Chapter 9 Chemotherapeutic Agents

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

2. Synthetic antibacterial agents • A number of organic compounds obtained by chemical synthesis on the basis of model compounds have useful antibacterial activity for the treatment of local, systemic, and /or urinary tract infections. • Some chemical classes of synthetic antibacterial agents include the • Sulfonamide, • Nitroheterocyclic compounds(e.g. the nitrofurans and metronidazole), • Quinolones.

3. Section 1. Quinolone Antimicrobial Agents

4. Introduction • The quinolones have a number of advantages over other classes of antibacterial agents. They are effective against many organisms, well-absorbed orally, well-distributed in tissues, and they have relatively long serum half-lives and minimal toxicity. Because of deep-tissue and cell penetration, they are useful for urinary tract infections, prostatitis, infections of the skin and bones, and penicillin-resistant sexually transmitted diseases.

5. The quinolone antimicrobials comprise a group of synthetic substance possessing in common an N-alkylated-3-carboxypyrid-4-one ring. The discovery of quinolone is an epoch-making events. Since 1962 the first quinolone, Nalidixic acid was developed, more than 100,000 quinolone compounds have been synthesized and screened their pharmacological activities. Currently, there are more than 20 quinolones used in clinic. The advantages of this kind of drugs are their lower cost in synthesis together with the excellent activities.

6. Brief History and Overview • The history can be traced to the discovery of an antibacterial by-product formed during the synthesis of antimalarial agent Chloroquine, an isomer of key intermediate, 7-chloro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1).

7. Brief History and Overview • In 1962, Lesher et al. described the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (2), also known as Nalidixic acid. It was the first commercially available compound of this class and was approved for treatment of urinary tract infections in 1964.

8. The first-generation quinolones

9. Norfloxacin, a fluoroquinolone with a broad spectrum of antibacterial activity, was patented in 1978. • Between 1978 and 1982, many new fluoroquinolones were prepared and patented. These fluoroquinolones now classified as second-generation quinolones.

10. The second-generation quinolones

11. The third-generation quinolones • A third advance was made in early 1990s. All third-generation fluoroquinolones have significantly improved activity against gram-positive bacteria, notably streptococcus pneumonia（肺炎链球菌）. Some of them have good activity against anaerobes and atypical pathogens.

12. Mechanism of action Quinolones enter the cell by passive diffuse. Intracellularly, they inhibit the synthesis of bacterial DNA by interfering with the action of DNA gyrase (DNA螺旋酶），topoisomerase（拓扑异构酶Ⅱor Ⅳ).

13. Mechanism of action Model of the formation of negative DNA supercoils by DNA gyrase. (1) A node of positive is created for(+) superhelix. (2) The enzyme introduces a double-strand break in the DNA and passes the front segment through the break. (3)The break is then resealed, creating a negative (-) supercoil. Quinolones inhibit both the nicking and closing activity of the gyrase.

14. Binding sites of quinolones A A • • ATP- ATP- B B Mechanism of action

15. Functional domains of quinolone antibacterial agents

16. The Metabolism of Quinolone The quinolones are often well absorbed following oral administration and are highly serum-protein bound. Peak value is 1-2 h after oral administration and keep high concentration in urea for most quinolones. Most metabolic reactions occur at the piperazine rings.

18. The structure-activity relationship of quinolones Briefly,the basic nucleus of quinolones can be modified at the N-1 position and at the C-6, C-7, and C-8 positions.

19. The structure-activity relationship of quinolones The C-4 ketone together with C-3 COOH are essential for activity

20. Pipemidic Acid (吡哌酸) • Chemical name: • 8-Ethyl-5，8-dihydro-5-oxo-2-（1-piperazinyl）pyrido[2，3-d]pyrimidine-6-carboxylic acid

21. The Pipemidic Acid was marketed in 1974, it was developed in the Nalidixic acid and Piromidic acid in order to overcome their disadvantages of narrow antibacterial spectrum, poor absorptions and side effects for them. The difference of structures between Pipemidic acid and Nalidixic acid, Pipemidic acid is the introducing of piperazine ring into the scaffold, the basic group, results in the increase of solubility and basicity. The increase of antibacterial activity due to the bound reaction between piperazine ring and the subunit B of DNA gyrase .

22. The synthesis of Pipemidic acid

23. Norfloxacin(诺氟沙星) • Chemical Name: 1-Ethyl-6-fluoro-4-oxo-1，4-dihydro-7-（piperazin-1-yl）quinoline-3-carboxylic acid

24. Norfloxacin(诺氟沙星） This drug was marketed in 1978, is the first quinolone attaching a F atom in the 6 position of structure. It is a broad-spectrum antimicrobial agent, active against both Gram-positive and Gram-negative bacteria, as well as Pseudomonas aeruginosa(绿脓杆菌). It has higher activity than Pipemidic acid. 35-40% of the drug is absorbed after oral administration. It is primary used to treatment of otitis (中耳炎) and infections of gynecology(妇科), surgery, dermatology(皮肤科).

