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1 -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. 2 Protozoal infections Amoebiasis Giardiasis Leishmaniasis Malaria Trypanosomiasis Toxoplasmosis Amebiasis Protozoa Schistosomiasis Malaria 3 Helminth infections Nematode Cestode Trematode Nematode Nematode Cestode 4 Ectoparasitic infections Scabies Pediculosis 5 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 6 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. 7 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 8 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: 1. Visceral leishmaniasis 2. Cutaneous leishmaniasis Visceral 3. Muco cutaneous leishmaniasis 4. Diffuse cutaneous leishmaniasis Cutaneous Muco cutaneous 9 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 10 body, depending on specific strain of organism. 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 11 Two distinct forms1. Chagas’ disease 2. 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. 12 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 13 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 14 15 • 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 16 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 17 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 18 19 H2N N Cl NH2 N Uses: C2H5 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 chloroquineresistant malaria. Combination of pyrimethamine and sulphadiazine- for chloroquine resistant P.falciparum., toxoplasmosis 20 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 21 H2N N Cl NH2 N Pyrimethamine C2H5 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. 22 Synthesis O CN OH CN CH2Cl CH2CN HC C C2H5 C C C2H5 KCN CH3CH2COOC2H5 Cl Cl p-chloro benzaldehyde Cl Cl -propionyl-p-chlorophenyl acetonitrile p-chlorophenyl acetonitrile CH2N2 H2N NH N Cl CN NH2CNH2 Cl NH2 C Cyclization C N C2H5 Pyrimethamine C2H5 OCH3 23 NH2 H2 C OCH3 N H2N N Uses: OCH3 OCH3 Antibacterial, effective against chloroquine and pyrimethamine resistant strains of P.falciparum. Used in combination with sulfalene. 24 Synthesis CHO HC C CH2OCH3 CN H3CO + CH3OCH2CH2CN OCH3 -methoxy propionitrile Na/ CH3OH H3CO OCH3 OCH3 OCH3 3,4,5- Trimethoxy benzaldehyde Na/ CH3OH H3CO NH2 H2 C OCH3 N H2N NH H3CO H CH C CH2 CN NH2CNH2 N OCH3 CH3OH H3CO trimethoprim OCH3 OCH3 OCH3 25 N H2N SO2NH N H3CO OCH3 N H2N SO2NH N 26 N H2N SO2NH N H3CO 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. 27 General synthesis ClSO3H H3COCHN -H2O ACETANILIDE -HCl NaOH SO2NHR H2N SO2Cl H3COCHN H3COCHN NH2R SO2NHR SULPHONAMIDE 28 R CH3 N Uses: Broad spectrum antihelminthic S C H C H C N pyrantel pamoate 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. 29 Synthesis R R + CHO S CNH2COOH cyano acetic acid knoevenagel reaction C H S CHCN Thiophene-2-carboxaldehyde R C H S R CH3 N C H NH2CH2CHCHNHCH3 N-methyl propylene 1,3- diamine C CH3OH HCl NH S C H C H COCH3 N Pamoic acid R CH3 N S C H C H HOOC OH HO COOH H2 C C N pyrantel pamoate 30 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. 31 Synthesis H3C HCOOC2H5 N CH3 + N HO CHO H3C N HO N 3-hydroxy benzaldehyde Oxantel 32 Used to treat Trypanosoma evansi infections in live stock (camels and horses). 33 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. 34 988 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. 35 997 Mechanism of action: They were isolated from D. febrifuga The drug seems to potentiate the production of nitric oxide in acute immune responses 36 37 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 38 Mechanism of action: 39 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 40 Mechanism of action: 41 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 42 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. 43 Mechanism of action: Hypoxanthine phospho ribosyl transferase Allopurinol Allopurinol-ribose-5'phosphate (Allo-5'-RP). IMP ATP RNA 44 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 45 46