1. ANTI PARASITIC AGENTS

2. Parasite
Any living thing that lives in (endoparasite) or on (ectoparasite) another living organism is called a parasite.
It obtains food and/ or shelter from the host and contributes nothing to its welfare.
Some parasites cause irritation and interference with bodily functions, others destroy host tissues and release toxins into the body, thus injuring health and causing disease.

3. Protozoal infections Amoebiasis Giardiasis Leishmaniasis Malaria
Trypanosomiasis
Toxoplasmosis
Amebiasis
Protozoa
Schistosomiasis
Malaria

4. Helminth infections Nematode Cestode Trematode Nematode Nematode

5. Ectoparasitic infections
Scabies
Pediculosis

6. Amebiasis Disesase of large intestine caused by Entamoeba histolytica
Organism- 2 forms 1. Motile trophozoite form
2. Dormant cyst form
Trophozoite form: found in intestine or Wall of colon, expelled with stools
Cyst form: encased by a chitinous wall, protects the organism from environment
Symptoms: intermittent diarrhea (foul smelling loose/ watery stools), tenderness and enlargement of liver (with extra intestinal form) to acute amebic dysentery.
Many patients- no symptoms- organism remains in body as commensal organism

7. Giardiasis Caused by Giardia lambia, found in duodenum and jejunum.
Organism- 2 forms 1. Motile trophozoite form
2. Infectious cyst form
Cyst form- can be deposited in water- contaminated water infects man.
Trophozoite- if expelled from G.I, will not survive.
Symptoms: may be asymptomatic or develop watery diarrhea, abdominal cramps, distention and flatulence, anorexia, nausea and vomiting.

8. Trichomoniasis Caused by Trichomonas vaginalis
Exists only in trophozoite form.
Infects vagina, urethra, prostate- so the disease is considered a veneral infection.
Infections in male- asymptomatic
Symptoms in female- vaginitis, profuse discharge which is foul smelling, burning and soreness upon urination, vulvar itching

9. Leishmaniasis Caused by genus Leishmania
Transmitted from rodents, canines and other mammals, to man by bites from female sand flies of the genus Phlehotomus, and then appearing in one of four major clinical syndromes:
Visceral leishmaniasis
Cutaneous leishmaniasis
Muco cutaneous leishmaniasis
Diffuse cutaneous leishmaniasis
Visceral
Cutaneous
Muco cutaneous

10. Visceral leishmaniasis
By Leishmania donovani- disease is systemic
Symptoms: nocturnal fever, diarrhea, cough, enlarged spleen and liver.
Death, if not treated, is due to diarrhea, super infections or gastro intestinal hemorrhage.
Cutaneous and mucocutaneous leishmaniasis:
Single or multiple localised lesions
These slow healing and possibly painful ulcers can lead to secondary bacterial infections.
Old world cutaneous leishmaniasis by L.topica, L.major, L,aethiopica
New world cutaneous leishmaniasis by L.peruviana, L.braziliensis, L.mexicana, etc.
Incubation period- few weeks to several months
Symptoms: slow healing lesions on skin, in various regions of the body, depending on specific strain of organism.

11. Pneumocystis Caused by Pneumocystis carinii
It is an opportunistic pathogen.
Also in patients receiving immuno suppressive agents.
Also in malnourished infants, whose immunogenic systems are impaired.
Symptoms- severe pneumonia, organism lines the walls of the alveoli, and gradually fills the alveolar spaces.
If untreated, fatal

12. Trypanosomiasis Chagas’ disease: Two distinct forms- Chagas’ disease
African sleeping sickness
Chagas’ disease:
Also called American trypanosomiasis
Caused by Trypanosoma cruzi
It lives in mammals and is spread by blood sucking insect- reduviid bug or kissing bug or assassin bug.
Insect-draws blood from infected mammal- releases protozoa through faeces- pathogen enters the new host through breaks of the skin.
Symptoms: inflammatory lesions at the site of entry, malaise, fever, anorexia and skin edema at the site where the protozoa entered the host.

