lec 1 medicinal penicillin.pdf

CHEMOTHERAPEUTIC AGENTS by Dr/ Nadia M. Mahfouz Professor of Pharmaceutical Medicinal Chemistry Assiut University & Now at October 6 University I) Chemotherapeutic agents: ❑ Antibiotics ❑ Synthetic antibacterial ❑ Antifungals ❑ Antiprotozoals ❑...

CHEMOTHERAPEUTIC AGENTS by Dr/ Nadia M. Mahfouz Professor of Pharmaceutical Medicinal Chemistry Assiut University & Now at October 6 University I) Chemotherapeutic agents: ❑ Antibiotics ❑ Synthetic antibacterial ❑ Antifungals ❑ Antiprotozoals ❑ anthelmintics ❑Anticancer Drugs ❑ Antiviral Agents II) Antihistaminics 2 Chemotherapeutic agents: 9hrs ❑ Antibiotics Beta lactam antibiotics Non Beta-lactam antibiotics ❑ Antivirals Antihistaminics 2hrs 3  A) Antibiotics The substance to be antibiotic should fulfill the following 4 cardinal requirements: A secondary metabolite of microorganism. It antagonizes the growth and/or survival of one or more species of other microorganisms. It is effective in low concentrations. Naturally occurring or synthetic product produced as a structural analogue of naturally occurring antibiotics.  Classes of Antibiotics β-Lactam antibiotics: Non β-Lactam antibiotics: 1) Classical β-Lactam: 1) Lincosamides Penicillins 2) Fusidic acid Cephalosporins 3) Macrolides 2) Nonclassical β-Lactam: 4) Polypeptides Clavulanic acid 5) Aminoglycosides Sulbactam 6)Tetracyclines Carbapenems 7)Amphenicols Monobactams R S R1 S N N O O R COOH NH O O H H O O OH S CH3 H2N N N CH3 O O N COOH COO Na O SO3H  I) β-Lactam antibiotics: A) Classical β-Lactam: Penicillins & Cephalosporins 1) PENICILLINS Introduction Accidental discovery of penicillins by sir Alex. Fleming. [penicillium notatum] 1928. The beginning of penicillin as a drug. Mass production 1943. Sir Alex. Fleming Uses in the world war II.  1) PENICILLINS a) The most widely prescribed and useful group of antibiotics b) Potent, nontoxic, and have fairly broad spectrum with use of β- lactamase inhibitors. R NH S Structural Features O N O Highly strained fused bicyclic rings COOH [ β-lactam + Thiazolidine] B-lactam Thiazolidine A free carboxylic function, pKa 2.6 -2.7. Substituted amino function. Penam 3 chiral C-atoms. The fused bicyclic rings are not coplanar along the C-5, O N-1 axis. This suppress the R NH normal amide resonance. H S CH3 CH3 O H N H COOH  Nomenclature 6-Aminopenicillanic acid H H H 4 R N 5 S CH3 6 3 O 7 N 2 CH3 O 1 COOH B-Lactam Thiazolidine Penam 6-Acylamino-3,3-dimethylpenam-2-carboxylic acid 6-Acylaminopenicillanic acid Steriochemistry (2S:5R:6R)  Mode of action of penicillin Selective inhibition of cell wall synthesis. β-Lactam antibiotics inhibited irreversibly transpeptidases, the targets that catalyze the formation of peptidoglycan layer consisting the cell wall of the bacterial. This result in the lowering strength and rigidity of the whole cell wall. Penicillin (beta lactams) Transpeptidase Peptidoglycan layer Cell wall precursors (Cell wall synthesis)  Bacterial resistance of penicillins Some bacterial strains [ especially the Gram negative bacilli] show natural resistance to the pencillins as its not affected with the mechanism of their action. Other strains show such resistance through selection of resistant individuals or mutations. The most important mechanism of resistance is through formation of enzymes cause penicillins inactivation = [ penicillinases] by catalysis of opening of β lactam ring (beta lactamase) and inactivation. Inactivation of Penicillin by enzymes and ions O H N S CH3 R N CH3 B-lactamase O OH COOH O H Amidase N S CH3 R H H2N S HOOC HN CH3 CH3 H 2O COOH N CH3 Penicilloic acid O COOH HOOC 6-APA S CH3 N N CH3 R COOH Penillic acid  H Penicillins Classes: N S CH3 O 1) Natural penicilins: N CH3 O COOH Penicillin G (Benzyl penicillin) and its derivatives. Penicillin G Produced naturally from Culture media. Derivatives: Sod. salt, water soluble for IV injection. Penicillin procaine, water insoluble, for IM injection (Depot effect) H N S O CH3 NH(C2H5)2 O O N CH3 O H2N COO Na+  Advantages: 1) Benzyl Penicillin is active against a wide range of Gram positive bacteria. 2) Nontoxic. 3) Administered by injection only. Drawbacks Allergic reaction. Acid labile. β- Lactamase sensitive and widespread use leads to bacterial resistance. Inactive against Gram negative bacteria (extra cell wall layer acts as a barrier). How can manufacturer make penicillins, acid stable, β-lactamase resistant and more active? 