Macrolides

The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. These are produced by streptomyces species and the products of actinomycetes. Active against most species of gram. The antibacterial spectrum of activity of the more potent macrolides resembles that of penicillin. It binds selectively to a specific site on the 50S ribosomal subunit to prevent the translocation of bacterial protein synthesis.

SAR of Macrolides
As macrolides are unstable in acidic pH, a no. of strategies have been utilized to improve the acidic stability of erythromycin.
The addition of hydroxylamine to the ketone to form oxime. Alteration of c-6 hydroxyl group: nucleophilic functionality which initiates erythromycin degradation. Addition of nitrogen atom to expand a 14membered precursor leads to an extended spectrum of action. Eg (Azithromycin)

 Slightly wider spectrum than penicillin, and is often used for people who have an allergy to penicillins. Mostly used for respiratory tract infections. Isolated from Streptomyces erythreus. Mostly in enteric coated dosage forms.

Erythromycin
6-[4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12, 13-trihydroxy-4-(5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl)oxy3,5,7,9, 11,13-hexamethyl-oxacyclotetradecane-2,10-dione

 Semisynthetic derivative of erythromycin obtained by methylation at c-6 position. Cannot undergo cyclic ketal formation, so it doesnt cause cramps in GI. used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia and etc. Does not experience acid instability which Clarithromycin causes side effects.
6-(4-dimethylamino-3-hydroxy- 6-methyl-tetrahydropyran-2-yl) oxy-14ethyl-12,13-dihydroxy- 4-(5-hydroxy-4-methoxy-4,6- dimethyltetrahydropyran-2-yl) oxy-7-methoxy-3,5,7,9,11, 13-hexamethyl-1oxacyclotetradecane-2,10-dione

 Derived from Amycolatopsis rifamycinica. Inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNAdependent RNA polymerase. Most serious adverse effect is hepatotoxicity. Orally administered
Rifampicin
2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22heptamethyl-26-[(E)-N-(4-methylpiperazin-1-yl)carboximidoyl]-6,23dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.1^{4,7}.0^{5,28}]triaconta1,3,5(28),9,19,21,25(29),26-octaen-13-yl acetate

Penicillins
Penicillin is a group of antibiotics derived from Penicillium fungi. Discovered by Sir Alexander Fleming in 1929. It consists of lactam ring fused with thiazolidine ring. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant.

R: Introduction of aryloxy group side chain is Acylamino increases the acid stability & oral essential absorption of penicillin.

STRUCTURE ACTIVITY RELATIONSHIP

Variation in the molecule is restricted to the acylamino sidechain

Note: The greater the Substitution of the strain, the greater an alpha carbon by the -lactam ring is activity, but the greater amino, guanidine and essential the instability of it the chloro makes molecule to other resistant against acid. Bicyclic system is factors. important

AminoAcid Essential Free group confers more activity to pass through cell wall barriers.

Penicillins
Aromatic ring attach to the carbonyl group and has some substitution on the aryl ring at the position ortho to the point of attachment Resistance to hydrolysis and degradation. (Cloxacillin) Size of Ring + Ortho Substituent = Penicillinase Resistance (Methicillin)

 Synonym: Benzylpenicillin The most popular penicillin and the gold standard type. The G refers to gold standard. Typically given by the parenteral route of administration because it is unstable with HCl. Noted to possess effectiveness mainly against gram-positive organisms.

Penicillin G
3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia1-azabicyclo[3.2.0]heptane-2-carboxylic acid

 Synonym: Phenoxymethypenicillin Resistant to hydrolysis and has uniform concentration in blood. Can be given orally. Acts by inhibiting the biosynthesis of cell-wall peptidoglycan. Less active against Gram-negative bacteria. Treatment of mild to moderate infections.

Penicillin V
3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

 Synonym: Procaine benzylpenicillin Through intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin. Widely used in veterinary settings.

