INTRODUCTION Penicillin is a group of antibiotics that are used in the treatment of various bacterial infections. Penicillin is derived from the Penicillium mould.
• It can be used to treat ailments such as strep throat, spinal meningitis, gangrene, and syphilis.• It destroys bacteria by inhibiting the enzymes responsible for the formation of the cell wall in the bacterial cells.
HISTORY Penicillin, the worlds first antibiotic, was discovered by British scientist Alexander Fleming in 1928 on accident.
Fleming accidentally left a dish of staphylococcus bacteria uncovered for a few days. He returned to find the dish dotted with bacterial growth, apart from one area where a patch of mold (Penicillin notatum) was growing.
The mold produced a substance, named penicillin by Fleming. Penicillin was finally isolated by Howard Florey and Ernst Chain. Fleming, Florey and Chain received a Nobel prize in 1945.
Structure Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by three fundamental structural requirements:
the fused beta-lactam structurea free carboxyl acid groupone or more substituted amino acid side chainsThe Beta-lactam structure can also be viewed as the covalent bonding of pieces of two amino acids - cysteine and valine
Mechanism of action Penicillins enter the bacteria via the cell wall. Inside the cell, they bind to penicillin- binding protein. Once bound, normal cell wall synthesis is disrupted. Result: bacteria cells die from cell lysis. Penicillins do not kill other cells in the body.
The compound consists of 2 basic structures:1. Thiazolidine Ring2. Beta-Lactam Ring H R H N S CH3 2 1 O N CH3 O COOH
- site of attachment of side chain, R,which determines many of theantibacterial and pharmacologiccharacteristics of a derivative(Spectrum and penicillin-resistance)
Derivatives of benzylpenicillin, from which the methyl benzene radical is split off by amidase producing6-aminopenicillanic acid, the parent compound of All semisynthetic penicillins.
Thiazolidine ring (A) connected to a b-lactam ring(B), to which is attached a side chain (R).
The penicillin nucleus itself is the chief structural requirement for biological activity; metabolic transformation or chemical alteration of this portion of the molecule causes loss of all significant antibacterial activity
SAR of Penicillins O H H S N H N O H COOH The presence of a carboxy group is a requirement for PBP recognition. When esterition of it, it behaves a pro-drug The bioavailability will be raisen.
O H H S N H N O H COOH Three chiral centers arerequirement for Penicillins bioactivity
Side chain can be replaced with different R group to obtain different compounds With broad antibacterial spectrum O H H S N H N O H COOH
Structural Activity Relationship Position 1 – When the H 1 sulfur atom of R N H 5 S 2 CH3 6 the thiazolidine ring is B A CH3 O 3 N oxidized to a sulfone or 7 4 O COOH sulfoxide, it improves acid stability, but decreases the activity of the agent.
Position 2 – No substitutions allow at this position, any change will lower activity. The methyl groups are necessary H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
Position 3 – The carboxylic acid of the thiazolidine is required for activity. If it is changed to an alcohol or ester, activity is decreased. H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
Position 4 – The nitrogen is a must. Position 5 – No substitutions allowed. H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
Position 7 – The carbonyl on the Beta- lactam ring is a must. H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
• Postion 6 – Substitutions are allowed on the side chain of the amide. An electron withdrawing group added at this position will give the compound better acid stability because this substitution will make the amide oxygen less nucleophillic.• H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
A bulky group added close to the ring will make the compound more resistant to Beta-lactamases. Steric hinderence provides protect to the Beta-lactam ring. H 1 H S CH3 R N 6 5 2 A CH3 B O 3 N 7 4 O COOH
ADVERSE EFFECTS diarrhea that is watery or bloody; fever, chills, body aches, flu symptoms; easy bruising or bleeding, unusual weakness; urinating less than usual or not at all;
severe skin rash, itching, or peeling; agitation, confusion, unusual thoughts or behavior; seizure (black-out or convulsions). nausea, vomiting, stomach pain;
vaginal itching or discharge; headache; swollen, black, or "hairy" tongue; or thrush (white patches or inside your mouth or throat).