Chapter 9 Chemotherapeutic Agents

1. Chapter 9 Chemotherapeutic Agents Prof. Wei-Min Chen

2. Topics in this class • Antiviral Agents • Antiparasitic Drugs

3. Section 5. Antiviral Agents

4. Introduction Viruses are microscopic organisms that can infect all living cells. They are parasitic and multiply at the host's metabolic system. Viruses may start their infections cycle immediately on attack or remain dormant in the cellular site of the host. Once the effective particles become active, they may produce cytotoxic effects or cause numerous diseases in animals and humans. The major routes of transmission of viral infections in humans are through the respiratory, gastrointestinal, and genital tracts, and the skin, urine, blood, and placenta(胎盘).

5. Viruses: Structure • Viruses contain a few proteins, lipids and nucleic acid which are accurately replicated by the infected cell to produce more virus.

6. Antiviral Agents Because viruses are intracellular parasites, their replication depends on the host's cellular processes. Ideally, a useful drug is considered most effective if it interferes with the viral replication without affecting normal cellular metabolic processes. Unfortunate1y, this objective has not been achieved with many antiviral compounds. Many of these drugs proved toxic to humans at therapeutic levels or had a limited spectrum of activity. This lack of success is one reason why antiviral drugs have not been developed as rapidly as antibacterial, antiprotozoal(抗原虫药 ), or antifungal agents. Despite much research on the mo1ecular biology of viruses and the complexity of the virus-host interaction, few antiviral agents have been licensed.

7. NucleosideAntiviralAgents

8. Acycle Nucleoside Antiviral Drugs

9. Others Antiviral Agents

10. Amantadine Hydrochloride (盐酸金刚烷胺) • Chemical Name: Tricyclo[3.3.1.13,7]decan-1-amine hydrochloride • Amantadine hydrochloride is symmetric tricyclic amine that inhibits the early stages of virus replication, blocking the uncoating of the viral genome and the transferring of nucleic acid into the host cell. It was approved for treatment of influenza type A virus infections.

11. The derivatives of Amantadine

12. Ribavirin(利巴韦林) • 1-b-D-Ribofuranosyl-1H-1，2，4-triazole-3-carboxamide）。 • 三氮唑核苷，病毒唑

13. Ribavirin (利巴韦林） Ribavirin is a purine nucleoside analog, it has broad spectrum antiviral activity against both DNA and RNA viruses. It is highly active against influenza A and B and the parainfluenza, Group of viruses, genital herpes(生殖器疱疹), herpes zoster(带状疱疹病毒), measles(麻疹), and acute Hepatitis(肝炎) type A, B and C. 4 2 1

14. Synthesis

16. Anti-AIDS Agents AIDS-Acquired Immuno deficiency Syndrome is a fatal pathogenic disease caused by Human Immunodeficiency Virus type-1(HIV-1). HIV-1 is an retrovirus (逆转录病毒), it release the Reverse Transcriptase (RT,逆转录酶) when it entrances the host cells. The RT is important enzyme system in the replication of DNA of HIV-1. To design a successful anti-HIV-1 agent, it is important to located a target that is unique to the virus. Also, because the HIV-1 is found mostly inside cells, it is essential for inhibitor to enter the host cell membrane to reach the virus. Another challenge for the design of such inhibitors is for the agent to be able to discriminate between a virally infected cell and a noninfected cell. But it is difficult, because the cellular membranes of virally infected cells differ only slightly from the membranes of noninfected cells.

17. HIV life cycle Binding of the virus to the T-cell through the gp120 and CD4 receptors Breakdown of the polyprotein precursor by the protease to give structural proteins and enzymes Fusion through viral gp41 and loss of its envelope, the uncoating Migration of viral RNA to the cytoplasm as mRNA to encode the synthesis of viral proteins Viral DNA formation by reverse transcriptase followed by RNase Splicing of viral RNA by host RNA polymerase to produce viral mRNA Viral DNA entry to the host cell nucleus through its nuclear pores

18. Anti-AIDS Drugs The anti-AIDS drugs can be divided into three classes according to their action mechanism: A：Nucleoside Reverse Transcriptase Inhibitors（NRTIS） B：Nonnucleoside Reverse Transcriptase Inhibitors（NNRTIS） C：HIV Protease Inhibitors（PIS）

19. HIV Approved Drugs for the Treatment of AIDS

20. Combination (Cocktail ) Therapy • Main problem：Drug Resistance • Combination Therapy—a group of three drugs 1 PI + 2 NRTI + 0 NNRTI 37% 0 PI + 2 NRTI + 1 NNRTI 32.4% 0 PI + 3 NRTI + 0 NNRTI 7.4% 2 PI + 2 NRTI + 0 NNRTI 6.8% 0 PI + 2 NRTI + 0 NNRTI 3.3% Others 13.3%

21. Combination therapy • HIV makes new copies of itself inside the infected cells at a very fast rate. Every day billions of new copies of HIV are made and millions of new cells die. One drug, by itself, can slow down the fast rate of infection. Two or more drugs can slow it down even more efficiently. Anti-HIV drugs from different drug groups attack the virus in different ways. For example, RT and protease are two different molecular targets. RT inhibitor will stop the HIV just after it enters the cell and a protease inhibitor stops it immediately before leaving it. Hitting at the different targets increases the chances of stopping HIV and protecting other cells from infection. In addition, different anti-HIV drugs can attack the virus in different cell types and different parts of the body. Combination therapy can reduce drug resistance to the virus, especially if the mutations counteract each other.