Pen G Procaine
2-diethylaminoethyl 4-aminobenzoate; (2S,5R,6R)3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

 The drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate. Stable in Gastric pH

Pen G Benzathine
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylethanoylamino)-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylate; phenylmethyl-[2(phenylmethylazaniumyl)ethyl]azanium

Aminopenicillins
Bactericidal beta-lactam antibiotics, which work by inhibiting bacterial cell wall synthesis. They have broader spectrum of activity than penicillins. They are not deactivated by acid hydrolysis. Aminopenicillins are effective against most gram-positive bacterial infections and gram-negative infections such as E.coli and H.influenza. They are used to treat upper and lower respiratory tract infections, endocarditis urinary tract infections, skin infections, and so on.

 A beta-lactam antibiotic and an equivalent to its successor, amoxicillin in terms of spectrum and level of activity. Alpha amino group plays an important role by allowing the molecule to cross cell wall barriers that are impenetrable to other penicillins. Produces allergic reactions

Ampicillin
(2S,5R,6R)-6-[(2R)-2-amino-2-phenylacetamido]3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid

 Hydroxy analog of ampicillin. Better GI absorption. Often combined with clavulanic acid, a beta lactamase inhibitor. Most common antibiotics prescribed for children.

Amoxicillin
(2S,5R,6R)-6-[(2R)-2-amino-2-(4hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Penicillinase Resistant Penicillins

Penicillinase resistant penicillins are antibiotics which are not inactivated by the penicillinase enzyme. Some bacteria produce the enzyme penicillinase that destroys the beta-lactam ring of the antibiotic, making the penicillin ineffective. Penicillinase resistant penicillins are used to treat resistant strains of staphylococci and other infections.

 No longer used to treat patients. Compared to other beta-lactamase-resistant penicillins, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis. Serves a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus.

Meticillin
(2S,5R,6R)-6-[(2,6-dimethoxybenzene)amido]-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid

Nafcillin
(2S,5R,6R)-6-(2-ethoxynaphthalene-1-amido)-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid

Cloxacillin
(2S,5R,6R)-6-[3-(2-chlorophenyl)-5-methyl-1,2oxazole-4-amido]-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid

Oxacillin
(2S,5R,6R)-3,3-dimethyl-6-(5-methyl-3-phenyl-1,2oxazole-4-amido)-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid

Extended-Spectrum Penicillin
Extended-spectrum penicillin is a group of antibiotics that has the widest antibacterial spectrum of all penicillins. It is also called antipseudomonal penicillins.

Carbenicillin
(2S,5R,6R)-6-(2-carboxy-2-phenylacetamido)-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid

Piperacillin
(2S,5R,6R)-6-[(2R)-2-{[(4-ethyl-2,3-dioxopiperazin1-yl)carbonyl]amino}-2-phenylacetamido]-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid

Sulfonamide
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group.

Sulfacetamide
N-[(4-aminobenzene)sulfonyl]acetamide

Sulfamethoxazole
4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzene-1sulfonamide

Co-trimoxazole
5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4diamine

Tetracyclines
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides (sometimes called sulfa drugs or sulpha drugs) are synthetic antimicrobial agents that contain the sulfonamide group.

Tetracycline
(4S,4aS,5aS,6S,12aS)-4-(dimethylamino)3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo1,4,4a,5,5a,6,11,12a-octahydrotetracene-2carboxamide

Minocycline
(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)3,10,12,12a-tetrahydroxy-1,11-dioxo1,4,4a,5,5a,6,11,12a-octahydrotetracene-2carboxamide

Doxycycline
(4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo1,4,4a,5,5a,6,11,12a-octahydrotetracene-2carboxamide

Oxytetracycline
(4S,4aR,5S,5aR,6S,12aS)-4-(dimethylamino)3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo1,4,4a,5,5a,6,11,12a-octahydrotetracene-2carboxamide

Quinolones
The quinolones are a family of synthetic broadspectrum antibacterial drugs. Quinolones, in comparison to other antibiotic classes, have among the highest risk of causing colonization with MRSA and Clostridium difficile.

Ciprofloxacin
1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4dihydroquinoline-3-carboxylic acid

Nalidixic Acid
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8naphthyridine-3-carboxylic acid

Ofloxacin
7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10oxo-4-oxa-1-azatricyclo[7.3.1.0^{5,13}]trideca5(13),6,8,11-tetraene-11-carboxylic acid