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the medicinal chemistry view of it

-Tuberculosis (treatments)
-Leprosy (Leprostatic agents)

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  2. 2. OUTLINES• Introduction• Classifications–Structures–MOA–SAR–Uses–Side effects
  3. 3. Definition• An antimycobacterial is atype of drug used to treatmycobacteria infections.• Types include:1. Tuberculosistreatments2. Leprostatic agents
  4. 4. TB• is a common, and in many caseslethal, infectious disease causedby various strains ofmycobacteria, usuallyMycobacterium tuberculosis.• Tuberculosis usually attacks thelungs but can also affect otherparts of the body.
  5. 5. TB• It is spread through the airwhen people who have anactive MTB infectioncough, sneeze, or otherwisetransmit their saliva throughthe air.
  6. 6. Symptomschest pain, coughing upblood, and aproductive, prolonged cough formore than three weeks.Systemic symptoms includefever, chills, nighsweats, appetite loss, weightloss, pallor, and fatigue.
  7. 7. First line• All first-line anti-tuberculous drugnames have a standard three-letterand 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. 8. Never use a single drugtherapy–Isoniazid –rifampicin combinationadministered for 9 months willcure 95-98% of cases .–Addition of pyrazinamide for thiscombination for the first 2months allows total duration tobe reduced to 6 months.
  9. 9. isoniazid
  10. 10. MOA–Bacteriostatic at low conc. &bacteriocidal at high conc.Especially against activelygrowing bacteria.–Inhibits synthesis of mycolicacid is an essentialcomponents of mycobacterialcell wall.–Readily absorbed from GIT.
  11. 11. MOA–Diffuse into all body fluids andtissues–Penetrates caseous materialand macrophages so it iseffective against intra andextracellular organisms.–Metabolized in liver byacetylation–Excreted mainly in urine
  12. 12. SAR1-Substitutionofhydrazine portion ofINH with alkyl and ar-alkyl substitutionresulted in a series ofactive and inactivederivatives.
  13. 13. SAR2-Substitution on theN2 position (R1,R2=alkyl,R3=H)----active compounds.
  14. 14. SAR2-Substitution on theN2 position (R1,R2=alkyl,R3=H)----active compounds.
  15. 15. SAR3-Any Substitution atN1-hydrogen(R3=alkyl)------------destroy theactivity.
  16. 16. SAR4-Any Substitution---not superior thanINH.
  17. 17. Uses–Mycobacterial infections (it isrecommended to be given withpyridoxine to avoid neuropathy).–Latent tuberculosis in patientswith positive tuberculin skin test–Prophylaxis against active TB inindividuals who are in great risk asvery young orimmunocompromised individuals.
  18. 18. Side effects–Peripheral neuritis–Optic neuritis.–Allergic reactions ( fever,skinrash,systemic lupuserythematosus )–Hepatitis–Gastric upset–Haemolytic anaemia–Enzyme inhibitor–CNS toxicity.
  19. 19. Ethambutol
  20. 20. MOA–Inhibits mycobacterial cell wallsynthesis by inhibiting arabinosyltransferase .–Bacteriostatic–Active against intra&extracellularbacilli .–Well absorbed from gut.–20% excreted in feces and 50% inurine in unchanged form.–Crosses BBB in meningitis
  21. 21. SAR– Ethylene diamine chain --↑this chain length --↓ordestroy.– Replacement of either N--↓or destroy.– Increasing the size of Nitrogen substituents--↓ordestroy.– Moving the location of alcohol groups--↓ordestroy.
  22. 22. Uses–Used only in mycobacterialinfections.
  23. 23. Side effects–Retrobulbar (optic) neuritiscausing loss of visual acuity andred-green colour blindness.–It is relatively contraindicated inchildren.–GIT .upset .–Hyperuricemia
  24. 24. 2nd line• Indication of 2nd line treatment :–Resistance to the drugs of 1stline.–Failure of clinical response–Increase of risky effects.–Patient is not tolerating thedrugs first line drugs.