2) Semisynthetic peniciliins: 2.1) Acid Stable peniciliins: Powerful electron withdrawing group in the acylamino side chain prevents the acidic rearrangement? The inductive pulling effect should draw electrons away from the carbonyl oxygen and reduce its tendency to act as a nucleophile.  Phenoxymethyl (Penicillin V) Acid stable ? Orally active H Gram positive bacteria only. O N S CH3 β-lactamase labile. O N CH3 O COOH 2.2) -Lactamase Resistant Bulky group attached to the side Methicillin chain, will sterically hinder the attack of the enzyme at the β- OCH 3 lactam ring. H N S No electron-withdrawing group, N OCH 3 O (acid labile). O COOH Mostly active against Staphylococcus species 2.3) -Lactamase Resistant & Acid Stable Introduction of bulky and electron withdrawing groups at acylamino side chain. CH3 O Oxacillins: H N N S X, Y = H,H: Oxacillin Y O N = H,Cl: Cloxacillin O X COOH = Cl,Cl: Dicloxacillin 2.4 Broad Spectrum Penicillin The presence of polar groups, e.g. NH2 or OH in the acylamino side chain, facilitates the penetration through the porin channel in the outer membrane of the Gram negative bacteria.  Characters Broad spectrum penicillins used primarily for treatment of Pseudomonas infections. Useful for anaerobic infections also. No resistance towards β-lactamase? Acid stable (can be taken orally)? a) α-Amino group: NH2 H N S Aminopenicillins R O O N COOH R = H Ampicillin = OH Amoxicillin (good absorption and no side effect (diarrhea) b) α-COOH group They are carboxypenicillins. They are more resistant by beta-lactamase than ampicillin. They are used for treatment of Gram-negative bacteria, They are limited against Gram-positive bacteria. They are not used orally WHY? COOR COOH H H OMe N S N S S O N O N O O COOH COOH Temocillin R = H, Carbinicillin B-Lactamase Resistant Temocillin is used primarily for the Carbinicillin is susceptible to degradation by β-lactamase treatment of multiple drug-resistant, Gram-negative bacteria. Latent Penicillins NH2 H N S CH3 Long duration O N CH3 O COOR O CH3 O Pivampicillin CH3 CH3 CH3 O O O CH3 Bacampicillin Ester prodrugs Good oral bioavailability  Structure Activity Relationships (SAR) Strained beta-lactam ring is essential COOH group is essential Acylamino group is essential Bicyclic ring system is important but not crucial Sulfur atom should be present but not essential. Sterochemistry. - EWG: acid stability - Bulky group: β-lactamase resistance. - Polar; ionizable: broad spectrum  β-lactamase resistant combinations Non-Classical β-lactams O 1)Clavulanic acid OH Combination therapy O N Amoxicillin & clavulanic acid COOH 1) Produced naturally (Streptomyces clavuligeris). 2) Clavulanic acid is an oxapenam (Non-classical antibiotic). 3) Absence of 6-acylamino group (acid stability) 4) 2-Hydroxyethylidene chain. 5) Weak antibacterial activity, but good β–lactamase inhibitor. 6) The presence of clavulanic acid extends the spectrum to include β–lactamase producing microorganisms including the important pediatric pathogen. Bacteriodes, some Klebsiella, some Enterobacter and β-lactamase producing H. influenzae 7) Available in tablet and suspension form. 8) Clavulanic acid does not inhibit all β –lactamases.  2) Sulbactam O O 2) Sulbactam S CH3 N CH3 O COO Na 1)Sulbactam is a synthetic non-classical β–lactam derivative. 2) Penicillanic acid sulfone. 3) Weak antibacterial activity, good β-lactamase inhibitor. 4) Combination with ampicillin. 5) For intravenous use as physical mixture, whereas for oral use as mutual ester prodrug (Sultamicillin®)? Sultamicillin is a mutual double ester prodrug of ampicillin and sulbactam. Ampicillin, a semi-synthetic orally active broad spectrum antibiotic, is linked via a methylene group with a beta- lactamase inhibitor. The pharmacokinetic properties of sultamicillin are improved compared to a combination of ampicillin and sulbactam. The inclusion of sulbactam extends ampicillin's spectrum of action. to β-lactamase producing strains of bacteria. Sulbactam Ampicillin 1) Mention the generic names of the following drugs and chemical names of compound I H H NH2 N S H CH3 N N S O O S N CH3 CH3 O O N O N CH3 COOH O O COOH COOH I II III 2) Mention the chemical modifications of the encircled group of the given structure to obtain: H a) Orally active penicillin N S b) Broad spectrum penicillin CH3 O CH3 c) β-lactamase resistant penicillin O N COOH  3) Draw the chemical structure of prodrugs of amipcillin and mention the rationale for its synthesis NH2 H N S O N O COOH 4) Mention the mechanism of action of β-lactam antibiotics 5) Mention Chemical class of the following compounds O O O S OH CH3 N N CH3 O O COOH COO Na