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:
1. Tuberculosis
treatments
2. 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.

8. 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

9. 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.

11. isoniazid

12. 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.

13. 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

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

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

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

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

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

19. 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.

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

21. Ethambutol

22. 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

23. 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.

24. Uses
–Used only in mycobacterial
infections.

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

26. 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.

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

28. Ethionamide

29. 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

30. Uses
Used in TB & leprosy.

31. Fluoroquinolones

32. CIPROFLOXACIN LEVOFLOXACIN

33. 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.

34. 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

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

36. 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.

37. 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

39. Drugs used in leprosy
• Dapsone
• Clofazimine

40. Dapsone

41. 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.

42. 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.

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

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

45. Clofazimine

46. 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.

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

48. 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

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

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

51. Thank you
=)