JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD Pharm. D III Year MEDICINAL CHEMISTRY Previous Question Paper (July/August - 2021 - R08)

Lipophilicity is a critical physicochemical property in QSAR, typically quantified by the partition coefficient (log P) or the substituent constant (π). It determines a drug's ability to cross biological membranes via passive diffusion. The relationship between lipophilicity and biological activity is often parabolic, represented by the Hansch equation, where activity increases with lipophilicity up to an optimal value before declining due to poor aqueous solubility or sequestration in lipid tissues.

Electronic parameters describe the influence of substituents on the electron density of a molecule, which affects its binding affinity and chemical reactivity. The most common parameter is the Hammett constant (σ), which measures the electronic effect of a substituent on the ionization of benzoic acid. Other parameters include the Swain-Scott constant and field effects. These parameters help in understanding how electron-withdrawing or electron-donating groups influence the interaction between the drug and its target receptor or enzyme active site.

Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that undergo biotransformation in vivo to release the active drug. They are designed to improve solubility, stability, absorption, site-specificity, or to minimize toxicity.

Types of prodrugs include:

• Carrier-linked prodrugs: The active drug is covalently attached to a promoiety that is cleaved enzymatically or chemically. Example: Ampicillin is converted to Bacampicillin to improve oral bioavailability.
• Bioprecursors: These are inactive molecules that require metabolic activation (e.g., oxidation or reduction) to become active. Example: Sulindac, a non-steroidal anti-inflammatory drug, is reduced to its active sulfide metabolite.
• Site-specific prodrugs: Designed to release the active drug at a target site, such as Sulfasalazine, which is cleaved by colonic bacteria to release 5-aminosalicylic acid for treating inflammatory bowel disease.