Antimycobacterial Agents

3. Antimycobacterial Agents • Mycobacteria: Mycobacterium tuberculosis => Tuberculosis Mycobacterium leprae => Leprosy (Hansen’s disease) • Slow-growing and difficult to stain (acid-fast bacilli). • Abnormally high lipid content (mycolic acid) of the cell envelope. • Treatment of mycobacterial infection complicated by: • Intracellular location of mycobacteria - phagocytes • Drug resistance • Chronic nature of these diseases • In tuberculosis, the bacilli reach the alveoli, ingested by pulmonary macrophages, fibroblasts then enclose the infection site leading to formation of granulomas or tubercles, hence the name Tubercle Bacillus (T.B). • Treatment requires the use of drug combinations • Delay resistance and enhance effectiveness

4. Diagram of cell wall

5. Leprosy primarily affects the skin as chronic granulomatous infection. • Tuberculosis primarily affects the lung (pulmonary tuberculosis) but infection may extend to brain, bones, eyes and skin (extrapulmonary tuberculosis) especially in HIV-infected patients.

6. Tuberculosis

7. Clinical picture of leprosy:

9. Antitubercular agents • Based on history of discovery, sulfanilamide then dapsone then streptomycin (a turning point) then PAS then isoniazid then ethambutol then rifampin. • Due to multiple drug resistance, a combination of two or three of these agents is usually used. • Classification: • p-Aminosalicylic acid derivatives. • Pyridine carboxylic acid derivatives. • Miscellaneous agents.

10. p-Aminosalicylic acid (PAS): Mode of action Two possible mechanisms: • Similar to the mode of action of sulfonamides: Being structurally similar to PABA, it acts as a competitive antagonist to PABA by inhibiting dihydropteroate synthetase eventually inhibits the biosynthesis of mycobacterial DNA. • It chelates trace elements. Disadvantages: • Gastrointestinal irritation. • Short half life (short duration). • To overcome these disadvantages: • It should be formulated in enteric-coated dosage form or an antacid (aluminum hydroxide) is prescribed concurrently. • Developing less GI irritaing and longer acting analogues such as Calcium benzoyl-PAS.

11. Pyridinecarboxylic acid derivatives: Isoniazid (INH): • Isonicotinic acid hydrazide. Synthesis: Mode of action: • Inhibition of the biosynthesis of mycolic acids (branched long chain fatty acids) which are important components of the cell wall of mycobacteria. • Active only against dividing mycobacteria.

12. NOTES: 1) INH is the most active antitubercular agent rather than any other synthetic or antibiotic. 2) the equation of the assay is as follows: 3)Ftivazide is hydrazone results from reaction of INH with benzaldehyde derivatives, It is as active as INH but non toxic.

13. Side effects of INH: • long-term therapy may result in fatal drug induced hepatitis. • It causes peripheral neuritis as it results in pyridoxine deficiency by acting as a pyridoxine antagonist therefore, the concurrent administration of pyridoxine (vitamin B6) prevents the occurrence of peripheral neuritis. • INH is metabolized by acetylation. Nearly half of the population are fast acylators of INH and the other half are slow acylators of INH. Slow acylators (including middle easterns) are genetically deficient of N-acetyltransferase and are more prone to the side effects of INH. Ethionamide: • Developed as a less toxic (5 times) analogue of INH. • Mode of action like INH. • Active only against dividing mycobacteria.

14. SAR: Aromatic ring: • If replaced by benzene, piperidine or thiazole  loss of activity. Hydrazide moiety: • The -position is the best position for activity. • Replacement of Ha with alkyl groups  decreases activity. • Replacement of Hb and/or Hc with small alkyl groups  increases activity. large alkyl groups decreases activity. • Replacement of Hb and Hc with alkylidene  retains activity.

15. Diazine derivatives ( pyrazinamide ).

16. Miscellaneous agents Ethambutol (Etibi): Mode of action: • Being structurally similar to cellular polyamines (spermidine and spermine), it interferes with their function (essential for integrity of nucleic acids). • It chelates divalent metals thus inhibiting essential enzymes.

17. Synthesis of ethambutol: Antitubercular antibiotics: • Streptomycin • Cycloserine • Rifampin

18. Antileprotic agents A) Sulfones: Dapsone:Di-(4-aminophenyl)sulphone. • The drug of choice for the treatment of leprosy. • In addition to the antileprotic effect, dapsone has also antimalarial and antileshmanial activities. Mode of action: • Acts by a mechanism similar to sulfonamides. Evidences: • PABA partially antagonizes the action of sulfones. • Cross resistance between sulfonamides and sulfones.

19. Disadvantage: • Poor solubility poor formulation Dapsone prodrugs (soluble dapsone analogs): Solapsone:Tetrasodium salt of Bis[4-(3-phenyl-1,3-disulphopropylamino)phenyl]sulphone • Solapsone undergoes acidic hydrolysis in the stomach to release dapsone which is the active antileprotic drug.

20. Synthesis of Dapsone

21. Synthesis of Solapsone

22. SAR of sulphones ( dapsone): 1) of the six isomers of diaminodiphenylsulphones only 4,4- is the active one. 2) additional substitution of phenyl ring cause loss of activity. 3)N-alkyl and N-acyl derivatives retain activity due to deacylation and dealkylation in vivo. 4)replacement of aminophenyl group with alkyl or aryl or heterocyclic group will cause loss in activity. 5)activity is exhibited by several mono and bis Schiffs base of aromatic aldehydes and aldehyde-bisulphite complexes as in glucosulphone, and glucosulphone has weak activity in vitro as no hydrolysis which regenerate ACTIVE DAPSONE. 6) sulphone group is essential for activity.

23. B) Miscellaneous agents: Clofazimine:N,10-bis-(4-chlorophenyl)-2,10-dihydro-2-[1-methylethylamino]-3-phenazinamine • A phenazine dye • Binds preferntially to mycobacterial DNA • Teratogenic Thiambutosine: • A thiourea derivative • N-(4-butoxyphenyl)-N- -(4-dimethylaminophenyl)thiourea Other agents used for leprosy: • Isoniazid, ethionamide, rifampin

24. The American Medical Association “AMA” states: • Treatment of leprosy is difficult and complex. • A combination of dapsone / clofazimine / rifampin should be used. • Therapy duration = 5 years – life time.