Antimycobacterial

Antimycobacterial
the medicinal chemistry view of it

-Tuberculosis (treatments)
-Leprosy (Leprostatic agents)

1. ANTIMYCOBACTERIAL AHMAD ALJIFRI

2. OUTLINES Introduction Classifications Structures MOA SAR Uses Side effects

3. Definition An antimycobacterial is a type of drug used to treat mycobacteria infections. Types include: Tuberculosis treatments Leprostatic agents

4. TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria , usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body.

5. TB It is spread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air.

6. Symptoms chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, nigh sweats, appetite loss, weight loss, pallor, and fatigue.

7. First line All first-line anti- tuberculous drug names have a standard three-letter and a single-letter abbreviation: Ethambutol is EMB or E, isoniazid is INH or H, pyrazinamide is PZA or Z, rifampicin is RMP or R, Streptomycin

8. Never use a single drug therapy Isoniazid – rifampicin combination administered for 9 months will cure 95-98% of cases . Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.

9. isoniazid

10. MOA Bacteriostatic at low conc. & bacteriocidal at high conc. Especially against actively growing bacteria. Inhibits synthesis of mycolic acid is an essential components of mycobacterial cell wall. Readily absorbed from GIT.

11. MOA Diffuse into all body fluids and tissues Penetrates caseous material and macrophages so it is effective against intra and extracellular organisms. Metabolized in liver by acetylation Excreted mainly in urine

12. SAR 1-Substitutionof hydrazine portion of INH with alkyl and ar -alkyl substitution resulted in a series of active and inactive derivatives.

13. SAR 2-Substitution on the N2 position (R 1,R2=alkyl,R3=H)----active compounds.

14. SAR 2-Substitution on the N2 position (R 1,R2=alkyl,R3=H)----active compounds.

15. SAR 3-Any Substitution at N1-hydrogen(R3=alkyl )------------ destroy the activity.

16. SAR 4-Any Substitution---not superior than INH.

17. Uses Mycobacterial infections (it is recommended to be given with pyridoxine to avoid neuropathy). Latent tuberculosis in patients with positive tuberculin skin test Prophylaxis against active TB in individuals who are in great risk as very young or immunocompromised individuals.

18. Side effects Peripheral neuritis Optic neuritis. Allergic reactions ( fever,skin rash,systemic lupus erythematosus ) Hepatitis Gastric upset Haemolytic anaemia Enzyme inhibitor CNS toxicity.

19. Ethambutol

20. MOA Inhibits mycobacterial cell wall synthesis by inhibiting arabinosyl transferase . Bacteriostatic Active against intra&extracellular bacilli . Well absorbed from gut. 20% excreted in feces and 50% in urine in unchanged form. Crosses BBB in meningitis

21. SAR Ethylene diamine chain --↑this chain length --↓or destroy . Replacement of either N--↓or destroy . Increasing the size of Nitrogen substituents --↓or destroy . Moving the location of alcohol groups--↓or destroy.

22. Uses Used only in mycobacterial infections.

23. Side effects Retrobulbar (optic) neuritis causing loss of visual acuity and red-green colour blindness. It is relatively contraindicated in children. GIT .upset . Hyperuricemia

24. 2nd line Indication of 2nd line treatment : Resistance to the drugs of 1st line. Failure of clinical response Increase of risky effects. Patient is not tolerating the drugs first line drugs.

25. Ethionamide Capreomycin Amikacin Ciprofloxacin & levofloxacin Rifapentine Aminosalicylic Acid (PAS)

26. Ethionamide

27. MOA As isoniazid blocks synthesis of mycolic acid . Available only in oral form. Metabolized by the liver ,excreted by kidney. It is poorly tolerated because of : intense gastric irritation neurologic symptoms hepatotoxicity

28. Uses Used in TB & leprosy.

29. Fluoroquinolones

30. CIPROFLOXACIN LEVOFLOXACIN

31. MOA Broad spectrum,antibacterial,but also active for M.tuberculosis , binding to DNA gyrase -DNA complex ( gyrA and gyrB ) inhibiting bacterial DNA replication and transcription, bactericidal.

32. SAR Non fluorinated quinolones are inactive against mycobacteria . Different substitution in quinolones improve activity toward Mycobacterium avium intracellular complex(MAC – MAI) known as biophores . A cyclopropyl ring at N1position. F atom at position C-6 and C-8 A C-7 heterocyclic substituents

33. SAR Excessive lipophillicity atN1 can↓activity . The N-7 substituents with greatest activity against mycobacteria include substituted piperazines and pyrrolidines .

34. Leprosy Leprosy or Hansen's disease (HD) is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis . granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign .

35. Leprosy Secondary infections, in turn, can result in tissue loss causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body usually spread from person to person in respiratory droplets

36. Drugs used in leprosy Dapsone Clofazimine

37. Dapsone

38. MOA Inhibits folate synthesis. Well absorbed orally,widely distributed . Half-life 1-2 days,tends to be retained in skin,muscle,liver and kidney. Excreted into bile and reabsorbed in the intestine. Excreted in urine as acetylated. It is well tolerated.

39. SAR Relpcemnet of 1 benzene ring results in thiazosulfones —less active than DDS Substitution on benzene ring results in acetosulphone --↓ activity, ↓ g.i.t irritation( bz increase solubility) Substitution by methanesulfinate (CH2SO2)-gives sulfoxone Na, which is water soluble, ↓ g.i.t irritation( bz increase solubility) –this drug is preferred who can’t tolerate DDS-but given 3times of DDS bz of its hydrolysis .

40. Uses Tuberculoid leprosy. Lepromatous leprosy in combination with rifampin & clofazimine . To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii ).

41. Side effects Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever,pruritus,rashes . Erythema nodosum leprosum

42. Clofazimine

43. MOA It is a phenazine dye. Unknown mechanism of action ,may be DNA binding. Antiinflammatory effect. Absorption from the gut is variable. Given orally , once daily .

44. MOA Excreted mainly in feces. Stored mainly in reticuloendothelial tissues and skin. Half-life 2 months. Delayed onset of action (6 weeks).

45. SAR Basic nucleus – phenazine Halogen substitution at P- position of two phenyls at C-3, and C-10-enhance activity but are not essential for activity. Br > Cl > CH3 >C2H5OH > H >F

46. Uses Multidrug resistance TB. Lepromatous leprosy Tuberculoid leprosy in : patients intolerant to sulfones dapsone -resistant bacilli. Chronic skin ulcers caused by M.ulcerans .

47. Side effects Skin discoloration ranging from red-brown to black. Gastrointestinal intolerance. Red colour urine. Eosinophilic enteritis

48. Thank you =)