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

Quantitative Structure-Activity Relationship (QSAR) models utilize physicochemical parameters to correlate chemical structure with biological activity. These three analyses are foundational:

Hammett Analysis: Focuses on the electronic effects of substituents on aromatic rings. It uses the substituent constant (σ), which measures the electron-withdrawing or electron-donating ability of a group relative to hydrogen. The relationship is expressed as log(K/K₀) = ρσ, where ρ is the reaction constant indicating sensitivity to electronic changes.

Taft Analysis: Extends electronic analysis to aliphatic systems and accounts for steric effects. It introduces the steric substituent constant (Es), which quantifies the bulkiness of a group, and the polar substituent constant (σ*), which accounts for electronic effects in non-aromatic compounds.

Hansch Analysis: Integrates multiple parameters into a single linear regression model to predict biological activity. It combines hydrophobic (π), electronic (σ), and steric (Es) parameters. The general equation is: log(1/C) = k1π + k2σ + k3Es + k4, where C is the molar concentration required for a specific biological response.

Antisense molecules are short, synthetic oligonucleotides designed to bind specifically to a target messenger RNA (mRNA) through complementary base pairing. By forming a DNA-RNA or RNA-RNA duplex, they prevent the translation of the target mRNA into a disease-causing protein.

Key mechanisms of action include:

• RNase H recruitment: Many antisense oligonucleotides (ASOs) recruit the enzyme RNase H, which cleaves the RNA strand of the DNA-RNA hybrid, leading to the degradation of the target mRNA.
• Steric blocking: Some molecules bind to the mRNA to physically block the ribosome or splicing machinery, preventing protein synthesis or altering pre-mRNA splicing.

To enhance stability against nucleases and improve cellular uptake, these molecules are often chemically modified, such as using phosphorothioate linkages or 2'-O-methyl modifications. They offer a highly specific therapeutic approach for treating genetic disorders, viral infections, and cancers by targeting the genetic code directly rather than the resulting protein product.