Drugs Containing Pyrrole

Introduction :

Heterocyclic chemistry is a branch of organic chemistry that studies the synthesis, properties and applications of heterocycles. Heterocycles have a wide range of applications in various fields. They are involved in the structures of bio-molecules such as: DNA, RNA, vitamins,…etc. They also affect the activity and pharmacological effect of many drugs.

Structure and natural source of pyrrole :

Pyrrole is a five-membered aromatic heterocyclic ring with nitrogen as the heteroatom. Its IUPAC name is 1H-Pyrrole. C2 and C5 are termed alpha carbons while C3and C4 are termed beta carbons.

Pyrrole ring system is involved in some naturally occurring phyto-compounds such as alkaloids and in some coloured natural products as chlorophyll as well as the heme part of haemoglobin and bile pigments. It is also found in corn acting as flavouring ingredient.

Structure of pyrrole

General properties :

1- Physical properties of Pyrrole :

Pyrrole is a colourless liquid that darkens on exposure to air with agreeable empyreumatic odour that resembles that of chloroform. It freezes at about -24°C and boils at 129°C and is soluble in alcohol, ether and dilute acids.

Pyrrole is almost insoluble in water as it makes intermolecular hydrogen bonding between its own molecules.

2-Aromaticity of pyrrole :

Pyrrole is considered an aromatic heterocycle as it satisfies Huckel’s rule (4n+2) with two pi bonds in the conjugated system representing 4 electrons and one lone pair of electrons on nitrogen atom to give a total of 6 pi electrons. Pyrrole is sp2-hybridized with each carbon atom having a p orbital with one electron and the heteroatom (nitrogen) has a p orbital with two electrons. These 5 p orbitals overlap to give 5 molecular orbitals with 6π electrons (aromatic sextet). Pyrrole is considered as resonance hybrid due to delocalization of electrons in the ring.

3-Basicity of pyrrole :

Pyrrole is weakly basic with PKa value of about 4 due to delocalization of lone pair of electrons of nitrogen atom in the aromatic ring

4-Reactivity of pyrrole :

Pyrrole is more activated towards electrophilic aromatic substitution than benzene because the lone pair of electrons on nitrogen atom provides electron density to the ring by resonance which stabilizes the formed sigma complex intermediate more effectively.

Electrophilic aromatic substitution occurs at alpha position(2,5) more preferable than beta position (3,4) due to greater delocalization of positive charge in sigma complex intermediate but if the two alpha positions are occupied, substitution occurs at beta position.

Synthesis of pyrrole and substituted pyrroles :

1-paal-knorr pyrrole synthesis :

It is the most common method for pyrrole synthesis.

Condensation of 1,4-dicarbonyl compounds in the presence of excess ammonia or amines yields pyrrole or N-substituted pyrroles.

This reaction can be carried out under neutral or acidic conditions but addition of weak acid as acetic acid accelerates the reaction.

Reaction steps :

2-iron-catalyzed synthesis of N-substituted pyrroles in water :

It is considered as an application to Paal-knorr synthesis where 2,5-dimethoxytetrahydrofuran is condensed with amines and sulfonamines in the presence of ferric chloride as catalyst in aqueous medium to yield N-substituted pyrroles.

3-Synthesis of alkyl and aryl-substituted pyrroles from reaction between secondary alcohols and 2-amino alcohols :

Secondary alcohols react with 2-amino alcohols in the presence of benzophenone to yield alkyl or aryl-substituted pyrroles via oxidation of secondary alcohols to ketones then condensation with 2-amino alcohols and cyclization to the target pyrrole ring.

4-Synthesis of 2,4-diaryl substituted pyrroles :

4-nitro-1,3-diaryl butanones react with ammonium acetate in the presence of morpholine and sulfur to yield 2,4-diaryl substituted pyrroles in the absence of solvent.

5-Synthesis of N-acyl substituted pyrroles :

Condensation of carboxylic acid with 2,4,4-trimethoxybutan-1-amine then acid-catalyzed cyclization of the product yields N-acyl substituted pyrroles.

Pyrrole-containing drugs :

Pyrrole moiety is involved in the structure of many classes of drugs as well as natural active constituents such as: alkaloids. Pyrrole compounds are used as lead compounds for the synthesis of many derivatives. Pyrrole has numerous applications in therapeutically-active compounds including: fungicides, antibiotics, anti-inflammatory drugs, anti-cancer drugs, cholesterol and lipid –lowering drugs, anti-psychotic drugs and many more.

5 examples of pyrrole-containing drugs are: atorvastatin, tolmetin, ketorolac, sunitinib and lorpiprazole.

