The document discusses various first and second-line antituberculosis drugs, including their mechanisms of action, structure-activity relationships, chemical syntheses, and clinical uses. It focuses on isoniazid, rifampin, pyrazinamide, ethambutol, and ethionamide. It explains how these drugs inhibit mycobacterial cell wall synthesis or RNA polymerase, and discusses factors influencing their activities and properties important for their pharmacokinetics and metabolism. The drugs are important components of combination therapies used to treat tuberculosis.
The document discusses various first and second-line antituberculosis drugs, including their mechanisms of action, structure-activity relationships, chemical syntheses, and clinical uses. It focuses on isoniazid, rifampin, pyrazinamide, ethambutol, and ethionamide. It explains how these drugs inhibit mycobacterial cell wall synthesis or RNA polymerase, and discusses factors influencing their activities and properties important for their pharmacokinetics and metabolism. The drugs are important components of combination therapies used to treat tuberculosis.
The document discusses various first and second-line antituberculosis drugs, including their mechanisms of action, structure-activity relationships, chemical syntheses, and clinical uses. It focuses on isoniazid, rifampin, pyrazinamide, ethambutol, and ethionamide. It explains how these drugs inhibit mycobacterial cell wall synthesis or RNA polymerase, and discusses factors influencing their activities and properties important for their pharmacokinetics and metabolism. The drugs are important components of combination therapies used to treat tuberculosis.
The document discusses various first and second-line antituberculosis drugs, including their mechanisms of action, structure-activity relationships, chemical syntheses, and clinical uses. It focuses on isoniazid, rifampin, pyrazinamide, ethambutol, and ethionamide. It explains how these drugs inhibit mycobacterial cell wall synthesis or RNA polymerase, and discusses factors influencing their activities and properties important for their pharmacokinetics and metabolism. The drugs are important components of combination therapies used to treat tuberculosis.
a. first-line antituberculin drugs (INH, rifamycins, pyrazinamide, and ethambutol [EMB]). b. second-line antituberculin drugs (aminoglycosides, ethionamide, p- aminosalicylic, cycloserine, and capreomycin) The SAR and Medicinal chemistry of antituberculin drugs. Discuss the physicochemical and pharmacokinetic properties of first-line antituberculin drugs. Clinical uses of antiTB drugs ACID-FAST BACILLI (MYCOBACTERIAL INFECTIONS) Mycobacteria is acid fast bacilli with certain different type of cell wall The mycobacterium outer layer of the cell envelope is rich in lipids (α-mycolic acid) and polysaccharides (poly α-D-arabinose, poly β-D-galactan, and poly α-D- mannan). Many of the antibacterials used to treat mycobacterial infections target the cell envelope of the pathogen because of features not found in human cell membranes. • Infections associated with the mycobacteria include TB (pathogen: Mycobacterium tuberculosis), leprosy or Hansen disease (pathogen: Mycobacterium leprae), and disseminated M. avium complex (MAC) disease (pathogen: M. avium and M. intracellulare). ANTI-TB DRUGS
First agent used as an anti-TB drug was sulfanilamide, but,
since, sulfonamides are bacteriostatic, resistance occurred rapidly Second agent tried was dapsone, though it was effective, but in long-term therapy found to be toxic…..discontinue In TB treatment, major breakthrough was the development of streptomycin-an aminoglycoside, that was highly effective against MT. Afterwards, many synthetic drugs were developed to eradicate TB, despite such developments, it is still prevailing due to emergence of multidrug resistant stain. ISONIAZID
It is synthetic anti-TB drug introduced in 1950
• Chemically, it is isonicotinic acid derivative- combination of isonicotinic acid and hydrazine: (Hydrazide) • It is a prodrug- in body is converted into electrophilic species which inhibit the synthesis of mycolic acid • It is effective against rapidly dividing MTB but less effective against dormant and semi- dormant MOA
