Antiviral-Antifungal-Antiparasitic Agents PDF

ANTIVIRAL – ANTIFUNGAL ANTIPARASITIC AGENTS Dr. Özge YILMAZLI Medical Microbiology Dept. Nucleoside Analogs ANALOG: Something that structurally different but provide tha same function They’re nucleosides that differentiation on base, sugar or base and sugar. Binding to viral enzymes is more than a f...

ANTIVIRAL – ANTIFUNGAL ANTIPARASITIC AGENTS Dr. Özge YILMAZLI Medical Microbiology Dept. Nucleoside Analogs ANALOG: Something that structurally different but provide tha same function They’re nucleosides that differentiation on base, sugar or base and sugar. Binding to viral enzymes is more than a few hundreds according to binding to cellular enzymes. Antivirals 1. Nucleoside Analogs: a) Acyclovir Viral thymidine kinase is required for the drug to be activated by phosphorylation. It prevents DNA replication. Medicine; It causes the termination of the viral DNA chain because the drug does not have the 3' OH group necessary for the elongation of the chain. Resistance: Thymidine kinase mutation - drug does not activate Mutation in DNA polymerase - drug cannot bind to enzyme Antivirals 1. Nucleoside Analogs: b) Valacyclovir: The valyl ester of ACV is rapidly converted to ACV with a more efficient absorption after oral ingestion, with greater bioavailability in the treatment of Herpes Simplex Virus and Varicella Zoster Virus. It inhibits DNA polymerase. c) Penciclovir: It inhibits HSV and VZV in the same way as ACV, but is more concentrated in infected cells than ACV. It prevents DNA replication. Antivirals 1. Nucleoside Analogs: d) Famciclovir: It is a precursor to penciclovir and is better absorbed. Converts to penciclovir in the liver or intestinal tract Resistance: Same mechanism with ACV e) Ganciclovir (GCV): It contains one more hydroxymethyl group and this addition makes the drug highly active against Cytomegalovirus (CMV) The activated drug inhibits all Herpesvirus DNA polymerases. GCV; highly effective in CMV retinitis It’s used limited due to its potential toxic effects on bone marrow Viral DNA polymerase has a drug affinity about 30 times greater than cellular DNA polymerase!!! So drug is found high level in infected cells!!! Antivirals 1. Nucleoside Analogs: f) Cidofovir and Adefovir: They are nucleoside analogs that contain a phosphate molecule attached to the sugar analog. They inhibits DNA polymerase. This feature eliminates the need for initial phosphorylation by viral enzyme Substrate for DNA polymerase and reverse transcriptases Extended spectrum Approved for the treatment of CMV infection in AIDS patients Adefovir: approved for the treatment of HBV Antivirals 1. Nucleoside Analogs: g) Azidothymidine: First effective treatment for cancer and HIV Inhibits HIV reverse transcriptase enzyme Inhibits complementary DNA (cDNA) synthesis Administered in HIV-infected individuals with low CD4 T-cell counts Administration to HIV(+) pregnant women may reduce the possibility of transmission of the virus to the baby. Antivirals 2. Non-Nucleoside Polymerase Inhibitors a.) Foscarnet: Similar to pyrophosphate Inhibits nucleotide binding and viral replication At pharmacological doses, they do not inhibit cellular polymerases Does not require phosphorylation by nucleoside kinases Inhibits all HPV DNA polymerases and HIV reverse transcriptase Antivirals 3. Protease Inhibitors: The unique nature of the HIV protease and its role in virion formation make this molecule a good target Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir; inhibits the enzyme's function by binding the hydrophobic active site of the viral polymerase May reduce the HIV load in the blood to undetectable levels Antivirals Anti-influenza drugs – Entry and Uncoating Inhibitors: a.) Amantadine and Rimantadine: Amine compounds and clinically active against influenza A It accumulates in endosomal vesicles and buffers the vesicle contents This effect inhibits the acid-mediated structural change of the hemagglutinin (HA) protein, which allows the cell membrane to associate with the virus envelope. May be beneficial if taken within 48 hours of exposure It is also useful in prophylactic treatment Antivirals Anti-influenza drugs - Releasing Inhibitors: b.) Zanamivir and Oseltamivir: Enzyme inhibitor of influenza neurominidase (NA), it is effective for both Influenza A and Influenza B Without neuraminidase, the hemagglutinin of the virus binds to the sialic acid of other glycoproteins on the surface during exit from the cell, causing aggregation and inhibition of virus release ANTIFUNGALS--according to their structure  POLYENES Amphotericin B, nystatin AZOLS Imidazole: Ketoconazole.. Triazoles: Fluconazole, itraconazole, voriconazole, posaconazole, ravuconazole ALLIYLAMINES Terbinafine MORPHOLINES Amorolfine FLUORINATED PYRIMIDINE Echinocandins Caspofungin, anidulafungin, micafungin PEPTIDE-NUCLEODE Nikkomycin Z TETRAHYDROFURAN DERIVATIVES Sordarins, azasordarins OTHER griseofulvin ANTIFUNGALS--by mechanism of action Drugs that disrupt the membrane Glucan synthesis Amphotericin B, nystatin Echinocandins Ergosterol synthesis inhibitors Azoles, allylamines, morpholine Nucleic acid inhibitors Flucytosine Anti-mitotic Grizeofulvin inhibitors fungin Chitin synthesis inhibitor Nikkomycin Protein synthesis inhibitors tetra Sordarins, azasordarins Amphotericin B: It has an antifungal effect by binding to ergosterol. Amphotericin B binds to ergosterol in the cell membrane, causes occur of pores and so it disrupts the cell membrane