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

Antimetabolites are a class of antineoplastic agents that act as structural analogs of essential metabolites (such as purines, pyrimidines, or folic acid). They function by interfering with the normal metabolic pathways of rapidly dividing cells, specifically by inhibiting enzymes involved in DNA and RNA synthesis. Because they mimic natural substrates, they are mistakenly incorporated into DNA or RNA, or they bind irreversibly to enzymes like dihydrofolate reductase or thymidylate synthase, leading to cell cycle arrest and apoptosis.

Common categories include:

• Antifolates: Methotrexate, which inhibits dihydrofolate reductase.
• Pyrimidine analogs: 5-Fluorouracil, which inhibits thymidylate synthase.
• Purine analogs: Mercaptopurine, which interferes with purine nucleotide biosynthesis.

The synthesis of Mercaptopurine (6-mercaptopurine) is as follows:

1. The synthesis begins with the reaction of ethyl formylchloroacetate with thiourea to form 4-amino-6-hydroxypyrimidine.
2. This intermediate undergoes nitrosation using sodium nitrite in acetic acid to produce 4-amino-5-nitroso-6-hydroxypyrimidine.
3. Reduction of the nitroso group using sodium hydrosulfite yields 4,5-diamino-6-hydroxypyrimidine.
4. Cyclization is achieved by heating with formic acid or formamide to form hypoxanthine (6-hydroxypurine).
5. Finally, the conversion of the 6-hydroxyl group to a 6-thiol group is performed by treating hypoxanthine with phosphorus pentasulfide (P₂S₅) in pyridine to yield 6-mercaptopurine.

H1-antagonists, also known as antihistamines, are drugs that competitively inhibit the action of histamine at H1-receptors. They are primarily used to treat allergic conditions such as rhinitis, urticaria, and hay fever. Structurally, they often feature a substituted ethylamine chain attached to two aromatic rings, which mimics the ethylamine side chain of histamine but prevents receptor activation. They are classified into several generations, with first-generation agents (e.g., Diphenhydramine) being lipophilic and capable of crossing the blood-brain barrier, leading to sedation, while second-generation agents are more selective and less sedating.

Synthesis of Diphenhydramine hydrochloride:

1. The synthesis begins with the reaction of benzhydrol (diphenylmethanol) with 2-dimethylaminoethyl chloride.
2. This is typically performed in the presence of an acid catalyst or by converting benzhydrol to benzhydryl chloride, followed by an etherification reaction with 2-dimethylaminoethanol.
3. The resulting tertiary amine, diphenhydramine, is then treated with hydrochloric acid to form the stable salt, Diphenhydramine hydrochloride.