4- chloramphenicol.pptx

chloramphenicol  Chloramphenicol Overview: Chloramphenicol is a broad-spectrum antibiotic derived from the bacterium Streptomyces venezuelae It exhibits activity against both aerobic and anaerobic Gram-positive and Gram-negative bacteria Mechanism of Action: Chlo...

chloramphenicol  Chloramphenicol Overview: Chloramphenicol is a broad-spectrum antibiotic derived from the bacterium Streptomyces venezuelae It exhibits activity against both aerobic and anaerobic Gram-positive and Gram-negative bacteria Mechanism of Action: Chloramphenicol binds reversibly to the 50S ribosomal subunit of bacteria, inhibiting protein synthesis  It contains a nitrobenzene moiety and is a derivative of dichloroacetic acid Since it has two chiral centers, four isomers are possible Stereochemistry of chloramphenicol: Chiral Centers: Chloramphenicol contains two chiral centers (asymmetric carbons) in its structure These chiral centers result from the presence of hydroxyl groups on the carbon atoms adjacent to the dichloroacetyl group Stereoisomers: Due to the chiral centers, chloramphenicol exists as four stereoisomers:  Threo-Chloramphenicol: Both hydroxyl groups are on the same side (cis configuration) Erythro-Chloramphenicol: Hydroxyl groups are on opposite sides (trans configuration). Each of these can further exist as R or S enantiomers Biological Activity: The threo form (specifically the R-threo enantiomer) is the active form responsible for antibacterial activity. The erythro form is inactive  It is synthesized chemically by modifying the nitrobenzene ring of the antibiotic A. Starting Material: The synthesis begins with p-nitroacetophenone B. Key Steps: Step 1: Synthesize -2-nitro-1-benzylcarbinol using benzaldehyde and nitromethane in the presence of a chiral catalyst Step 2: React the intermediate with formaldehyde to obtain (1R,2R)-2-nitro-1-benzyl-1,3-propanediol Step 3: Perform hydrogenation reduction to obtain (1R,2R)-2- amino-1-benzyl-1,3-propanediol Step 4: Nitrate and dichloroacetylate the intermediate at low temperature to yield chloramphenicol  Structure-Activity Relationship (SAR): 1. p-Nitrophenyl Ring: The presence of the p-nitrophenyl ring is essential for activity. Substituting it with other structures affects potency 2. Position of Nitro Group: The nitro group must be in the para position. Ortho or meta substitutions reduce activity 3. Dichloroacetyl Group: This group is critical for binding. Replacing it with dibromoacetyl reduces activity 4. Hydroxyl Groups: The two hydroxyl groups are important. Converting them to ketones decreases activity