INH is a prodrug which is activated within the bacillus through a peroxidase- catalyzed oxidation to a potent radical acylating agents . Mycolic acid, an essential component of the mycobacterium cell envelope, is biosynthesized in a step that requires an NADH reduction. NADH plus the enzyme inhA enoyl reductase reduces a double bond in one arm of mycolic acid. INH inactivates the reduction via acylation of NAD+ thus blocking cell wall synthesis. INH is bactericidal. Resistance is associated with mutation in peroxidase enzyme. ISONIAZID
Structure activity relationship
Pyridine ring, if replaced with piperidine then the compound is less active than the original. Hydrazide linkage when converted into hydrazone derivatives, a series of active compounds are produced. Later it was found that in the body Hydrzones are converted into isoniazid • If hydrazide is shifted to position If hydrazide is shifted to position 2 or 3 instead of 4 then the compound is less active ISONIAZID
INH contains two nitrogen atoms, when an alkyl
group is introduced at N1 then the compound became inactive When any alkyl group is introduced at N2 then a series of active compounds are obtained but these are less active If hydarzide group is replaced totally by alkyl or aryl then the compound remains active but less than isonaizide CHEMICAL SYNTHESIS
Basic hydrolysis of 4- cyano pyridine converts cyano/nitrile group to an amideIsonicotinamide- which then reacts with hydrazine to produce isoniazid ISONIAZID
Physicochemical and Pharmacokinetic Properties
• INH is water soluble, readily absorbed (∼100%), and is distributed to the CNS • Poorly bound to plasma protein
Metabolism CLINICAL APPLICATION
Monotherapy with INH is used in patients with dormant or latent mycobacterial
infections. For active TB, INH is used in combination therapy PYRAZINAMIDE
Pyrazinamide is a bioisostere (those having same biological and physicochemical properties)of
nicotinamide. Nitrogen has atomic number 7 whereas CH also has 7, hence isosteres It is a prodrug and converted into pyrazinoic acid in the body Contains pyrazine ring in its structure, which is a six memberd heterocyclic ring containing two nitrogen at a distance of 2 carbon atoms Pyrazinamide has amide group at position 2 Activity is pH dependent and maximum at pH 5.5 MOA
Pyrazinamide is converted to Pyrazinoic acid lowers the pH in the
M. tuberculosis environment inhibiting its growth and can also penetrate the cell membrane lowering the pH in the cytoplasm with a bactericidal effect. Resistant M. tuberculosis exhibits a point mutation leading to reduced hydrolysis of pyrazinamide to pyrazinoic acid. As a bioisostere of nicotinamide pyrazinamide/pyrazinoic acid may interfere with mycolic acid synthesis. Pyrazinamide is active at pH 5.5, but inactive at pH 7. STRUCTURE ACTIVITY RELATIONSHIP
When pyrazine ring is replaced with alternate heterocyclic ring e.g pyridine or pyrimidine, the compound became less active
Pyrazine ring is mono-substituted while disubstituted derivatives are less active
Metabolism : conjugated with glycine. Clinical application : Pyrazinamide is active against the semidormant intracellular form of M. tuberculosis. When used in combination with other first-line drugs pyrazinamide has significantly lowered the patient treatment time (see combination therapy below). RIFAMYCIN
MOA The rifamycins block bacterial DDRP(DNA-dependent RNA polymerase) resulting in inhibition of RNA synthesis. Binding of the rifamycins to DDRP occurs through π–π bonding between naphthalene and aromatic amino acids of DDRP. Chelation occurs between the C1 and C8 phenolic groups of the drug and zinc ion, a component of DDRP. Hydrogen bonding occurs between C21 and C23 alcohols to the DDRP. RIFAMYCIN ANTIBIOTICS
SAR Free –OH groups are required at C1, C8, C21, and C23 (i.e., acetylation of C21 or C23 destroys activity). Reduction of any of the double bonds in the macrocyclic ring progressively reduces biologic activity. Opening the macrocycle results in an inactive compound. Substitution at C3 and/or C4 gives varying degrees of antibacterial activity. RIFAMYCIN ANTIBIOTICS