  25. 25. –Ethionamide–Capreomycin–Amikacin–Ciprofloxacin & levofloxacin–Rifapentine–Aminosalicylic Acid (PAS)
  26. 26. Ethionamide
  27. 27. MOA–As isoniazid blocks synthesis of mycolicacid .–Available only in oral form.–Metabolized by the liver ,excreted bykidney.–It is poorly tolerated because of :• intense gastric irritation• neurologic symptoms• hepatotoxicity
  28. 28. UsesUsed in TB & leprosy.
  29. 29. Fluoroquinolones
  31. 31. MOA–Broadspectrum,antibacterial,butalso active forM.tuberculosis,– binding to DNA gyrase-DNAcomplex (gyrA and gyrB )–inhibiting bacterial DNAreplication andtranscription, bactericidal.
  32. 32. SAR–Non fluorinated quinolones areinactive against mycobacteria.–Different substitution inquinolones improve activitytoward Mycobacterium aviumintracellular 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. 33. SAR–Excessive lipophillicity atN1can↓activity.–The N-7 substituents with greatestactivity against mycobacteriainclude substituted piperazinesand pyrrolidines.
  34. 34. Leprosy• Leprosy or Hansens disease (HD) is achronic disease caused by the bacteriaMycobacterium leprae andMycobacterium lepromatosis.• granulomatous disease of theperipheral nerves and mucosa of theupper respiratory tract; skin lesionsare the primary external sign.
  35. 35. Leprosy• Secondary infections, in turn, canresult in tissue loss causing fingersand toes to become shortened anddeformed, as cartilage is absorbedinto the body• usually spread from person toperson in respiratory droplets
  36. 36. Drugs used in leprosy• Dapsone• Clofazimine
  37. 37. Dapsone
  38. 38. MOAInhibits folate synthesis.– Well absorbed orally,widelydistributed .– Half-life 1-2 days,tends to beretained in skin,muscle,liver andkidney.– Excreted into bile and reabsorbed inthe intestine.– Excreted in urine as acetylated.– It is well tolerated.
  39. 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)-givessulfoxone Na, which is water soluble, ↓g.i.t irritation(bzincrease solubility) –this drug is preferred who can’ttolerate DDS-but given 3times of DDS bz of its hydrolysis.
  40. 40. Uses– Tuberculoid leprosy.– Lepromatous leprosy incombination with rifampin &clofazimine.– To prevent & treat Pneumocystispneumonia in AIDS caused byPneumocystis jiroveci (Pneumocystis carinii).
  41. 41. Side effects– Haemolytic anaemia– Methemoglobinemia– Gastrointestinal intolerance– Fever,pruritus,rashes.– Erythema nodosum leprosum
  42. 42. Clofazimine
  43. 43. MOA– It is a phenazine dye.– Unknown mechanism ofaction ,may be DNAbinding.– Antiinflammatory effect.– Absorption from the gut isvariable.– Given orally , once daily.
  44. 44. MOA– Excreted mainly in feces.– Stored mainly inreticuloendothelial tissuesand skin.– Half-life 2 months.– Delayed onset of action (6weeks).
  45. 45. SAR– Basic nucleus –phenazine– Halogen substitution at P-position of two phenyls atC-3, and C-10-enhanceactivity but are notessential for activity.– Br > Cl > CH3 >C2H5OH > H>F
  46. 46. Uses– Multidrug resistance TB.– Lepromatous leprosy– Tuberculoid leprosy in :• patients intolerant tosulfones– dapsone-resistant bacilli.– Chronic skin ulcers caused byM.ulcerans.
  47. 47. Side effects– Skin discoloration ranging fromred-brown to black.– Gastrointestinal intolerance.– Red colour urine.– Eosinophilic enteritis
  48. 48. Thank you=)
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