REVIEW 1: PHARMACEUTICAL AND MEDICINAL ORGANIC CHEMISTRY VID 2-3

Anthelminthics

Are drugs that are capable of eliminating parasitic worms or helminths

• Cestodes (tapeworms)

• Trematodes (flukes)

• Nematodes (roundworms)

Different helminths

(PPT MAID)

1. Piperazine

2. Pyrantel pamoate

3. Thiabendazole

4. Mebendazole

5. Albendazole

6. Ivermectin

7. Diethylcarbazine

Drugs used for nematodes

Block response of ascaris muscle to Ach → leading to placid paralysis

Piperazine MOA

Piperazine

• Leads to placid paralysis

• Used in the treatment of pinworm and roundworm

Depolarizing neuromuscular blocking agent → spastic paralysis

Pyrantel pamoate MOA

Pyrantel pamoate

• Should not be used with piperazine (opposite effects).

• Treatment of pinworm, roundworm (Ascaris)

Inhibit fumarate reductase/antimitotic/antimicrotubule

Thiabendazole MOA

Thiabendazole

• Broad spectrum antheminthic

• In veterinary practice as anthemintic in livestock

Irreversiblly blocks glucose uptake → depleted glucose/antimitotic/antimicrotubule

mebendazole MOA

Broad spectrum (whip, pin, round, hook)

Mebendazole spectrum of activity

Antimitotic/antimicrotubule

Albendazole MOA

Broad spectrum

Albendazole spectrum of activity

Streptomyces avermitilis

Ivermectin is extracted from what bacteria

Stimulating gaba → blocked interneuron-motor neuron transmission

Ivermectin MOA

Ivermectin

Used in the treatment of onchoceriasis (river blindness) - Oncocerca volvulus

Diethylcarbamazine

• Has an unknown MOA

• Treatment of Filariasis (causative agent: Wuchereria bancroftr → mosquito as carrier)

(PNOB)

1. Praziquantel

2. Niridazole

3. Oxamniquine

4. Bithionol

Drugs used for trematodes

Increase Ca2+ membrane permeability → loss of Ca → contraction → paralysis → phagocytosis (DEATH)

Praziquantel MOA

praziquantel

• Broad spectrum

• Agent of choice for blood flukes (schistosomes)

Niridazole

For schistosomiasis

Inhibit DNA, RNA, protein synthesis

Oxamniquine MOA

Oxamniquine

Treatment of schistosomiasis caused by Schistosoma mansoni

Bithionol

Agent of choice for liver fluke (Fasciola hepatica) and lung fluke (Paragonimus westermani)

1. Niclosamide

Drugs used for cestodes

Inhibit oxidative phosphorylation

Niclosamide MOA

Antiprotozoal

Used to treat protozoal infections:

• Malaria

• Amoebiasis

• Giardiasis

• Trichomoniasis

• Toxoplasmosis

• Pneumocystis carinii pneumonia or PCP (now known as Pneumocystis jirovecii Pneumonia or PJP)

Bites of infected female Anopheles mosquitoes

Malaria is spread to people through

• P falciparum

• P vivax

• P malariae

• P ovale

• P knowlesi

5 plasmodium parasite

P falciparum and P vivax

Pose the greatest threat among the plasmodium parasites

P falciparum

Is the deadliest malaria parasite and the most prevalent on the African continent

P vivax

Is the dominant malaria parasite in most countries outside of Sub-Saharan Africa

• P malariae

• P ovale

• P knowlesi

Other malaria species aside from P falciparum and P vivax that can infect humans

Amoebiasis or amoebic dysentery

Is a parasitic intestinal infection caused by any of the amoebas of the Entamoeba group (e.g., Entamoeba histolytica)

Gardiasis

• Caused by Giardia duodenalis (syn. G lamblia, G intestinalis)