22. Zidovdine (AZT,齐多夫定) 3`-Azido-2`,3`- didoxythymidine AZT is the first synthesized in 1964, but its biological activity was found in 1974, in 1986 demonstrated application of AZT in clinical trials of AIDS and related disease. It is an analog of thymidine in which the azido group is substituted at the 3`-carbon atom of dideoxyribose moiety.

23. Mechanism of Action Deoxythymidylic acid

24. Mechanism of Action of NRTIS • Mechanism of Action

25. Synthesis

26. Marketed NRTIS

27. Protease Inhibitors The HIV-1protease belongs to the family of aspartyl（天冬酰） proteases and is an enzyme that elicits its action during viral budding. The protease inhibitors are peptidomimetic compounds. *Saquinavir(沙奎那韦)

28. Ritonavir(雷托那韦) Indinavir(茚地那韦)

30. Acyclovir (阿昔洛韦) • Chemical Name: • （9-（2-Hydroxyethoxymethyl）guanine）。 • (无环鸟苷)

31. Acyclovir (阿昔洛韦,无环鸟苷) This drug is the first non-glucoside analog of nucleoside possessing a unique mechanism of action. It inhibits the virus-specific thymidine kinase(胸苷激酶) and / or DNA polymerase. Acyclovir significantly reduces DNA synthesis in virus-infection cells without disturbing the active replication of uninfected cells. The herpesvirus(疱疹病毒,HSV) that are sensitive to acyclovir are HSV. It is not active against vaccinia(牛痘) ,adenovirus（腺病毒）, and parainfluenza（副流感病毒）infection.

32. Mechanism of action

33. The disadvantages of Acyclovir are poor solubility in water, lower bioavailability(15-20%), less frequently side effects including nausea, vomiting, headache, skin rashes. Synthesis

34. The derivatives of Acyclovir

36. Antiparasitic Drugs

37. Intestinal nematode infection • Ascariasis(蛔虫) • Hookworm(钩虫) • Threadworm(蛲虫) • Trichuriasis(鞭虫) • Pinworm (蛲虫)

38. Albendazole(阿苯达唑) • Albendazole, marketed as Albenza, Eskazole, or Zentel, is a member of the benzimidazole compounds used as a drug indicated for the treatment of a variety of worm infestations. Although this use is widespread in the United States, the FDA has not approved albendazole for this indication. It is marketed by GlaxoSmithKline.

39. Structure and Name • [(5-Propylthio)-1H-benzimidazol-2-yl]carbamic acid methyl ester

40. Usage of Albendazole • Albendazole is widely throughout the world for the treatment of intestinal nematode infection. It is effective as a single-dose treatment for ascariasis(蛔虫病), hookworm infections, and trichuriasis. • Multiple-dose therapy with albendazole can eradicate pinworm, threadworm, capillariasis, clonorchiasis, and hydatid disease. The effectiveness of albendazole against tapeworm is generally more variable and less impressive.

41. Drugs for treatment of schistosomiasis (血吸虫病) • Any of various generally tropical diseases caused by infestation with schistosomes, widespread in rural areas of Hunan, Jiangxi, and Hubei surrounding lake area through use of contaminated water, and characterized by infection and gradual destruction of the tissues of the kidneys, liver, and other organs.

42. Drugs for treatment of schistosomiasis

43. Praziquantel • 2-（Cyclohexylcarbonyl）-1，2，3，6，7，11b-hexahydro-4H-pyrazino [2，1-a] isoquinolin-4- one

44. Fused heterocycle name

45. Usage of Praziquantel • Praziquantel is a broad-spectrum agent that is effective against a variety of trematodes (flukes). it has become the agent of choice for the treatment of infections caused by schistosomes (blood flukes). • It can also be used for treatment of liver fluke .

46. Metabolism of Praziquantel • Following oral administration, about 80% of the dose is absorbed. Maximal plasma concentrations are achieved in 1 to 3 h. The drug is rapidly metabolized in the liver in the first pass. It is likely that some of the metabolites are also active. Praziquantel occurs as a white crystalline solid that is insoluble in water. It is available as 600mg film-coated tablets. The drug is generally well tolerated.

47. Synthesis

48. Homework • Question: • Can the virus infection be cured by chemotherapeutic agents? • Assignment: • 1.Read textbook pp230-246,367-389 • 2.Do homework Exercises of medicinal chemistry and药物化学学习指导,第9章