Antifungal Drugs 2025 PDF

Antifungal drugs Introduction Antifungal drugs are medications used to treat fungal infections such as athlete’s foot, ringworm, and candidiasis (thrush) as well as serious systemic infections like crypto-coccal meningitis. Antifungal drugs work by exploiting differences between mammalian and fung...

Antifungal drugs Introduction Antifungal drugs are medications used to treat fungal infections such as athlete’s foot, ringworm, and candidiasis (thrush) as well as serious systemic infections like crypto-coccal meningitis. Antifungal drugs work by exploiting differences between mammalian and fungal cells to kill the fungal organism without significantly harming the host. Fungal infections are conventionally divided into three categories; 1- Systemic fungal infections They are very rare, although they represent a serious problem since they are difficult to diagnose and treat. 2- Mucocutaneous infections It caused primarily by the fungus Candida albicans occur in regions of moist skin and mucous membranes (i.e. gastrointestinal tract, perianal, and vulvovaginal areas). 3- Dermatophytic infections They are the most widespread fungal infections, which include skin, hair, and nails. Most infections can be cured by using topical drugs, such as tolnaftate and clotrimazole. Systemic drugs like griseofulvin & fluconazole are used orally for deep infections. From the chemical point of view, antifungal drugs can be divided into 1. Polyenes They include; nystatin, amphotericin B and natamycin, act by binding with sterols in the fungal cell wall, principally ergosterol. This causes leakage of the cell contents out, resulting in cell death. Human cells (and other animals) contain cholesterol rather than ergosterol so are much less susceptible to polyenes. 2. Imidazole and triazole derivatives The imidazole and triazole groups of antifungal drugs such as; miconazole, ketoconazole, clotrimazole, econazole, fluconazole, butoconazole and inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell-wall synthesis. These drugs also block steroid synthesis in humans. 3. Allylamines Examples of allylamines are naftifine, terbinafine, butenafine, amorolfine. They inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis. 4. Others Other antifungal drugs include griseofulvin, which acts by binding to polymerized microtubules and inhibits fungal mitosis, and the antimetabolite flucytosine. I- Systemic antifungal drugs 1- Amphotericin B An antifungal antibiotic, produced by Streptomyces nodosus. It is an amphoteric polyene macrolide (polyene; containing many double bonds, macrolide; containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water. Mechanism of action: Amphotericin B acts by binding with sterols, in particular, ergosterol in the cellular membrane of sensitive fungi. This reaction makes pores in the membrane and increases its permeability to small molecules, thus reducing the function of the membrane as an osmotic barrier, and making the cells more sensitive to be destroyed. Amphotericin B possesses fungistatic and fungicidal activity depending on the dose used. It is active against growing cells and cells that are dormant. However, this compound is not highly selective and reacts with host mammalian cells. Despite the many side effects, amphotericin B remains the primary drug for treating of severe acute systemic fungal infections. It is used for generalized fungal infections, including Candida albicans, Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum. The use of amphotericin B is limited by its toxicity, especially drug-induced renal impairment Formulations a. Amphotericin B sodium desoxycholate for I.V injection: Associated with nephrotoxicity b. Colloidal suspension of amphotericin B: A colloidal dispersion of a stable complex of amphotericin B with cholesteryl sulphate (1:1), associated with less nephrotoxicity. c. Liposomal Amphotericin B: New formulations, in which amphotericin B is packaged in a lipid-associated delivery system. Amphotericin binds to the lipids in these vehicles with a different affinities to fungal ergosterol and human cholesterol. The lipid vehicle then serves as an amphotericin reservoir, reducing nonspecific binding to human cell membranes (least side effects) 2- Flucytosine (5-FC) H Water-soluble pyrimidine analog related to the chemotherapeutic N O agent fluorouracil (5-FU). Its spectrum of action is much F N narrower than that of amphotericin B. It is administrated orally. NH2 5-Fluorocytosine Mechanism Flucytosine is taken up by fungal cells via the enzyme cytosine permease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively. Human cells are unable to convert the parent drug to its active metabolites. Clinical use Spectrum of activity of flucytosine is restricted to Cryptococcus neoformans, some candida species, and the dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent because of its demonstrated synergy with other agents, and to avoid the development of secondary resistance. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis. Adverse effects The adverse effects of flucytosine results from its metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently. A form of toxic enterocolitis can occur. An increased risk of toxicity was observed with higher drug levels, and resistance develops rapidly at subtherapeutic concentrations. The use of well measured drug doses may help in reducing the incidence of toxic reactions, especially when flucytosine is combined with nephrotoxic agents such as amphotericin B. Synthesis O Cl NH2 NH2 H F F F F N POCl3 N N H2O/HCl N NH3 O N Cl N Cl N O N H H 3- Azoles Azoles are synthetic compounds that can be classified as either R imidazoles or triazoles according to the number of nitrogen atoms in N the five-membered azole ring. X N Imidazoles include ketoconazole, miconazole and clotrimazole. The X = C, imidazole latter two drugs are now used only in topical therapy. X = N, triazole Triazoles include itraconazole, fluconazole and voriconazole. Mechanism of Action Antifungal activity of azole drugs results from reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from their greater affinity for fungal than human cytochrome P450 enzymes. Imidazoles exhibit a lesser degree of specificity than triazoles, accounting for their higher incidence of drug interactions and side effects. Resistance to azoles occurs via multiple mechanisms. Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be the cause for clinical drug resistance in certain settings.  i- Ketoconazole N N 4 2 O Cl 4 1 O O 4 2 Cl O N N 1-Acetyl-4-[4-[2-( 2,4-dichlorophenyl(-2-(1H-imidazole- 1-ylmethyl(-1,3-dioxolan-4-ylmethoxy]phenyl]piperazine  Ketoconazole was the first oral azole introduced for clinical use.  It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes (↓adrenal & gonadal steroidogenesis).  Ketoconazole has a broad spectrum of antifungal activity, including many candida infections. It possesses fungicidal and fungistatic activity with respect to dermatophytes, yeast fungus, dimorphous fungi, and eumycetes. It is also active with respect to staphylococci and streptococci. It is effective for chronic diseases, treating fungal infections of the gastrointestinal tract, sex organs, skin, hair, and nails. It is used in combination with a shampoo for treating and preventing mycelial fungi, seborrheic dermatitis, and dandruff.  N ii- Itraconazole N N H3C O 2O CH3 Cl 4 4 N O 4 N O N N Cl N1 4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4- yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4- triazol-3-one Itraconazole is available in oral and intravenous formulations and is used at a dosage of 100-400 mg/d. Drug absorption is increased by food and by low gastric pH (empty stomach). It interacts with hepatic microsomal enzymes less than ketoconazole. It does not affect mammalian steroid synthesis, and has little effects on the metabolism of other hepatically metabolized drugs. While itraconazole displays potent antifungal activity, effectiveness can be limited by reduced bioavailability. Like ketoconazole, it penetrates poorly into the cerebrospinal fluid. Itraconazole is the azole of choice for treatment due to the dimorphic fungi histoplasma, blastomyces, and sporothrix. Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.  N iii- Fluconazole N F N 2,4-Difluoro-a,a-bis(1H-1,2,4-triazol-1-ylmethyl)benzyl alcohol. N 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol. N N OH F Fluconazole displays a high degree of water solubility and good cerebrospinal fluid penetration. Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance than other azoles, fluconazole has the widest therapeutic index, permitting more aggressive dosing in a variety of fungal infections. The drug is available in oral and intravenous formulations. Fluconazole is the azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis. Intravenous fluconazole has been shown to be equivalent to amphotericin B in treatment of candidemia in patients with normal white blood cell counts. Fluconazole is the agent most commonly used for the treatment of mucocutaneous candidiasis. Prophylactic use of fluconazole has been demonstrated to reduce fungal disease in bone marrow transplant recipients and AIDS patients. II- Systemic