25. Drugs modified from Norfloxacin

26. Ciprofloxacin Hydrochloride (盐酸环丙沙星) • Chemical Name: 1-Cyclopropyl-6-fluoro-1，4-dihydro-4-oxo-7-（1-piperazinyl）-3-quinolinecarboxylic acid hydrochloride monohydrate

27. Ciprofloxacin（环丙沙星） The antibacterial spectrum of Ciprofloxacin is familiar with that of Norfloxacin, but the MIC values against E.coli, Bacillus blue-pus, Streptococcal infection, Staphylococcal infection, Bacillus anthracis(碳疽杆菌) are lower other quinolones as well as antibiotics.

28. Synthesis of Ciprofloxacin

29. Drugs modified from Ciprofloxacin

30. Levofloxacin(左氟沙星） （S)-(-)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid The drug was marketed in 1991, it is the optical isomer of Ofloxacin(氧氟沙星), the antibacterial activity is two times as high as that of Ofloxacin. It exhibits activities for both Gram-negative and Gram-positive bacteria .

31. Keynotes in this class • Typical drugs • Pipemidic acid • Norfloxacin • Ciprofloxacin • SAR of Quinolones

33. Section 2. Tuberculostatics

35. The evolution of antitubercular agents • The discovery of the antitubercular activity of aminoglycoside antibiotics streptomycin by Waksman et al in 1944 ushered in the modern era of tuberculosis treatment.

36. This development was quickly followed by discoveries of antitubercular properties of p-amino-salicylic acid(PAS) first and then, in 1952, of isoniazid, • Later, the usefulness of the synthetic drug ethambutol and, eventually, of the semisynthetic antibiotics rifampin was discovered.

37. Classification • Synthetic drugs: • p-Amino-salicylic acid (PAS) • Isoniazid • Ethambutol • Antibiotics • Streptomycin • Rifampin

38. Combination therapy • A major advance in the treatment of tuberculosis was signaled by the introduction of the antibiotic rifampin into therapy. • Clinical studies indicated that when rifampin is included in the regimen, particularly in combination with isoniazid and ethambutol (or pyrazinamide), the period required for successful therapy is shortened significantly( 6-9 months, 2 ys without rifampin).

39. Isoniazid • Chemical name: • 4-Pyridinecarboxylic acid hydrazide

40. Mechanism of action

41. Formation of complex with metal ion • Don’t contain isoniazid using metal container.

42. Reduction • Isoniazid has hydrazine(-NH2NH2) moiety, so it has strong reduction.

43. Synthesis

44. Sodium Aminosalicylate • 4-Aminosalicylic acid (PAS) occurs as a white to yellowish-white crystalline solid that darkens on exposure to light or air. It is slightly soluble in water but more soluble in alcohol. Alkali metal salts and the nitric acid salt are soluble in water, but the salts of hydrochloric acid and sulfuric acid are not. The acid undergoes decarboxylation when heated. An aqueous solution has a pH of ~3.2.

45. Ethambutol hydrochloride • (2R,2R)-(+)-2，2-（ 1，2-Ethanediyldiimino）bis-1-butanol dihydrochloride • A white crystalline powder freely soluble in water and slight. lt is soluble in alcohol.

46. Ethambutol • This compound is remarkably stereospecific. Tests have shown that , although the toxicities of the dextro, levo, and meso isomers are about equal, their activities vary considerably. The dextro isomer is 16 times as active as the meso isomer. • Ethambutol is not recommended for use alone, but in combinations with other antitubercular drugs in the chemotherapy of pulmonary tuberculosis.

47. Antitubercular antibiotics-Rifamycins

48. Rifampin • Rifampin, a semisynthetic derivative of rifamycin B, was released as an antitubercular agent in US in 1971. • Chemical name: 3-[[（4-methy- 1-piperazinyl）imino]methyl]rifamycin • An inhibitor of DNA-dependent RNA polymerase

49. Toxic effects • Toxic effects associated with rifampin are relatively infrequent. • Interfere with liver function in some patients • The incidence of hepatotoxicity was significantly higher when rifampin was combined with isoniazid than when either agent was combined with ethambutol. • Allergic and sensitivity reactions to rifampin have been reported, but they are infrequent and usually not serious.

50. Key Notes • Tuberculostatics • Classification • Isoniazid • Mechanism of action • synthesis • Sodium Aminosalicylate • Ethambutol hydrochloride • Rifamcins