug. It is a very effective drug for Tinea cruris, tinea carporis. It is effective for the local application of skin affected.

Mechanism of action– – It is a topical fungicide. It is believed that it performs to prevent ergosterol biosynthesis by inhibiting squalene peroxidase. Tolnaftate is also reported as to distort the hyphae and to stunt mycelial growth in susceptible organisms. It is nontoxic.

Molecular formula- C19H17NOS

Molecular Weight-307.4g/mol

IUPAC Name- O-naphthalen-2-yl N-methyl-N-(3-methylphenyl) carbamothioate  

Structure-
Structure-of-Tolnaftate

Properties and uses– It occurs as a white crystalline powder. It is very less soluble in water, soluble in acetone and in methylene chloride, and very slightly soluble in alcohol. It gets metabolized in the liver.

-It is effective for the treatment of most cutaneous mycoses, such as Trichophyton rubrum and Microsporum canis.

-Used in the treatment of a verity of fungal skin infections such as ringworm, athlete’s foot, and jock itch.

Ciclopirox olamine-

It is used as a topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum.

Mechanism of action- It acts through the chelation of polyvalent metal cations, such as Fe3+ and Al3+. These cations inhibit many enzymes, including cytochromes, thus disrupting cellular activities such as mitochondrial electron transport processes and energy production.

It also appears to modify the plasma membrane of fungi, resulting in the disorganization of internal structures. The anti-inflammatory action of ciclopirox is most likely due to the inhalation of 5-lipoxygenase and cyclooxygenase.

It may exert its effect by disrupting DNA repair, cell division signals, and structures as well as some elements of intracellular transport.

Molecular formula- C14H24N2O3

Molecular Weight- 268.35g/mol

IUPAC Name- 2-aminoethanol;6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one 

Structure-
Structure-of-Ciclopirox-Olamine
Source-internet

Properties and uses– Ciclopirox is a white or yellowish-white crystalline powder. It is slightly soluble in water, soluble in ethanol, and in methylene chloride.

-It is available as 1% cream on cotton for the treatment of cutaneous candidiasis and for Tinea corporis, T. cruris, T. pedis, and Pityriasis Versicolor.

Undecylenic acid-

Its salts are found in topical over-the-counter (OTC) or mixture products as antifungal agents. It serves as an acid moiety for anabolic steroid boldenone.

Mechanism of action– It inhibits biofilm formation of Candida albicans with an optimal concentration above 3mM and disrupts hyphal growth, which is the morphological transition from yeast to filamentous phase, at a concentration above 4mM.

It also inhibits an enzyme involved in lipid metabolism and abolishes germ tube formation by carrying protons across the plasma membrane, thus altering cytoplasmic pH.

Molecular formula- C11H20O2

Molecular Weight- 184.27g/mol

IUPAC Name- undec-10-enoic acid  

Structure-
Structure-of-Undecylenic-acid

Properties and uses-

Used as a topical antifungal agent that treats skin infections such as athlete’s foot and relieves itching, burning, and irritation associated with the skin condition.

Due to its bifunctional properties, it is also used as a linking molecule to conjugate other biomolecules such as proteins.

Benzoic acid-

Benzoic acid is a fungistatic compound that is widely used for a food preservative. Benzoic acid is conjugated to glycine in the liver and then excreted as hippuric acid.

Molecular formula- C7H6O2

Molecular Weight- 122.12g/mol

IUPAC Name- benzoic acid  

Structure-
Structure-of-Benzoic-acid

Butenafine-

It is a synthetic benzylamine antifungal agent. The fungal activity of butenafine is exerted through the alteration of cellular membranes, which results in increased membrane permeability, and growth inhibition. It is mainly active against dermatophytes.

Butenafine has superior fungicidal activity against the fungus. It also active against Candida albicans and this activity is superior to that of terbinafine and others.

Mechanism of action– It involves the synthesis inhabitation of sterols. In particular, it acts to inhibit the activity of the squalene epoxidase enzyme that is essential in the formation of sterols necessary for fungal cell membranes. By inhibiting squalene monooxygenase, an enzyme responsible for converting squalene to 2,3-oxydosqualene.

The inhibition of its own synthesis results in increased cellular permeability that causing leakage of cellular contents. The blockage of squalene monooxygenase also leads to subsequent accumulation of squalene. When the concentration of squalene is reached high, it is thought to have an effect of directly kill fungal cells.

Molecular formula- C23H27N

Molecular Weight-317.5g/mol

IUPAC Name- 1-(4-tert-butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl) methenamine 

Structure-
Structure-of-Butenafine

Quiniodochlor-

It is a weak antifungal drug and has less antibacterial action. It is used for local application. It is available in the formulation of quiniodochlor cream in combination with hydrocortisone acetate or Dexamethasone trimethyl acetate.

The adverse effect of antifungal drugs-

For topical anti-fungal agents such as creams are-

-Itching

-A mild burning sensation

-Redness

For oral anti-fungal agents such as capsules are-

-Feeling sick

-Abdominal pain

-Diarrhea

-Flatulence

-Headache

-A rash

-Indigestion

-Swelling on face, neck or tongue

-Difficulty in breathing

For intravenous anti-fungal agents are-

-Loss of appetite

-Feeling sick

-Vomiting

-Fever

-Chill

-Headache

-Muscle and joint pain

-Anemia

-Rush

-Epigastric pain (upper part of the stomach)


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