antifungal drugs for mucocutaneous infections 1. Griseofulvin OCH3 O OCH3 3 2- 7-Chloro-4,6-dimethoxycoumaren-3-one-2-spiro-1`- O (2`-methoxy-6`-methylcyclohex-2`-en-4`-one) H3CO 1 H3C Cl Griseofulvin is a very insoluble fungistatic drug derived from species of penicillium. It’s only used is in systemic treatment of dermatophytosis, and administered in a microcrystalline form at a dosage of 1 g/d. Absorption is improved when it is given with fatty foods. Griseofulvin's mechanism of action at the cellular level is unclear, but it is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection. The antifungal activity may be explained by its ability to inhibit cell mitosis in fungi, causing the formation of multiple-nuclei defective cells. Because its action is to prevent infection of these new skin structures, griseofulvin must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail, and is often followed by relapse. Adverse effects include an allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital. Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine. 2- ALLYLAMINES N N (E)-N-methyl-N-((naphthalen-1-yl)methyl)-3- N-[(2E)-6,6-Dimethyl-2-hepten-4-ynyl]-N-methyl-1- phenylprop-2-en-1-amine naphthalenemethanamine Naftifine Terbinafine Naftifine was the first representative of allylamine drugs, and only permitted to be used externally and only superficially. Terbinafine can be administered topically or orally. Allylamines posses a broad spectrum of action against dermatophytes and candida infections. The fungicide activity of these drugs is based on its ability to inhibit the fungal enzyme squalene epoxidase, thus lowering the concentration of ergosterol, and also leads to the accumulation of the sterol squalene, which is toxic to the organism. The corresponding enzyme in mammals is significantly less inhibited. Synthesis III- Topical antifungal therapy 1- Nystatin Nystatin was isolated in 1949 from the products of the vital activity of the actinomycete Streptomyces noursei. It is too toxic for parenteral administration and is only used topically. Nystatin is currently available in creams, ointments, vaginal suppositories, and other forms for application to skin and mucous membranes. It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste. It has a broad spectrum of activity. Mechanism Like amphotericin B it binds to ergosterol and inhibits cell wall synthesis. It is used for prevention and treatment of candida infections of the skin and mucous membranes. In terms of preventative action, it is used to prevent development of candidomycosis during prolonged treatment with penicillin drugs and antibiotics of other group, especially during oral use of tetracycline antibiotics, levomecytin, and others. Nystatin is active against most candida species and is most commonly used for suppression of local candidal infections.  N 2- Topical azoles N Cl i- Miconazole 1-(2-(2,4-dichlorobenzyloxy)-2-(2,4- O dichlorophenyl)ethyl)-1H-imidazole Cl Cl Cl Miconazole is primarily used externally for candida and dermatophyte infections of the skin and vaginal candidiosis as well as for acute internal mycoses. O H N O H 2 NaBH4 2 Cl C C Br Synthesis N Cl C C N N Cl H Cl N H2 N OH Cl C Br Cl H2 Cl C C N N Cl O H Cl Cl Cl Cl ii- Econazole, X = O N N 1-{2-[(4-chlorophenyl)methoxy]-2-(2,4- dichlorophenyl)ethyl}-1H-imidazole X iii- Sulconazole, X = S Cl Cl Cl iv- Clotrimazole C N N 1-((2-Chlorophenyl)diphenylmethyl)-1H-imidazole Cl Clotrimazole is very similar to miconazole. It has a broad spectrum of antifungal activity. It is effective with respect to dermatophytes, and it also has an antimicrobial effect against streptococci and staphylococci. It is also effective with respect to trichomoniases. It is very widely used, for externally for treating superficial infections. Synthesis 3- Topical allylamines Terbinafine and naftifine are available as topical creams. Both are effective for treatment of tinea cruris and tinea corporis.  4- Undecylenic acid O HO 10-Undecylenic acid Undecylenic acid, like zinc undecylenate, is very effective as an external drug for treating moderate dermatophyte infections and yeast dermatitis, but it is not effective for shingles and for candida infections. Synthesis H H2 400 °C, p(50mm) CH3 (CH2)5 C C CH CH (CH2)7 COOH H2C CH (CH2)8 COOH CH3 (CH2)5 CH=O OH pyrolysis  Name R 5- Toluene deratives CH3 1 Tolnaftate O N CH3 R 2 Tolindate S Tolnaftate: O-(2-Naphthyl)-N-methyl- 3 Tolcyclate N-(3-tolyl)-thiocarbamate Tolnaftate is used as an external drug for moderate dermatophyte infections (shingles), and it is not effective for treating candida infections. Synthesis thiophosgene