13. African sleeping sickness:
-Also called African trypanosomiasis
Caused by several sub species of Trypanosoma brucei.
Infected animal- bitten by blood sucking tsetse fly – it transmits the protozoa via inoculation during biting of man.
Infection- 2 stages
Stage I- fever and high temperatures lasting several days. Hematologic and immunologic changes occur.
Stage II- occurs after the organism enters the CNS.
Symptoms: day time somnolence, loss of spontaneity, halting speech, listless gaze and extra pyramidal signs like tremors and choreiform movements, hypoglycemia

14. Malaria Transmitted by infected female Anopheles mosquito.
Genus Plasmodium causes malaria: P.falciparum, P.vivax, P.malariae, P.ovale
Clinical symptoms: chills, fever, sweating, head aches, fatigue, anorexia, nausea, vomiting, diarrhea

16. Modes Of Transmission Four main mechanisms for parasitic transfer:
Ingestion of eggs from the fecal material of an infected individual
Ascaris lumbricoides
The larva of the parasite can burrow into the skin of a person
Schistosomes
The larva of the parasite can move from person to person through an insect vector
Trypanosomes
Plasmodia
Sexual transmission
Trichomonas vaginalis

17. General approaches to protozoal therapy
Amebiasis and giardiasis:
Prevention
Avoid taking contaminated food and water
Drinking boiled or bottled or disinfected water
Personal hygiene and sanitation
Malaria, leishmaniasis and Trypanosomiasis
Use of insectisides, preventive clothing, using insect repellants
Early detection and drug therapy

18. Purine and Pyrimidine related agents
Antiparasitic
Purine and Pyrimidine related agents
Pyrimidine related agents:
Pyrimethamine
Trimethoprim
Sulphadoxine
Sulphadiazine
Sulphalene
Pyrantel pamoate
Oxantel
Quinapyramine
Pyrimidine analogues
Arylene bis(methyl ketone) compound
Febrifugine
Isofebrifugine
Purine related agents:
Adenosine analogues
Nucleotide analogues
Allopurinol

19. Pyrimidine analogues

20. Pyrimethamine
Uses:
Used in suppressive treatment and radical cure agent of malaria.
Acts on both erythrocytic and exoerythrocytic forms of P.falciparum and exoerythrocytic forms of P.vivax. It is a powerful erythrocytic schizonticide.
Combination of pyrimethamine and sulphadoxine- to treat presumed exposure to P.falciparum and chloroquine- resistant malaria.
Combination of pyrimethamine and sulphadiazine- for chloroquine resistant P.falciparum., toxoplasmosis

21. Mechanism of action: Metabolism
Folic acid
Reduction
Dihydro folic acid (FAH2)
Dihydrofolate reductase
Tetrahydro folic acid(FAH4)
Precursors
Purine/ pyrimidine aminoacids
Mechanism of action:
Pyrimethamine inhibits the dihydrofolate reductase of malarial parasites.
Metabolism
Primarily by oxidation to pyrimethamine 3-N oxide

22. Structure- activity relationship:
Pyrimethamine
Structure- activity relationship:
Presence of ethyl group at C-6 is essential for activity.
Presence of halogen atom, preferably at 4th position is essential for interaction with Dihydro folate reductase enzyme.
The two six membered rings should not be separaed even by a single carbon atom.

23. Synthesis
Pyrimethamine

24. Trimethoprim
Uses:
Antibacterial, effective against chloroquine and pyrimethamine resistant strains of P.falciparum.
Used in combination with sulfalene.

25. Synthesis

26. Sulphadoxine
Sulphadiazine

27. Sulphalene Mechanism of action: Effective against P.falciparum.
Given in combination with quinine or pyrimethamine against chloroquine resistant strains of P.falciparum.
Mechanism of action:
Active only against the asexual blood forms of malarial parasite, and to act slowly.
Interfere with maturation of preerythrocytic and exoerythrocytic stages.
Also interfere with development of sporozoites in the mosquito.

