Chapter 9 Chemotherapeutic Agents

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

2. Topics in this class • Antimicrobial Sulfonamides and Antibacterial Synergists • Antifungals Drugs

3. Section 3. Antimicrobial Sulfonamides and Antibacterial Synergists

4. Sulfonamide Structure • Sulfonamides derived from p-amino-benzenesulfonamide are commonly referred to as sulfa drugs. Sulfonamides are synthetic antibacterial agents with an illustrious history. • In 1935, they were the first class of antibacterial agents with life-saving potency to be used systematically for the treatment of bacterial infection, initiating the era of the sulfa drugs.

5. Basic Structure

6. Discovery of Sulfonamides • The discovery of sulfonamides is a significant milestone event in the human chemotherapeutic history. Sulfonamides are synthetic compounds that have activity against both gram-positive and gram- negative bacteria. • Originally, sulfonamides were synthesized in Germany as azodyes. In an attempt to expand on earlier ideas of using dyes as antimicrobial agents, a man by the name ofDomagk

7. Gerhard Domagk (1895-1964) German bacteriologist and pathologist who was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery (announced in 1932) of the antibacterial effects of Prontosil, the first of the sulfonamide drugs.

8. The process of discovery for sulfonamides

9. Mechanism of Action (Wood-fields Theory) The structure of folic acid

12. Both the size and distribution of charge of the sulfonamides and PABA molecule are very similar, so sulfa drug play a role of metabolism antagonist. Antimetabolite Theory Antimetabolites are compounds that prevent the biosynthesis or use of normal cellular metabolites. The usually are closely related in structure to the metabolite that is antagonized. Many antimetabolites are enzyme inhibitors. They may combine with active site as if they were the substrate or cofactor.

13. Structure-Activity Relationship ( SAR )

14. The metabolism of sulfonamides

15. Sulfadiazine (磺胺嘧啶) Chemical Name: 4-Amino-N-2-pyrimidinyl benzenesulfonamide A white powder, slightly soluble in EtOH or CH3COCH3, insoluble in etherand CHCl3. Soluble in diluted HCl and Strong base. mp: 255-256C The drug is one of a few sulfonamides that still used in clinic.

16. Silver and Zinc Salts of Sulfadiazine The silver and zinc salts of Sulfadiazine is a very potent antimicrobial in the treatment of burns、scald and wound infections

17. General synthetic methods of sulfonamide Synthetic methods of sulfdiazine

18. Sulfamethoxazole( SMZ)(磺胺甲恶唑) Chemical Name: 4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide. It’s plasma half-life is 11 hours. The combination of SMZ and Trimethoprim（TMP） (5:1), the preparation named Sinomin, can increase the potency of antimicrobial activities. It is mainly used to treatment of urinary track infection, respiratory track infection and typhoid bacillus (伤寒杆菌).

19. Synthesis of Sulfamethoxazole

20. Trimethoprim (甲氧苄嘧啶, TMP) Chemical Name: 5-[（3，4，5-trimethoxyphenyl）methyl]-2，4-pyrimidine diamine TMP inhibits the dihydrofolate reductase (DHFR), so that the tetrahydrofolic acid can not be biosynthesized, which is the important materials in the Biosynthesis of DNA and RNA.

22. Selective toxicity Where the bacterial enzyme and mammalian enzyme both efficiently catalyze the conversion of dihydrofolic to tetrahydrofiolic acid , the bacteria enzyme is sensitive to inhibition by trimethoprim by up to 40,000 times lower concentration than the mouse enzyme. This difference explains the useful selective toxicity of trimethoprim. TMP is frequently used as a single agent clinically for the oral treatment of uncomplicated urinary track infection. It is, however, most commonly used in a 1:5 fixed ratio with the sulfonamide sulfamethoxazole.