Physicochemical : oxidized to 1,4 dihydroxynaphthaline is converted to 1,4 dihydroquinon ---
zwitterionic in nature Pharmacokinetic Properties Due to the extended conjugation the rifamycins cause a red or orange coloration of urine, stools, and sweat and tears Food effects absorption (decrease with rifampin; increase with rifapentine). Highly bound to plasma protein (rifampin 89%, rifabutin 85%, rifapentine ∼98%). Variable bioavailability (rifampin ∼90%, rifabutin ∼20%, rifapentine depends on meal). Metabolism: C25 deacetylation is major metabolism Clinical uses: active against gram positive and negative, Part of combination in antiTB ETHAMBUTOL (EMB)
Due to its efficacy and less adverse effects it is included in first-line therapy of Tuberculosis It has synergistic action with other anti-Tb drugs It contains 2 asymmetric carbon atoms It is stereo-specific and d-ethambutol (hydroxy methyl groups are in front and H is at back) is 16 times more active than the levo form It is more active on dividing cells, whereas, low or inactive on non-dividing cells. It inhibits the formation of cell wall MOA
EMB inhibits the enzyme arabinosyl
transferase which catalyzes the polymerization of β-D-arabinofuranosyl- 1-monophosphate to various polyarabinose components of the mycobacterial cell envelope (arabinogalactan [AG] and lipid arabinomannan [LAM]) Resistance is associated with overexpression of arabinosyl transferase. Damage to the cell envelope confers antibacterial action (bacteriostatic at low dose). SAR
If OH groups are replaced by OCH3 or OC2H5, the compound remains active, and if replaced by aromatic system (phenyl or pyridine) the compound became inactive By removing OH groups activity is lost Extension of ethane diamine results in loss of activity Removal of either of the amino groups activity is lost Increase in size of N-substituent activity is lost CHEMICAL SYNTHESIS PHYSICOCHEMICAL AND PHARMACOKINETIC PROPERTIES
(+) EMB is the biologically active drug. The (-) isomer and the symmetrical isomer are not effective drugs. Bacteriostatic Specific for most of the strains like MT and M. kansasii Metabolism : 73% of the drug is excreted in urine as unchanged,15% is metabolized into metabolite A and B, both of them are inactive Good bioavailability (∼80%). Clinical use : used as first line in combination ETHIONAMIDE
A 2nd line anti TB agent, analogue of
isonicotinamide but it is di-substituted and contains S in place of O It contains ethyl group at position 2 In vitro it is less active but in vivo more active because of increased lipocity due to C2H5 Mechanism of action is similar to INH Its active metabolite is ethionamide sulfoxide ETHIONAMIDE
MOA Ethionamide, a derivative of isonicotinamide, is a prodrug which requires oxidative activation via a flavin monooxygenase enzyme (EtaA) to an acylating agent Similar to INH, ethionamide acetylates within inhA enoyl reductase blocking mycolic acid synthesis. Site of action of ethionamide appears to be the same as that of INH. ETHIONAMIDE
Metabolism Less than 1% of the drug is excreted unchanged in urine. Rest of the drug is excreted as one of the following metabolites, which are given as follows: P-AMINOSALICYLIC ACID (PAS)
Once a very popular drug, but resistance, and adverse
effects have reduced its value MOA PAS is an antimetabolite of PABA blocking folic acid synthesis with bacteriostatic action (see mechanism of action of sulfonamides). Blocks acetylation of INH when used in combination with INH and thus reducing inactivation of INH. CYCLOSERINE
Analogue of amino acid serine and it exists in cyclic form- a five member ring containing O and N at an adjacent positions, Also called Isoxazolidine or oxazolidine Obtained naturally as d-isomer Contains Keto group at position 3 and NH2 at position 4, which is in front d-isomer is more active It is 2nd line anti TB drug first isolated from Streptomyces orchidaceus, but now being synthesized in laboratory It causes CNS toxicity Bacteria become resistant after sometime It acts on cell wall of bacteria and is not selective against MT because all bacteria contain peptidoglycan CHEMICAL SYTHESIS OTHER AGENTS DAPSONE, CAPREOMYCIN
