Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.



Published on

Medicinal Chemistry for drugs required to treat tuberculosis.
Rifampicin, Isoniazid etc


  1. 1. INFECTIOUS DISEASES  Infectious diseases, also known as contagious diseases or transmissible diseases, and include communicable diseases, comprise clinically evident illness (i.e., characteristic medical signs and/or symptoms of disease) resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism.  The pathogen can be a bacteria, virus, fungus or a protozoan
  2. 2. TUBERCULOSIS : A GLOBAL EPIDEMIC  Tuberculosis (TB) is an ancient disease that has caused inestimable suffering and claimed millions of lives over the centuries.  and close to 1.8 million deaths annually  Caused by various strains of mycobacteria usually Mycobacterium tuberculosis, an airborne pathogen, that infects macrophages in the lungs  Two possible outcomes :  Infected macrophage can be recognized by effectors of immune system and eradicated  Bacilli may further multiply in the cell leading to its destruction and the infection of new macrophages drawn to the site of infection. This initiate T cell mediated adaptive immunity to eradicate the bacilli which if fails then it grows and spread to extra pulmonary sites.
  3. 3.  Most infections asymptomatic, latent infection  About one in ten latent infections eventually progress to active disease, which, if left untreated, kills more than 50% of those infected.  HIV increases the risk of developing a full –borne disease.
  5. 5. MEDICAL HISTORY OF CURRENT TB CHEMOTHERAPY  TB drugs introduced in 1940’s and 1950’s Pyrazinamide Streptomycin p-aminosalicyclic acid Isoniazi d Others like kanamycin,viomycin,cyclose rine,ethionamide
  6. 6.  TB drugs introduced in 1960’s and 1970’s Thioacteazon e rifampicin Others like capreomycin,clofazimine Ethambuto l
  7. 7. CLASSIFICATION First line Ethambutol is EMB or E, isoniazid is INH or H, pyrazinamide is PZA or Z, rifampicin is RMP or R,  Streptomycin is no longer considered as a first line drug by ATS/IDSA/CDC because of high rates of resistance)
  8. 8. Second line    it may be less effective than the first-line drugs (e.g., paminosalicylic acid it may have toxic side-effects (e.g., cycloserine) or it may be unavailable in many developing countries (e.g., fluoroquinolones) aminoglycosides: e.g., amikacin (AMK), kanamycin (KM); polypeptides: e.g., capreomycin, ; Fluoroquinolones e.g., ciprofloxacin (CIP) ,levofloxacin, moxifl oxacin (MXF); thioamides: e.g. ethionamide, prothionamide
  9. 9. Third Line  Other drugs that may be useful, but are not on the WHO list of SLDs:  rifabutin  macrolides: e.g., clarithromycin (CLR);  linezolid (LZD);  thioacetazone (T);  thioridazine;  arginine;  vitamin D;  R207910.  they are not very effective (e.g., clarithromycin)  because their efficacy has not been proven (e.g., linezolid, R207910).  Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.
  10. 10. EMERGENCE OF DRUG RESISTANT TB  Combination resistance therapy used to limit development of  Who developed DOTS  Even then high relapse rates and 1990’s marked a period of increasingly resistant TB from mono to MDR-TB(resistant to INH and RIF)  Treatment with second line drugs with unproven efficacy and use of broad spectrum agents like fluoroquinolones
  11. 11.  Five per cent of all TB cases are now estimated to be MDR  If cases are there which are resistant to first and second line drugs , then third line agents that are non-WHO approved are given.  Emergence of XDR-TB .  Now we have TDR-TB for which no chemotherapeutic options
  12. 12. SPECIAL CHALLENGES IN TB DRUG DEVELOPMENT Why we need improved stategies ?  improved (shorter and simpler, but still affordable) multidrug regimens for DS-TB to improve adherence and prevent development of more resistant strains of M. tuberculosis  shorter, more efficacious, less toxic and less expensive regimens for MDR-TB and XDR-TB  short,simple, easily tolerable and safe regimens for LTBI  TB drugs with minimal interactions with the cytochrome P450 (CYP)enzyme and other metabolic systems
  13. 13. PROBLEMS  Problems with rifampicin  Malabsorption : patients with this disease are malnourished and weight loss is a common symptom  Heterogeneity of TB pathology- differences in clinical manifestation, host and pathogen physiology  Each lesion a distinct microenvironment  Drug penetration is limited  Drug should not only penetrate cell wall of bacteria but should be able to reach it ,within the fibrous necrotic lesion harboring the persistent organisms.
  15. 15. RIFAMYCINS  Most effective and widely used  Rifampin was developed in the Dow-Lepetit Research Laboratories( Milan, Italy) as part of an extensive program of chemical modification of the rifamycins, the natural metabolites of Nocardia mediterranei.  Developed in 1960 after extensive SAR performed on rifamycin B  Rifamycin B was the least active component of the rifamycin complex but showed an extremely low level of toxicity and a moderate level of therapeutic activity in infections in animals
  16. 16.   First compound with ansa structure consisting of an aromatic nucleus spanned by an aliphatic bridge, therefore, known as ansamycins Rifamycin SV is active compound
  17. 17. FROM RIFAMYCIN SV TO RIFAMPICIN  Extensive chemical modifications were made    better oral absorption; more prolonged antibacterial levels in blood; and greater activity against mycobacterial infections and infections due to gram-negative bacteria
  18. 18. Changes in ansa chain –less active Essential Subsitution or elimination-less active Subsitutuion to keto groups –no effect