23. Synthesis

24. Some 4-substituted derivatives of TMP

25. Key Notes • The basic terms about antibacterial agents • The discovery process of Sulfonamides. • Mechanism of Action(Wood-fields Theory) • SAR of Sulfonamides • The structures of typical drugs • The synthetic methods of typical drugs

26. Section 4.Antifungals Drugs

27. Antifungal Agents • Fungi are plant-like, eukaryotic organisms. Most fungi live as saprophytes in soil or on dead plant materials and are important in the mineralization of organic matter. • There are 300,000 kinds of fungi, but only 270 of which cause disease in humans and animals. These fungi are divided into two classes according to mycotic illnesses in humans they caused. • Mucocutaneous Fungi : cause skin and hair infections (shallow infections) • Systemic Fungi : cause visceral infections (deep infections)

28. Fungal infections In recent year, the incidence of fungal infections has reached alarming proportions. This duo to a number of factors .

29. The classification of antifungal agents Antimycotic antibiotics: Polyenes ( Amphotericin B) Others (Griseofulvin) Fluorinated pyrimidines (Fluorocytosine) Synthetic antifungal Agents: Imidazoles (ketoconazole) Triazoles (Fluoconazole) Azoles Allyamines (Terbinafine) Thioureas (Tolnafate) Others (Ciclopirox)

30. Mechanism of action

31. Antimycotic antibiotics

33. Amphotericin B (AMB) (两性霉素B) AMB was marked in 1951, it is most commonly antibiotics used to treatment systemic fungal infections and is the only polyene antibiotic antifungal agents for injection use.

34. Mechanism of Action of (AMB) This kind of antifungal agents act against sensitive fungal by combining with membrane ergosterols with subsequent alteration in permeability and loss of essential organic and inorganic cell constituents. In mammalian cell membranes, the principal sterol is cholesterol (胆甾醇), AMB binds approximately times more tightly to vesicles containing ergoesterol rather than to those containing cholesterol. Side-effects The most serious are hypokalemia and distal tubular acidosis. the Nephrotoxicity has been lessened to some extent by lipid-complexed formulations.

35. Azoles • Azoles have emerged as the preeminent class of antifungal agents for all except the most life-threatening infections, and even in these cases highly active new variants are being developed. The most significant agents in clinical use are shown in next slide.

36. Azole Antifungal Agents

37. Structure-Activity Relationship • From the many series of azoles that have been reported by diverse groups, several common structural features emerge: an imidazole or triazole heme-coordinating group, a halo-substituted aromatic separated from the azole moiety by two atoms, and a side chain .

38. Azoles Beginning in the late of 1960s, an extensive series of azole compounds have been synthesized and tested for antifungal activity.Currently, the R&D for antifungal agents are also focused on this scaffold.

39. SAR of Azoles

40. The mechanism of action of azoles • Inhibition of cytochrome P-450 that catalyzes 14--demethylation of lanosterol to ergosterol, accumulation of 14-methylated sterols cause permeability disturbance azoles

41. Econazole nitrate (硝酸益康唑) • 1-[2-[（4-chlorophenyl）methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole Nitrate • It is only slightly soluble in water and most organic solvents. • Econazole is used as a 1% cream for the topical treatment of local tinea infection and cutaneous candidiasis.

42. Synthesis

43. Fluconazole(氟康唑 ) • 2-（2，4-Diflurophenyl）-1，3-bis-（1H-1，2，4-triazole-yl）-2-propanol

44. Synthesis

45. Ketoconazole (酮康唑) Cis-1-acetyl-4-{4-[(2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl- methyl-1,3-dioxolan-4-yl)methoxy]phenyl}piperazine Ketoconazole was marked in 1981 in US. It is a broad-spectrum antifungal activity, used to the treatment of skin fungi infections and intestinal yeast infections.

46. The Others

47. Homework • Question: • What is the difference of the action mechanism between the Sulfonamides and Penicillins? • Assignment: • 1.Read textbook pp268-279 • 2.Do homework Exercises of medicinal chemistry and药物化学学习指导,第9章