1-Atorvastatin (Lipitor®) :

Atorvastatin is a lipid-lowering drug which belongs to a class of drugs called statins which act on the liver as their site of action. Statins are drugs used for treatment of hypercholesterolemia by reducing the LDL (low-density lipoprotein) or bad cholesterol level in blood thus decreasing the risk of cardiovascular diseases such as: stroke, heart attack, hypertension, angina and atherosclerosis.

Structure of atorvastatin

Uses of atorvastatin :

Atorvastatin is intended for use in:

1-treatment of several types of dyslipidemias which represent an increased risk for development of atherosclerosis.

2-prevention of myocardial infarction, heart attack, fatal and non-fatal stroke, revascularization and angina and hospitalization for congestive heart failure and angina in patients with coronary heart disease.

3-lowering the risk of stroke, heart attack, or other heart complications in people with type 2 diabetes.

Synthesis of atorvastatin :

Several schemes for atorvastatin synthesis have been proposed. In the following scheme the starting material is ethyl 2-bromo-2-(4-fluorophenyl)acetate which was converted through a series of reactions including: condensation, acylation, hydrolysis, cyclization, transesterification into the desired RR-(+)-enantiomer of atorvastatin.

Chirality of atorvastatin :

Atorvastatin has two chiral centres. It exists in four active optical forms (RR-RS-SR-SS) which differ in their efficacy and cytotoxicity, but it is used as an enantiopure drug (only one single enantiomer). The activity of different enantiomers of atorvastatin varies in the order (RR>RS = SR>SS). The most used enantiomer of atorvastatin is the RR enantiomer. In short, atorvastatin is stereospecific in its action on the human hepatocytes with its different enantiomers.

Side effects of atorvastatin :

1. Gastro-intestinal symptoms such as diarrhoea.
2. Cold symptoms such as runny nose.
3. Insomnia.
4. heartburn.
5. Indigestion problems.
6. Anorexia.
7. Limb pain.
8. Muscle spasm.

Other pyrrole-containing drugs :

Side effects Uses Chemical structure Drug name

Some common side effects include :

1. Indigesion.
2. Headache.
3. Dizziness.
4. Weakness and changes in weight. It is a NSAID drug used for treatment of signs and symptoms of rheumatoid arthritis and osteoarthritis.

1-Tolmetin

Ketorolac overdose may cause :

1. Abdominal pain.
2. Dyspepsia.
3. Nausea.
4. Headache.
5. Lethargy.
6. Epigastric pain. 
7. Gastrointestinal bleeding.
8. Drowsiness. 

It is a NSAID drug used for treatment of post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

2-Ketorolac

1. Some common side effects include :
2. Oral candidiasis.
3. Asthenia.
4. Ventricular ejection fraction.
5. Hypokalemia.
6. diarrhoea.
7. neutropenia.
8. vomiting.
9. Hypertension. It is a receptor tyrosine kinase

(RTK) inhibitor used for treatment of advanced tumours of the stomach, intestines, pancreas or kidneys.

3-Sunitinib

Side effects are minor but some rare side effects were reported as: cardiotoxicity, imbalance between sympathetic and parasympathetic nervous systems as well as potential hepatoxicity. It is a pyrrole derivative functions as serotonin antagonist and re-uptake inhibitor used as anti-psychotic and anxiolytic drug.

References :

1. Lectures taken in the course.
2. Drug Bank.
3. Drugs.com.
4. Pubchem.
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6. J.-A. Shin, J. Kim, H. Lee, S. Ha, H.-Y. Lee, J. Org. Chem., 2019, 84, 4558-4565 ‘General Transition Metal-Free Synthesis of NH-Pyrroles from Secondary Alcohols and 2-Aminoalcohols’.
7. M. Adib, N. Ayashi, F. Heidari, P. Mirzaei, Synlett, 2016, 27, 1738-1742 ‘Reaction between 4-Nitro-1,3-diarylbutan-1-ones and Ammonium Acetate in the Presence of Morpholine and Sulfur: An Efficient Synthesis of 2,4-Diarylpyrroles’.
8. T. Maehara, R. Kanno, S. Yokoshima, T. Fukuyama, Org. Lett., 2012, 14, 1946-1948 ‘A Practical Preparation of Highly Versatile N-Acylpyrroles from 2,4,4-Trimethoxybutan-1-amine’.
9. R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006 ‘Chapter 20: Hypolipidemic and Antihyperlipidemic drugs’.
10.  M. Stepankova, A. D. Vavrova, Z. Dvorak, 2015 ‘Optical Isomers of Atorvastatin, Rosuvastatin and Fluvastatin Enantiospecifically Activate Pregnane X Receptor PXR and Induce CYP2A6, CYP2B6 and CYP3A4 in Human Hepatocytes’.