directly Clin Microbiol Rev 1999; 12: 501 Polyenes Amphotericin B and it’s lipid formulations; Used to the treatment of severe mycoses Nystatin is used topically. Main mechanism of action: binding to ergosterol, that the most important membrane sterol Ion channels are formed, the osmotic integrity of the fungal cell membrane is disrupted and the cell dies It also binds (weakly) to cholesterol, the principal membrane sterol of mammalian cells. That's why most of the toxicity! Additional mechanism of action: free oxygen radicals formed as a result of the oxidative reaction and it contributes to the fungicidal effect AZOLES: Inhibits ergosterole synthesis! As a result of the inhibition of the enzyme lanosterol (14-alpha) demethylase, toxic intermediates occur, these compounds inhibit the growth of the fungus. Azoles Imidazoles (2 nitrogens in the azole ring) and triazoles (3 nitrogens) Of the imidazoles, only ketoconazole has systemic efficacy. All of the triazoles are systemic (fluconazole, itraconazole, posaconazole and voriconazole) Inhibits lanosterol 14-∝-demethylase Ergosterol formation and accordingly membrane synthesis are disrupted. TERBINAFINE: It has an antifungal effect by inhibiting ergosterol synthesis.. TERBINAFINE By inhibiting the squalene epoxidase enzyme, it causes a decrease in ergosterol and an increase in squalene in the fungal cell membrane. Nucleic acid Inhibitors-Antimetabolites Flucytosine (5-FC); The only antifungal that works as an anti-metabolite Inhibits DNA, RNA and protein synthesis Flucytosine is taken into fungal cell by cytosine permease and is converted to 5-fluorouracil (5-FU) by deamination. It competes with uracil during RNA synthesis. RNA is miscoded, DNA and protein synthesis is inhibited Echinocandins Caspofungin, Micafungin, Anidulafungin Inhibition of β-(1-3)-glucan synthesis by inhibiting the glucan synthase enzyme In molds, they have a static effect at the end and branching points of the hyphae. In yeast, they inhibit the bud to leave the parent cell They sensitize the fungi cell to osmosis Aminoquinoline Analogs 4-aminquinoline (chloroquine), quincona alkaloids quinine, quinidine), 8-aminoquinolines (primakine), and synthetic quinoline compounds (mefloquine). antimalarial activity ANTIPARASITERS Antiprotozoal Drugs: accumulates in infected red blood cells binds DNA and inhibits replication of the DNA increases the pH in intracellular acid vesicles, impairing the parasite's ability to break down hemoglobin ANTIPARASITERS Antiprotozoal Drugs: Folic Acid Antagonists: Requires folic acid for nucleic acid synthesis and DNA production Cannot absorb exogenous folic acid, sensitive to drugs that inhibit folate synthesis Includes diaminopyrimidines (pyrimethamine and trimethoprim) and sulfonamides They inhibit the folic acid pathway at different steps Toxoplasmosis and malaria ANTIPARASITERS Antiprotozoal Drugs: Protein Synthesis Inhibitors: Some antibiotics that inhibit protein synthesis in bacteria also show antiparasitic effects!!! Clindamycin, Tetracycline and Doxycycline Clindamycin and tetracycline: to Plasmodium spp., Babesia spp. and amoeba Doxycycline: P. falciparum prophylaxis Tetracycline + quinine: chloroquine R P. falciparum malaria treatment strategies for use are quite different from antiprotozoal drugs ANTIPARASITERS Antihelminthic Drugs: targets non-reproducing adult organisms frequently used; Benzimidazoles, tetrahydropyrimidine, piperazine, avermectins, phenol ANTIPARASITERS - Antihelminthic Drugs Benzimidazoles broad-spectrum anthelmintics Mebendazole, thiabendazole, triclabendazole and albendazole basic structure: imidazole and benzene ring linked together mechanism of action (1): inhibition of fumarate reductase (carbonhydrate metabolism)( (2) glycogen depletion due to inhibition of glucose transport, cessation of ATP production, paralysis and death (3) disruption of microtubular function ANTIPARASITERS - Antihelminthic Drugs Benzimidazols It is used in the treatment of intestinal nematodes (Ascaris, Trichuris, Necator, Enterobius vermicularis) as well as some cestodes (Taenia, Hymenolepis and Echinococcus). Albendazole: shows greater activity than others against intestinal nematodes and cestodes, as well as Echinococcus spp. In addition to its anthelmintic effect, it is also effective against Giardia species. ANTIPARASITERS-ANTHELMINTIC DRUGS Tetrahydropyrimidines It is a cholinergic agonist and has the effect of binding to the cholinergic receptor on the muscle cells of nematodes, resulting in cell depolarization and muscle contraction. This paralyzing effect allows the parasite to be expelled from the host's intestines. Effective against Ascaris, Enterobius vermicularis (pinworm) and Necator americanus (hookworm) Frequently used is Dietilkarbamezin (DEC) ANTIPARASITERS - ANTHELMINTIC DRUGS Piperazines Stimulates cholinergic receptors and depolarizes muscle cells Cause paralysis Facilitates the adhesion of leukocytes to the microfilariae Stimulates phagocytic cells ANTIPARASITERS - ANTHIELMINC DRUGS Avermectins Ivermectin interacts with chloride channels in the membrane of nerve and muscle cells and causes hyperpolarization The parasite becomes paralyzed and dies Strongyloides, Ascaris, Enterobius sp. Side effect; less than piperazines ANTIPARASITERS-ANTHELMINTIC DRUGS Phenols Niclosamide; Shows selective activity against intestinal cestodes Disrupts oxidative phosphorylation mechanism in mitochondria Movement stops due to loss of ATP Easier to be excreted with feces