  19. 19. ACTIVITY REQUIRED  two free hydroxyls in positions C-21 and C-23 on the ansa chain  two polar groups (either free hydroxyl or carbonyl) at positions C-1 and C-8 of the naphthoquinone nucleus  conformation of the ansa chain that resulted in certain specific geometric relations among these four functional groups.
  20. 20.     Rifamycin derivatives with substitutions in position C-3 and/or position C-4 di-alkylamino-4-deoxyrifamycins; phenazino- and phenoxazinorifamycins; 3dialkylamino-alkylrifamycins. Extensive studies on the 3-dialkylaminomethyl derivatives of rifamycin SV. the hydrazone of 3-formylrifamycin SV with N-amino-N'methylpiperazine, designated rifampicin or rifampin was the most active and least toxic
  21. 21. RIFAMPICIN
  22. 22. MECHANISM OF ACTION  Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its betasubunit, Rifampicin acts directly on messenger RNA synthesis.  Much of this acid-fast positive bacteria's membrane is mycolic acid complexed with peptidoglycan, which allows easy movement of the drug into the cell.  cannot stop the elongation of mRNA once binding to the template-strand of DNA has been initiated.  The Rifampin-RNA polymerase complex is extremely stable and yet experiments have shown that this is not due to any form of covalent linkage. It is hypothesized that hydrogen bonds and π-π bond interactions between naphthoquinone and the aromatic amino acids are the major stabilizers,  It is this last hypothesis that explains the explosion of multi-drug-resistant bacteria: mutations in the rpoB gene that replace phenylalanine, tryptophan, and tyrosine with nonaromatic amino acids result in poor bonding between rifampicin and the RNA polymerase.  Rifampicin-resistant bacteria produce RNA Polymerases with subtly different β subunit structures which are not readily inhibited by the drug.
  23. 23. SYNTHESIS  wherein rifamycin S is reacted with a 1,3,5-trisubstituted hexahydro-1,3,5triazine in an aprotic dipolar solvent and optionally in the presence of formaldehyde, the reaction preferably being carried out without modifying the pH of the medium and preferably in the presence of certain acid substances, using controlled time and temperature conditions  1-amino-4-methylpiperazine is then added directly to the reaction mixture, while keeping the pH value in the range of from 5 to 7, and then isolating the rifampicin formed.
  24. 24. INTERACTIONS   Rifampicin is an inducer of many enzymes of the cytochrome P450 family Other possible interactions which may not be listed include antiretroviral agents, everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, ADVERSE EFEECTS    Influenza like symptoms Hepatotoxicity Altered liver function
  25. 25. ISONIAZID     also known as isonicotinylhydrazine (INH). discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid(wax coat). never used on its own to treat active tuberculosis because resistance quickly develops. Isoniazid also has an antidepressant effect, and it was one of the first antidepressants discovered
  26. 26. SAR  Analog of anti-tubercular drug thiacetazone which had limited use because of toxic effects  Phenyl ring was replaced with pyridine ring as nicotinamide had growth inhibitory isonicotinaldehyde thiosemicarbazone more active   Other intermediates in synthesis were evaluated leading to discovery of INH  Hundreds of derivatives synthesised bt none improved on activity .N acetyl INH inactive  N alkyl derivatives such as iproniazid and hydrazones such as verazide  Invivo metabolite is INH effect on Mtb.
  27. 27. SYNTHESIS Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine to give the amide, followed by displacement of ammonia by hydrazine
  28. 28. MECHANISM OF ACTION activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG. INH Isonictinoyl radical acyclic isonicotinoyl –NAD(P) adducts NAD(P ) Inhibits NADH dependent enoyl ACP reductase InhA involved in fatty acid biosynthesis
  29. 29. OTHER DRUGS  PYRAZINAMIDE –intracellular acidification following hydrolysis by Mtb nicotinamidase, inhibition of fatty acid synthesis  CYCLOSERINE-prevents D –alanine incorporation into peptidoglycan by inhibiting enzyme alanine racemase  CAPREOMYCIN-inhibit protein synthesis by binding at interface of 30S and 50S subunit of bacterial ribosome
  30. 30. ANTIFUNGAL AGENTS  are increasingly common in immunocompromised and other vulnerable patients.  The use of antifungal drugs, primarily azoles and polyenes, has increased in parallel.  azoles are fungistatic and vulnerable to resistance, whereas polyenes cause toxicity  echinocandins, pneumocandins, and improved azoles.  Promising novel agents in preclinical development include several inhibitors of fungal protein, lipid and cell wall syntheses
  31. 31. AZOLES  An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulfur, or oxygen ketoconazole cklotrimazole fluconazole
  32. 32. POLYENES
  35. 35. EMERGING TARGETS      Microtubulin inhibitors like griseofulvin Topoisomerase inhibitors Phosphnribosylaminoimidazole carboxylase, an enzyme of them purine pathway Amino acid analogs to interfere with amino acid synthesis Proton ATPases and efflux pumps
  36. 36. REFERENCES  Third world diseases by Richard Elliot  Foyes’ Medicinal Chemistry  History of the development of azole derivatives . J. A. Maertens ,Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004  The discovery and development of amphotericin B. James Dutcher ,Dis Chest 1968;54;296-298  Antifungals: mechanism of action and resistance, established and novel drugs . Nafsika H Georgopapadakou Current Opinion in Microbiology 1998, 1:547-557  History of the Development of Rifampin . P.sensi ,From the Dow-LepetitR esearchL aboratories, Milan, Italy. Reviews of infectious diseases * vol. 5, supplement 3 * july-august 1983 