JNTU B.Pharmacy III Year MEDICINAL CHEMISTRY-III Previous Question Paper (August - 2022 - R17)

Aminoglycoside antibiotics are a class of potent bactericidal agents characterized by amino sugars linked to an aminocyclitol ring via glycosidic bonds. They are highly polar, polycationic compounds that are not absorbed orally and are typically administered parenterally.

Key features include:

• Mechanism of Action: They bind irreversibly to the 30S ribosomal subunit of bacteria, causing misreading of the genetic code and inhibition of protein synthesis.
• Spectrum: They are primarily effective against aerobic Gram-negative bacilli, such as Pseudomonas aeruginosa, and are often used in combination with beta-lactams for synergistic effects.
• Pharmacokinetics: Due to their high polarity, they exhibit poor lipid solubility, meaning they do not cross the blood-brain barrier or enter cells easily. They are excreted unchanged by glomerular filtration in the kidneys.
• Toxicity: The major clinical limitations are nephrotoxicity and ototoxicity (both auditory and vestibular), which are dose-dependent.
• Examples: Streptomycin, Gentamicin, Amikacin, and Tobramycin.

Nomenclature: Beta-lactam antibiotics are named based on the presence of a four-membered cyclic amide (beta-lactam) ring. Penicillins are derived from 6-aminopenicillanic acid (6-APA), consisting of a thiazolidine ring fused to a beta-lactam ring. Cephalosporins are derived from 7-aminocephalosporanic acid (7-ACA), featuring a six-membered dihydrothiazine ring fused to the beta-lactam ring.

Stereochemistry: The stereochemistry is critical for biological activity. In penicillins, the fusion of the thiazolidine and beta-lactam rings creates a strained bicyclic system. The absolute configuration at the chiral centers C-3, C-5, and C-6 must be (3S, 5R, 6R) for the molecule to be active. The beta-lactam ring must be in a specific conformation to be recognized by the bacterial transpeptidase enzymes.

Chemical Degradation: The beta-lactam ring is highly susceptible to chemical and enzymatic degradation:

• Acid-catalyzed hydrolysis: In acidic conditions, the strained ring undergoes nucleophilic attack, leading to the formation of penillic acid and penilloic acid, which are inactive.
• Base-catalyzed hydrolysis: Hydroxide ions attack the carbonyl carbon of the beta-lactam ring, resulting in the opening of the ring to form penicilloic acid.
• Enzymatic degradation: Bacterial enzymes known as beta-lactamases (penicillinases) catalyze the hydrolytic cleavage of the C-N bond of the beta-lactam ring, rendering the antibiotic ineffective.