• Fecal-oral transmission

• Manifests as watery and greasy diarrhea, stomach cramps, excessive gas

Trichomoniasis

• Is a common sexually transmitted infection caused by a parasite

• Causal agent: Trichomonas vaginalis

Trichomoniasis

• Found particularly in the female population

• Visible in women as thick frothy yellow to green or gray vaginal discharge and smells very fishy

• Present in male but is mild and silent

• In women, this can cause a foul-smelling vaginal discharge, genital itching, and painful urination

• Men who have this typically have no symptoms/mild itchiness

Toxoplasmosis

• Is an infection caused by single-celled parasite called Toxoplasma gondii

• Transmitted by animals or orally via oral route or fecal-oral route

• Parasite is normally from cats

Pneumocystis carinii pneumonia or Pneumocystis jirovecii pneumonia

Is a fungal infection that most commonly affect the immunocompromised and, in some cases, can be severely life-threatening

(TEM)

• Emetine and Dehydroemetine

• Metronidazole

• Tinidazole

Amebecides that are effective against BOTH intestinal and extraintestinal (liver, lungs, skin, brain) forms of amoeba

Emetine and dehydroemetine

• Amebicides from the alkaloids from Ipecac (Carapichea ipecacuanha)

• Also used for balatidial dysentery, fascioliasis, paragonimiasis

• limited use due to toxic effects:

  • GI

  • Cardiovascular

  • neuromuscular

Inhibit protein synthesis by preventing protein elongation (proptoplasmic poison)

Emetine and dehydroemetine MOA

Covalent binding of reactive intermediate from the reduction of 5-nitro group to the DNA → lethal effect

Metronidazole MOA

Metronidazole

• Treatment of amoeba, giardiasis, trichomonas, anaerobic bacterial infections

• a/e: disulfiram-like effect (if taken with alcohol)

(8-ID)

• 8-hydroxyquinoline

• Iodoquinol

• Diloxanide

Amebicides that are effective ONLY against intestinal form

Chelation of metal ions

8-hydroxyquinoline MOA

Iodoquinol

• A derivative of 8-hydroxyquinoline

• For acute and chronic intestinal amebiasis

Diloxanide

• Treatment of asymptomatic carriers of E histolytica

• From discovery of alpha-dichloroacetamides

(CAP)

• Cotrimoxazole

• Pentamide isethionate

• Atovaquone

Drugs used to treat Pneumocystis carinii pneumonia (CAP)

Cotrimoxazole

Is a combination of sulfamethoxazole + trimethoprim

Cotrimoxazole

DOC for Pneumocystic pneumonia

Pentamide isethionate

Prophylaxis for African trypanosomiasis (rapidly distributed to tissues where it is stored)

Atovaquone

An analogue of Ubiquinone a component of mitochondrial electron transport chain

Interfere with the electron transport chain as it is an antimetabolite for ubiquinone

Atovaquone MOA

(MEN BS)

• Eflornithine

• Nifurtimox

• Benznidazole

• Melarsoprol

• Suramin

Treatment for tripanosomiasis

Irreversible inactivation of Ornithine decarboxylase

Eflornithine MOA

Eflornithine

• Used in the treatment of African sleeping sickness or Human African Trypanosomiasis (HAT)

• HAT is caused by protozoan parasites transmitted by infected tsetse flies (type of fly that bites the human person)

• Myelosuppressive (→ anemia, leukopenia, thrombocytopenia)

• Trypanosoma brucei gambiense

• Trypanosoma brucei rhodesiense

African trypanosomiasis causative agents

Cattle and other ungulates

Are reservoirs of Trypanosoma brucei gambiense

Nifurtimox

Treatment of South American trypanosomiasis or Chagas Disease (Trypanosoma cruzi)

Benznidazole

Treatment of Chagas disease (Trypanosoma cruzi)

Chagas disease

Can be transmitted by the triatomine bug (vector-borne), as well as orally (food-borne), during pregnancy or birth (congenital), through blood/blood products, organ transplantation or laboratory accidents

