Medicinal Chemistry · Short notes

Prodrugs and Bioisosterism: Short Notes & Cheat Sheet

Why prodrugs are made, carrier-linked and bioprecursor prodrugs, mutual prodrugs, soft drugs, and classical and non-classical bioisosteres.

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Short notes

Read these before you attempt the topic's MCQs.

Why chemists make prodrugs

Every prodrug fixes a problem with the parent drug. In MCQs, identify the problem it solves.

Prodrugs

A prodrug is an inactive (or much less active) compound converted to the active drug in the body.
Better absorption: enalapril, oseltamivir and pivampicillin are esters; valacyclovir (the L-valyl ester of acyclovir) gives about 3–5 times higher bioavailability.
Site-specific delivery: levodopa crosses the blood–brain barrier as an amino acid; sulfasalazine releases 5-ASA in the colon; capecitabine is converted to 5-FU mainly in tumour tissue.
Longer action: depot esters such as fluphenazine decanoate and testosterone enanthate.
Better taste or solubility: chloramphenicol palmitate (tasteless suspension); fosphenytoin and hydrocortisone sodium succinate (water-soluble injections).
Less GI irritation: sulindac is a sulfoxide prodrug reduced to the active sulfide after absorption.

Types of prodrug

Carrier-linked prodrugs join the drug to a carrier group, usually by an ester or amide, which is removed by enzymes.
Bioprecursors contain no carrier; the molecule itself is changed metabolically (e.g. omeprazole activated by acid, cyclophosphamide and clopidogrel activated by CYP enzymes).
Mutual prodrugs join two active drugs: sulfasalazine (5-ASA + sulfapyridine), sultamicillin (ampicillin + sulbactam), benorilate (aspirin + paracetamol).
Soft drugs are the opposite of prodrugs: active drugs designed to be inactivated quickly and predictably (esmolol and remifentanil by esterases).

Bioisosterism

Bioisosteres are groups with similar size, shape and electronic properties that can replace each other while keeping (or improving) activity.
Classical bioisosteres share valency: –F for –H; –O–, –S–, –NH– and –CH₂– for each other; –N= for –CH= in rings; benzene, thiophene and pyridine rings.
Non-classical bioisosteres differ in atom count: a tetrazole for a carboxylic acid (losartan), a sulfonamide for a carboxylic acid.
Classic examples: 5-fluorouracil (F in place of H blocks thymidylate synthase), 6-mercaptopurine (SH in place of OH of hypoxanthine), and procainamide (amide in place of procaine's ester, so it resists hydrolysis and lasts longer).
In cimetidine's development a cyanoguanidine replaced metiamide's thiourea, removing the agranulocytosis risk.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Prodrug → active form

Prodrug	Active drug · reason
Enalapril	Enalaprilat · oral absorption
Valacyclovir	Acyclovir · bioavailability
Levodopa	Dopamine · crosses BBB
Sulfasalazine	5-ASA · colon targeting
Capecitabine	5-FU · tumour targeting
Fosphenytoin	Phenytoin · IV solubility
Chloramphenicol palmitate	Chloramphenicol · taste
Codeine	Morphine · (CYP2D6)
Clopidogrel	Active thiol · (CYP2C19)

Bioisostere swaps

Original → replacement	Example
H → F	5-Fluorouracil
OH → SH	6-Mercaptopurine
OH → NH₂	Aminopterin (from folic acid)
Ester → amide	Procaine → procainamide
COOH → tetrazole	Losartan
Thiourea → cyanoguanidine	Metiamide → cimetidine

Memory aids

Soft drugs are 'Soon' gone: Soft drugs are made to be broken down quickly (esmolol, remifentanil); prodrugs are made to be switched on.

Exam traps

Soft drugs are active drugs designed for rapid inactivation; they are not prodrugs.
Omeprazole is a bioprecursor prodrug activated by acid, not by an esterase.
Procainamide lasts longer than procaine because amides resist hydrolysis better than esters.
In sulfasalazine the sulfapyridine part mainly causes side effects; 5-ASA is the active part in the colon.

Revised? Now test yourself.

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