Lesson 8.4. Antiparasitic Agents

Protozoal infections

amebiasis, giardiasis, trichomoniasis, Pneumocystis carinii pneumonia (PCP) infection, trypanosomiasis, leishmaniasis, and malaria

Helminth Infections

roundworms, tapeworms, and filariasis

Ectoparasite Infections

parasites on skin surface; scabies and pediculosis

Nitroimidazoles

its nitro group generate ROS (superoxide radicals) that damages key cellular components (e.g. DNA/RNA) leading to protozoal cellular death

Aromatic ester-amide

inhibit pyruvate: ferredoxin oxidoreductase (PFOR) → no formation of dactyl thiamine pyrophosphate (TPP) complex → no lactic acid formation (lactic acid is essential metabolite for protozoa survival)

amebiasis, giardiasis and trichomoniasis

use of Nitroimidazoles and Aromatic Ester Amides

Metronidazole Structure

NITROIMIDAZOLES

Tinidazole Structure

NITROIMIDAZOLE

Nitazoxanide

AROMATIC ESTER AMIDES

• prodrug for Tizoxanide

• ester is hydrolyzed into OH

Nitazoxanide Structure

AROMATIC ESTER AMIDES

Diloxanide Structure

AROMATIC ESTER AMIDES

Emetine

OTHER ANTIPROTOZOAL AGENTS:

• alkaloidal antiprotozoal that induce vomiting

Emetine Structure

OTHER ANTIPROTOZOAL AGENTS:

Iodoquinol

OTHER ANTIPROTOZOAL AGENTS:

• used as luminal amebicide chelates ferrous ions

Iodoquinol Structure

OTHER ANTIPROTOZOAL AGENTS:

Paromomycin

OTHER ANTIPROTOZOAL AGENTS:

• antiprotozoal

• aminoglycoside

Paromomycin Structure

OTHER ANTIPROTOZOAL AGENTS:

Pneumocytsis carinii pneumonia (PCP)

common life-threatening condition among immunocompromised patients (e.g HIV, organ transplant, cancer patients)

TMP-SMX (Trimethoprim-Sulfamethoxazole)

Drug of Choice for PCP

TMP-SMX Structure

AGENTS FOR PCP:

Pentamidine

2ND LINE DRUGS FOR PCP:

• amino groups binds DNA causing interference in DNA synthesis

• inhibits topoisomerase II

Pentamidine Structure

2ND LINE DRUGS FOR PCP:

Atovaquone

2ND LINE DRUGS FOR PCP:

• has structural similarity with Co-Q10 hence activity on ETC complex

• inhibits nucleic acid/ATP synthase

Atovaquone Structure

2ND LINE DRUGS FOR PCP:

Tritryps Agents

agents used to combat infections caused by: Leishmania spp, Trypanosoma cruzi, and Trypanosoma brucei gambiense/rhodisiense

neglected parasitic tropical diseases (NTDs)

Infections caused by Leishmania spp, Trypanosoma cruzi, and Trypanosoma brucei gambiense/rhodisiense are classified as _____________________________

Suramin

AGENTS FOR AFRICAN TRYPANOSOMIASIS

• has 6 sulfone groups

• inhibits dihydrofolate reductase, thymidine kinase, glycolytic enzymes

Suramin Structure

AGENTS FOR AFRICAN TRYPANOSOMIASIS

Eflornithine

AGENTS FOR AFRICAN TRYPANOSOMIASIS

• irreversible inhibitor of ornithine decarboxylase (ODC) → blocks putrescine synthesis → no polyamine for membrane potential/ATPase

Eflornithine Structure

Melarsoprol

AGENTS FOR AFRICAN TRYPANOSOMIASIS

• inhibits trypanothione reductase with trivalent As (high affinity for -SH in proteins)

Melarsoprol Structure

AGENTS FOR AFRICAN TRYPANOSOMIASIS

Benznidazole

AGENTS FOR AMERICAN TRYPANOSOMIASIS

• contains nitro-imidazole ring

• prodrug that is metabolized into a nitroso intermediate → interferes with trypanothione

Benznidazole Structure

AGENTS FOR AMERICAN TRYPANOSOMIASIS

Nifurtimox

AGENTS FOR AMERICAN TRYPANOSOMIASIS

• contains nitro-furan ring

• prodrug that generates ROS → damages trypanosomes DNA and trypanothione reductase

Nifurtimox Structure

AGENTS FOR AMERICAN TRYPANOSOMIASIS

Stibogluconate

AGENTS FOR LEISHMANIASIS

• contains trivalent/pentavalent Sb

• induces apoptosis on Leishmania by acting in biopolymers

Stibogluconate Structure

AGENTS FOR LEISHMANIASIS

Miltefosine

AGENTS FOR LEISHMANIASIS

• orally active agent with unclear MOA vs Leishmania

Miltefosine Structure

AGENTS FOR LEISHMANIASIS

Antimony Potassium Tartrate

AGENTS FOR LEISHMANIASIS

• tartar emetic

• inorganic agent previously used for Leishmaniasis

Antimony Potassium Tartrate Structure

AGENTS FOR LEISHMANIASIS

Quinolines

ANTI-MALARIAL AGENTS

• Includes natural and synthetic derivatives (e.g., quinine, chloroquine, mefloquine)\

