Medicinal chemistry of Antiamoebic agents
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This document discusses amebiasis, an intestinal infection caused by the protozoan Entamoeba histolytica. It describes the life cycle and symptoms of E. histolytica, from ingesting cysts to formation of trophozoites that penetrate the intestinal wall and may cause liver abscesses. Diagnosis involves isolating E. histolytica from feces. Treatment aims to eliminate actively infected and asymptomatic carriers to prevent future infections. Several antiamoebic drugs are discussed including metronidazole, diloxanide, and 8-hydroxyquinolines that act on intestinal and extraintestinal amebiasis. Metronidazole's mechanism of action involves reductive activation by susceptible
![4.Alkaloids: Emetine, Dehydroemetine
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N OCH3
OCH3
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H3CO
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(2S,3R,11bS)-2-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-ethyl-9,10-dimethoxy-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline
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Medicinal chemistry of Antiamoebic agents
- 2. AMEBIASIS Amebiasis (also called amebic dysentry) is an infection of intestinal tract caused by Entamoeba histolytica. The disease can be acute or chronic, with the patients showing varying degrees of illness, from no symptoms to mild diarrhea to fulminating dysentery (Dysentery in which the symptoms are intensely acute, leading to prostration, collapse, and often death). 2
- 3. The diagnosis is established by isolating E. histolytica from fresh feces. Therapy is aimed not only at the acutely ill patients but also at those who are asymptomatic carriers, because dormant E. histolytica may cause future infections in the carrier and be a potential source of infections for others. 3
- 4. Life cycle of Amoeba 4
- 5. Life cycle of Entamoeba histolytica Entamoeba histolytica exists in two forms: 1. Cysts form (That can survive out side the body). 2. Trophozoites form (That are labile and don’t persist outside the body). Life cycle Life cycle consists of following steps: 5
- 6. 1. Ingestion of cysts Cysts are ingested through feces, contaminated food or water. 2. Formation of trophozoites Cysts are passed into the lumen of intestine, where the trophozoites are liberated. 3. Penetration and multiplication of trophozoites Trophozoites are penetrated in intestinal wall and multiply within colon wall. They either invade and ulcerate the mucosa of large intestine or simply feed on intestinal bacteria. 6
- 7. 4. Systemic invasion Large numbers of trophozoites within the colon wall can also lead to systemic invasion and caused liver abscess. 5. Cysts discarded The trophozoites within the intestine are slowly carried toward the rectum, where they return to cyst form and are excreted in feces. 7
- 8. Antiamoebic drugs • These are drugs useful in infection caused by the protozoa Entamoeba histolytica. A. Tissue amoebicides a) For both intestinal and extraintestinal amoebiasis: I. Nitroimidazoles: Metronidazole,Tinidazole, Secnidazole, Ornidazole,Satranidazole II. Alkaloids: Emetine, Dehydroemetine b) For extra intestinal amoebiasis only:Chloroquine B. Luminal amoebicides a) Amide : Diloxanide furoate, Nitazoxanide b) 8-Hydroxyquinolines: Quiniodochlor(Iodochlorohydroxyquin, Clioquinol),Diiodohydroxyquin (Iodoquinol) (c) Antibiotics: Tetracyclines 8
- 10. 2.Acetanilide-Diloxanide HO H N C O CH Cl Cl 2,2-dichloro-N-(4-hydroxyphenyl)acetamide 3. 8-Hydroxyquinoline- N OH I I 5,7-diiodoquinolin-8-ol Qunophenol Iodoquinol N OH quinolin-8-ol 10
- 11. 4.Alkaloids: Emetine, Dehydroemetine N N OCH3 OCH3 H3CO H3CO CH3 H H H (2S,3R,11bS)-2-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-ethyl-9,10-dimethoxy- 2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline 11
- 14. Mechanism of action of Metronidazole Metronidazole is a prodrug. It requires reductive activation of nitro group by susceptible organism. Its selective toxicity towards anaerobic and microaerophilic pathogens such as E. histolytica, G. lamblia, etc. These organisms contain electron transport components such as ferridoxin, small Fe-S proteins that have sufficiently negative redox potential to donate electrons to metronidazole. The single electron transfer forms a highly reactive nitro radical anion that kills susceptible organisms by radical- mediated mechanisms that target DNA, resulting in cell death. 14
- 15. Mechanism of action of Metronidazole 15
- 16. Infected cell Reduced to highly reactive nitro radicals Ferredoxin MOA 16
- 17. Competes with biological electron acceptor Acts as electron sink – electrons by PFOR p/w Energy metabolism disrupted Reduced to highly reactive nitro radicals 17
- 18. Therapeutic Uses Amoebiasis: DOC in all tissue infections Acute intestinal Amoebiasis / Amoebic colitis with dysentery-- 800 mg TDS-10 d course with a luminal amoebicide Mild intestinal amoebiasis-400mg TDS for 5-7 days Hepatic Amoebiasis :1g iv followed by 0.5g every 8-12 hr till oral therapy-------------10 d course cures 95 % cases For cases in which initial therapy fails – Aspiration of abscess & addition of Chloroquine 18
- 19. • Giardiasis Treatment of choice--- 400mg TDS 7days or 2g/d for 3 days • Trichomoniasis : DOC, 400mg TDS 7days Vaginal & urethral Trichomoniasis----- topically. • Bacterial vaginosis: Can be used topically as a gel. 19
- 20. • Anaerobic bacterial infection-after pelvic surgery, appendicectomy • Eradication of H. Pylori in Peptic ulcer--a component of 14 days triple therapy regimen. Metronidazole 500mg BD along with a proton pump inhibitor BD, Clarithromycin 500mg BD • Pseudomembranous enterocolitis by Clostridium difficile. DOC. (Vancomycin is the drug of second choice) 20
- 21. • Ulcerative Gingivitis, Trench mouth • Facilitates extraction of adult guinea worm in Dranculosis • Acne rosacae. 21
- 22. emetine • MOA-These inhibit protein synthesis by blocking chain elongation. • Uses- used as alternative agents for the treatment of amebiasis. 22
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