diseases or transmissible diseases, and include communicable
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
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
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.
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.
MEDICAL HISTORY OF CURRENT TB CHEMOTHERAPY
TB drugs introduced in 1940’s and 1950’s
TB drugs introduced in 1960’s and 1970’s
Others like capreomycin,clofazimine
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
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.,
aminoglycosides: e.g., amikacin (AMK), kanamycin (KM);
polypeptides: e.g., capreomycin, ;
Fluoroquinolones e.g., ciprofloxacin (CIP) ,levofloxacin, moxifl
thioamides: e.g. ethionamide, prothionamide
Other drugs that may be useful, but are not on the WHO list of
macrolides: e.g., clarithromycin (CLR);
they are not very effective (e.g., clarithromycin)
because their efficacy has not been proven (e.g., linezolid,
Rifabutin is effective, but is not included on the WHO list because
for most developing countries, it is impractically expensive.
EMERGENCE OF DRUG RESISTANT TB
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
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
Emergence of XDR-TB .
Now we have TDR-TB for which no chemotherapeutic
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
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
DEVELOPMENT OF THE TWO MOST COMMONLY USED
FIRST LINE AGENTS
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
First compound with ansa structure consisting of an
aromatic nucleus spanned by an aliphatic bridge, therefore,
known as ansamycins
Rifamycin SV is active compound
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
Changes in ansa chain –less
Subsitutuion to keto
groups –no effect
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.
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
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
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.
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 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,
Influenza like symptoms
Altered liver function
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
Isoniazid also has an antidepressant effect, and it was one of the first
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.
Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine
to give the amide, followed by displacement of ammonia
MECHANISM OF ACTION
activated by a bacterial catalase-peroxidase enzyme that in M.
tuberculosis is called KatG.
acyclic isonicotinoyl –NAD(P) adducts
Inhibits NADH dependent enoyl
ACP reductase InhA involved
in fatty acid biosynthesis
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
are increasingly common in immunocompromised and other vulnerable
The use of antifungal drugs, primarily azoles and polyenes, has increased in
azoles are fungistatic and vulnerable to resistance, whereas polyenes cause
echinocandins, pneumocandins, and improved azoles.
Promising novel agents in preclinical development include several inhibitors of
fungal protein, lipid and cell wall syntheses
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
Microtubulin inhibitors like griseofulvin
Phosphnribosylaminoimidazole carboxylase, an enzyme of
them purine pathway
Amino acid analogs to interfere with amino acid synthesis
Proton ATPases and efflux pumps
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