• prevent the conversion of toxic hematin to non-toxic hemozoin, leading to accumulation of toxic heme and death of the malaria parasite

Antifolates

ANTI-MALARIAL AGENTS

• Inhibit folate metabolism in Plasmodium (e.g., sulfadoxine-pyrimethamine)

• targets dihydrofolate reductase (DHFR) similar to trimethoprim

Artemisinin and derivatives

ANTI-MALARIAL AGENTS

• natural product of chinese medicine (qinghaosu) or from sweetworm wood (Artemissia annua)

• MOA is unknown but the endoperoxide bridge in its structure is believed to generate reactive oxygen species (radicals) that interact with hemozoin, damaging the malaria parasite

Quinine

QUINOLINE ANTIMALARIALS

• natural agent first extracted from Cinchona

Quinine Structure

QUINOLINE ANTIMALARIALS

Primaquine

QUINOLINE ANTIMALARIALS

• artificial agent that is considered as a “radical cure”

Primaquine Structure

QUINOLINE ANTIMALARIALS

Chloroquine

QUINOLINE ANTIMALARIALS

• artificial agent

• C7-Cl gives higher activity

Chloroquine Structure

QUINOLINE ANTIMALARIALS

Proguanil

ANTIFOLATE ANTIMALARIALS

• lead compound, prodrug for cycloguanil

Proguanil Structure

ANTIFOLATE ANTIMALARIALS

Pyrimethamine

ANTIFOLATE ANTIMALARIALS

• developed from proguanil given usually with sulfadoxine to mimic TMP-SMX

Pyrimethamine Structure

ANTIFOLATE ANTIMALARIALS

Arteminol/Dihydroartemisinin

ARTEMISININ ANTIMALARIALS

• source molecule for other derivative

Arteminol/Dihydroartemisinin Structure

ARTEMISININ ANTIMALARIALS

Artemotil

ARTEMISININ ANTIMALARIALS

• lipid-soluble derivative

Artemotil Structure

ARTEMISININ ANTIMALARIALS

Artesunate

ARTEMISININ ANTIMALARIALS

• water-soluble derivative

Artesunate Structure

ARTEMISININ ANTIMALARIALS

Artemether

ARTEMISININ ANTIMALARIALS

• lipid-soluble derivative

Artemether Structure

ARTEMISININ ANTIMALARIALS

Anti-helminthic Agents

agents are used for parasitic helminthic infection (e.g. round worms, tape worms, filariasis)

fumarate reductase

MOA OF ANTI-HELMINTHIC AGENTS:

a. inhibits ______________________ (benzimidazoles)

b. induces _________________ in the helminth parasite (other agents)

a = ?

muscular paralysis

MOA OF ANTI-HELMINTHIC AGENTS:

a. inhibits ______________________ (benzimidazoles)

b. induces _________________ in the helminth parasite (other agents)

b = ?

Benzimidazoles

ANTI-HELMINTHIC AGENTS:

a. ____________ - Mebendazole, Thiabendazole, and Albendazole

b. __________ - Ivermectin (for river blindness), Praziquantel (fluke infection), Pyrantel pamoate, Diethylcarbamazine, Piperazine

a = ?

Other agents

ANTI-HELMINTHIC AGENTS:

a. ____________ - Mebendazole, Thiabendazole, and Albendazole

b. __________ - Ivermectin (for river blindness), Praziquantel (fluke infection), Pyrantel pamoate, Diethylcarbamazine, Piperazine

b = ?

Mebendazole Structure

ANTI-HELMINTHIC AGENTS:

Thiabendazole Structure

BENZIMIDAZOLES:

Albendazole Structure

BENZIMIDAZOLES:

Ivermectin Structure

OTHER ANTI-HELMINTHIC AGENTS:

Diethylcarbamazepine Structure

OTHER ANTI-HELMINTHIC AGENTS:

Praziquantel Structure

OTHER ANTI-HELMINTIC AGENTS:

Sarcoptes scabiei

ECTOPARASITES:

a. scabies

b. pediculosis

c. other ectoparasites

a = ?

Pediculus humanus

ECTOPARASITES:

a. scabies

b. pediculosis

c. other ectoparasites

b = ?

Cimex reticularis

ECTOPARASITES:

a. scabies

b. pediculosis

c. other ectoparasites

c = ?

Spinosad

ECTOPARASITE AGENTS:

• mixture of macrocyclic lactones that paralyzes parasite by hyper exciting nicotinic acetylcholine receptors

Benzyl alcohol

ECTOPARASITE AGENTS:

• not an insecticide

• instead, it eradicates lice by asphyxiation, blocking their respiratory spiracles and preventing gas exchange

Lindane

ECTOPARASITES AGENTS:

• blocks GABA receptor leads to parasite paralysis

Lindane Structure

ECTOPARASITE AGENTS:

Pyrethrin

ECTOPARASITE AGENTS:

• P-I R = -CH3, P-II R = -CO2CH3

• binds to Na channel resulting to paralysis

Pyrethrin Structure

Permethrin

ECTOPARASITE AGENTS:

• used for scabies, lice and also against mosquitos

Permethrin Structure

ECTOPARASITE AGENTS

Crotamiton

ECTOPARASITE AGENTS:

• scabicical agent approved by FDA

Crotamiton Structure

ECTOPARASITE AGENTS