28. General synthesis

29. Pyrantel pamoate Uses: Mechanism of action
Broad spectrum antihelminthic
Treat infections with Ascaris lumbricoides, Enterobius vermiculosis, Ancyclostoma duodenale (hook worms), Trichostringlylus species and Necatos americanus
Mechanism of action
Pyrantel depolarizes and paralyses worm muscle by persistent nicotinic activation.
Intestinal nematodes can then no longer maintain the tone necessary to attack to host tissues and are expelled by host peristalysis.
Note: pyrantel causes depolarisation where as piperazine causes hyperpolarisation with mutually antagonistic properties. So, simultaneous use- avoided.

30. Synthesis

31. Oxantel Structure- activity relationship
The Ar can be varied with the order of reactivity 2-thienyl > 3-thienyl > phenyl > 2-furyl.
Tetrahydro pyrimidine (n=3) derivatives displayed maximum acivity.
When X is a trans derivative, the activity is more.
In substituents in Ar group, ortho substitution produces active compounds.
N- methyl substitution produces active derivatives.

32. Synthesis
3-hydroxy benzaldehyde
Oxantel

33. Quinapyramine
Used to treat Trypanosoma evansi infections in live stock (camels and horses).

34. Pyrimidine analogues Mechanism of action:
1063
Mechanism of action:
Inhibitors of Dihydrofolate Reductase/Pteridine Reductase in L. major.
Compound (72) more active compound, has activity in the low micromolar range.

35. Arylene bis(methyl ketone) compound
988
Mechanism of action:
It has good activity in vitro against chloroquine and pyrimethamine resistant P. falciparum in vitro and against P. berghei in vivo.
The drug displayed activity against the plasmodial dihydrofolate reductase at achievable concentrations.

36. Febrifugine and Isofebrifugine
997
Mechanism of action:
They were isolated from D. febrifuga
The drug seems to potentiate the production of nitric oxide in acute immune responses

37. Purine analogues

38. Adenosine analogues Mechanism of action:
Inhibits glyceraldehyde-3-phosphate dehydrogenase in glycolysis cycle.
compound (21) had good activity against cultured L. mexicana, T. brucei, and T.cruzi

39. Mechanism of action:

40. Adenosine analogues Mechanism of action:
MDL 73811, 5'-[(Z-4- amino-2 butenyl)methylamino]-5‘ deoxyadenosine
Mechanism of action:
Inhibitors of S Adenosylmethionine Decarboxylase.
Intracellular concentrations of putrescine and AdoMet were increased and the level of spermidine was decreased in trypanosomes treated with (27)
It is a time-dependent irreversible inhibitor to the AdoMetDC in T. b. brucei,. It also proved to be active against trypanosome infections in animal models

41. Mechanism of action:

42. Nucleotide analogues Mechanism of action:
1063
Hydroxyethylthioadenosine; HETA
Mechanism of action:
These two agents strongly inhibit protein methylation enzymes (mostly carboxyl methylation) that use AdoMet as a cosubstrate.
Trypanocidal activity against T. b. brucei and strains of trypanosomes

43. Allopurinol Mechanism of action:
1074
Mechanism of action:
Allopurinol is a substrate for hypoxanthine phospho ribosyl transferase (HPRT) from L. donovani, forming allopurinol-ribose-5'-phosphate (allo-5'-RP).
Allo-5'-RP is a substrate for the rest of the parasite enzymes involved in converting IMP to ATP and incorporation of ATP into RNA.
Allo-5'-RP is an inhibitor of GMP reductase and IMP dehydrogenase, and the allo- 5'-RP compounds cause an increase in the breakdown of RNA in L. donovani .
The antileishmanial activity of allopurinol is probably a sum of all of these toxic effects on purine interconversion.
The clinical efficacy of allopurinol by itself is weak; however, the activity of allopurinol improves when it is combined with fluconazole.

44. Allopurinol-ribose-5'-phosphate (Allo-5'-RP).
Mechanism of action:
Hypoxanthine phospho ribosyl transferase
Allopurinol
Allopurinol-ribose-5'-phosphate
(Allo-5'-RP).
IMP
ATP
RNA

45. references
Text book of organic medicinal & pharmaceutical chemistry- wilson & gisvold
Burger’s medicinal chemistry and drug discovery volume v
Foye’s priniples of medicinal chemistry fifth edition
Text book of medicinal chemistry- S.PANDEY volume II

46. THANK YOU