Melarsoprol

DOC for later stages of both forms of African trypanosomiasis

Trypanosoma brucei gambiense

West African trypanosomiasis is caused by

Trypanosoma brucei rhodesiense

East African trypanosomiasis is caused by

Suramin

• Bisurea derivative containing six sulfonic acid group

• Used as a long-term prophylactic agent for trypanosomiasis (due to high protein binding, effect can last up to 3 months)

Sulfadiazine + pyremethamine

Most effective therapy for toxoplasmosis

Sodium stibogluconate

Treatment for leishmaniasis

Inhibit phosphofructokinase

Sodium stibogluconate MOA

Sodium antimony gluconate

Sodium stibogluconate is aka

• Scabicides

  • Benzyl benzoate

  • Crotamiton

• Scabicides and pediculicides

  • Permethrin

  • Lindane

Antiscabies and antipedicular agents

Scabicides

Agents that control the mite Sacroptes scabiei

Pediculicides

Used to eliminate head, body, and crab lice

Benzyl benzoate

• From Peru balsam, also from benzyl alcohol + benzoyl chloride

• Topical scabicide

Crotamiton

• Antipruritic (local anesthetic action)

• 10% - lotion/cream for scabies

• A colorless, odorless oily liquid

Acts on nerve cell membranes → disrupt Na+ channel conductance → paralysis

Permethrin MOA

Permethrin (Kwell)

• Synthetic pyrethrin

• 1% lotion - for the treatment of lice; 5% cream - for the treatment of scabies

Direct contact poison, fumigant effect, stomach poison

Lindane MOA

Lindane

Chlorinated benzene (benzene hexachloride) used as scabicide and pediculicide

• Inhibition of cell wall synthesis

• Inhibition of protein synthesis

• Inhibition of cell metabolism

• Inhibition of nucleic acid transcription and replication

• Interactions with plasma membrane

Mechanisms of antibacterial action

• Beta-lactam antibiotics

• Cycloserine

• Bacitracin

• Vancomycin

• Teicoplanin

• Fosfomycin

Antibacterial agents that inhibit cell wall synthesis

• Penicillin

• Cephalosporins

• Carbapenems

• Monobactam

Beta lactam antibiotics

Alexander Fleming

Penicillins are discovered by

• Old: penicillium notatum

• New: penicillium chrysogenum

Source of penicillin (fungus)

Florey and Chain

Penicillins are isolated by ___ via freeze drying/lyophilization

Penicillin

• Contains an unstable bicyclic system

  • Beta-lactam & thiazolidine ring

  • Nucleus: 6-aminopenicillanic acid (6-APA)

• Precursors: cysteine and valine

• Shape: half open book

6-aminopenicillanic acid

Nucleus of penicillin

Cystein and valine

Precursors of penicillin

Electron withdrawing groups

In the structure of penicillin, these groups decrease nucleophilicity of carbonyl oxygen → increasing stability

Bulky groups

These groups in the penicillin structure provide resistance to beta lactamase

Polar groups

In the structure of penicillins, these groups make the structure more hydrophilic

Carbonyl oxygen

In penicillin structure, this is electrophilic because the lone pair electrons on N is not provided for resonance. Thus, =0 is ready for nucleophilic attack

Bicyclic system

In the penicillin structure, this confers further strain to beta-lactam ring

Increase strain → increase activity → increase instability

Carboxylic group

In penicillin structure,

1. Is usually ioniszed to form sodium or potassium salts

2. Bind amino group of lys at binding site

3. Is important for activity for which is reduced if modified to alcohol or ester

Thiazolidine

5-membered saturated ring contains nitrogen. The geminal dimethtyl group at C-2 position is characteristic of the penicillin

Electron withdrawing group

Addition of this group increases penicillin’s acid stability

Bulky groups

Addition of this group helps with penicillin’s resistant

Amino group

Addition of this group increases penicillin’s spectrum activity

Benzylpenicillin

Chemical name of penicillin G

Phenoxymethylpenicillin

Chemical name of penicillin V