JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B.Pharmacy III MEDICINAL CHEMISTRY-I Previous Question Paper (October/November-2020 - R17)

Phase I metabolism involves the chemical modification of a drug molecule to introduce or expose a functional group, making the compound more polar and facilitating its excretion or preparing it for Phase II conjugation. These reactions are primarily carried out by the cytochrome P450 (CYP450) monooxygenase system located in the endoplasmic reticulum of liver cells.

The major Phase I transformation reactions include:

• Oxidation: This is the most common reaction. It involves the addition of oxygen or removal of hydrogen. Examples include aromatic hydroxylation (e.g., phenytoin to p-hydroxyphenytoin), aliphatic hydroxylation (e.g., ibuprofen), and N-dealkylation (e.g., conversion of codeine to morphine).
• Reduction: These reactions occur less frequently than oxidation and typically involve the reduction of functional groups like nitro, azo, or carbonyl groups. For example, the reduction of chloramphenicol's nitro group to an amine or the reduction of warfarin to its corresponding alcohol.
• Hydrolysis: This involves the cleavage of chemical bonds by the addition of water, typically affecting esters and amides. Enzymes responsible include esterases and amidases. An example is the hydrolysis of aspirin (acetylsalicylic acid) into salicylic acid and acetic acid, or the hydrolysis of procaine.

Phase I reactions generally result in metabolites that are slightly more water-soluble than the parent drug. If the metabolite is sufficiently polar, it may be excreted directly; otherwise, it undergoes Phase II conjugation reactions to become highly water-soluble and easily eliminated from the body.

Bioisosterism refers to chemical groups or molecules with similar physical or chemical properties that produce broadly similar biological effects in a living organism. These groups, known as bioisosteres, are used in drug design to optimize the pharmacokinetic or pharmacodynamic properties of a lead compound without significantly altering its biological activity.

Bioisosteres are classified into two main types:

• Classical Bioisosteres: These possess similar electronic and steric characteristics. Examples include monovalent atoms or groups like -H, -F, -Cl, -OH, -NH2, and -CH3. Another example is the replacement of a divalent oxygen atom with a sulfur atom, such as in the conversion of ethers to thioethers.
• Non-classical Bioisosteres: These do not follow the strict electronic or steric rules of classical isosteres but still produce similar biological responses. They often involve functional group replacements that mimic the spatial arrangement or electronic distribution of the original group. Examples include the replacement of a carboxylic acid group (-COOH) with a tetrazole ring, which maintains acidity and hydrogen-bonding capability while improving metabolic stability.

Geometrical isomerism, or cis-trans isomerism, is a form of stereoisomerism resulting from the restricted rotation around a double bond or a cyclic structure. Because rotation is restricted, substituents attached to the carbons of the double bond are locked in specific spatial orientations relative to each other.

The two configurations are defined as:

• Cis-isomer: The identical or high-priority groups are on the same side of the double bond.
• Trans-isomer: The identical or high-priority groups are on opposite sides of the double bond.

A classic pharmacological example is Diethylstilbestrol, a synthetic estrogen. The trans-isomer is highly potent as an estrogen receptor agonist because its spatial configuration allows it to fit into the receptor binding site, whereas the cis-isomer is significantly less active. Another example is Fumaric acid (trans) and Maleic acid (cis), which exhibit different physical properties such as melting points and solubility due to their distinct spatial arrangements.