Fundamentals of Bioorganic Chemistry (Study Guide) - H. O. Syrova - 2018

Topic

Topic

Biologically Important Heterofunctional Compounds

Relevance of the topic. Heterofunctional compounds serve as the basis for Major Groups of drugs and physiologically active substances, including non-narcotic analgesics, local anesthetics, antimicrobial and antiparasitic agents, and medications for Tuberculosis Treatment.

General objective: to reinforce knowledge regarding the Structure and Chemical properties of key heterofunctional compounds of medicinal importance.

Specific objectives: to analyze the relationship between biological and pharmacological activity, electronic structure, and functional composition.

Theoretical Questions

Amino alcohols and their derivatives as Pharmaceuticals.

Derivatives of p-aminobenzoic and sulfanilic acids.

Natural and artificial flavors.

Heterofunctional compounds are hydrocarbon derivatives that contain two or more different functional groups:

A - R - B

A and B are different functional groups.

The most important classes of heterofunctional compounds include amino alcohols, aminophenols, aminosulfonic acids, hydroxy acids, oxo acids, and Amino Acids.

Amino alcohols simultaneously contain an alcoholic hydroxyl group and an amino group in their molecular structure, thus acting as both alcohols and amines.

The most prominent amino alcohols are colamine (2-aminoethanol) and Choline ((2-hydroxyethyl)trimethylammonium hydroxide), which are of primary metabolic significance. They are Key Components of Phospholipids and serve as structural fragments for certain catecholamines and numerous pharmaceutical drugs.

Colamine is synthesized in living organisms through the decarboxylation of The amino acid Serine, which contains three distinct functional groups (carboxyl, amino, and hydroxyl).

Upon methylation in the body, colamine forms choline, which is oxidized by the enzyme oxidase to produce the zwitterion betaine, serving as a methyl group donor in the methylation of various metabolic products:

In the body, betaine acts as a methyl group donor during the methylation of numerous metabolic products. Choline is acetylated with the assistance of acetyl-CoA to form acetylcholine, which is an ester of the amino alcohol choline and acetic acid:

Acetylcholine is one of the most vital Neurotransmitters (the primary neurotransmitter of the parasympathetic Nervous system). It interacts with cholinergic receptors and activates them, leading to Muscle contraction and enabling various bodily movements. Acetylcholine itself is hydrolyzed by the enzyme acetylcholinesterase. Introducing compounds that block acetylcholinesterase leads to the accumulation of substantial amounts of acetylcholine, causing severe excitation of The Nervous System, continuous muscle contractions, and ultimately death. This mechanism underlies the Toxic effects of chemical warfare agents (such as sarin and tabun) and insecticides (such as dichlorvos). They interact with serine amino acid residues within acetylcholinesterase, thereby blocking its activity.

Medical practice utilizes several choline derivatives: acetylcholine chloride (decreases Heart rate, dilates peripheral Blood Vessels, lowers blood pressure); carbachol (an ester of carbamic acid and choline), which is not hydrolyzed by acetylcholinesterase and therefore has a more prolonged effect than acetylcholine; and suxamethonium chloride / dithilin (an ester of choline iodide and succinic acid), used for muscle relaxation during short-term surgical and orthopedic Procedures.

The colamine residue is a structural component of essential catecholamines such as norepinephrine and epinephrine. In the body, catecholamines are synthesized from the essential amino acid phenylalanine:

Epinephrine is a hormone produced by The adrenal medulla. In stressful situations, significant amounts are released into the bloodstream, triggering feelings of anxiety and fear, which is why it is commonly known as the "fear hormone." Epinephrine affects heart function, constricts blood vessels, and raises blood pressure. Epinephrine hydrochloride is widely used in medical practice. Norepinephrine serves as the primary neurotransmitter of the sympathetic nervous system.

The molecules of norepinephrine and epinephrine contain an asymmetric carbon atom; consequently, both compounds exist as two stereoisomers: one is physiologically active, while the other is inactive (unable to interact with cellular receptors due to the spatial incompatibility of its atomic groups).

In terms of structure and physiological action, the medications ephedrine and mezaton are similar to adrenaline:

The colamine residue is part of The structure of diphenhydramine, an antihistamine with a hypnotic effect:

Heterofunctional compounds containing both an acid and an amino group include p-aminobenzoic acid (PABA) and sulfanilic acid:

PABA is a vital metabolite and a building block of Folic acid, which is abundant in spinach leaves, carrots, and other plants. It is not synthesized by The Human Body and must be obtained from food. The name "folic" comes from the Latin word folium, meaning leaf.

A pteridine ring linked to PABA residues is known as pteroic acid.

The most important derivatives of PABA include anesthesine, tetracaine (dicaine), and novocaine. These are PABA esters widely used in anesthetic practice. Novocaine also exhibits moderate antiarrhythmic activity.

Novocaine is used as a salt: the hydrochloride of the β-diethylaminoethyl ester of p-aminobenzoic acid.

Procainamide is an active antiarrhythmic agent with local anesthetic properties:

Procainamide is also administered as a salt: the hydrochloride of the β-diethylaminoethylamide of p-aminobenzoic acid.

o-Aminobenzoic (anthranilic) acid serves as the structural basis for the anti-inflammatory drug mefenamic acid:

Mefenamic acid also shares structural similarities with salicylic acid, exhibiting comparable pharmacological effects—namely, anti-inflammatory, analgesic, and antipyretic properties.

Most modern nonsteroidal anti-inflammatory drugs (NSAIDs) contain a carboxyl group in their structure, which Functions here as the anti-inflammatory pharmacophore.

Sulfanilic acid also belongs to amino acids, in which the sulfo group acts as the acidic center. Like carbon-based amino acids, sulfanilic acid forms zwitterions. The amide of sulfanilic acid is known in medical practice as white streptocide, which serves as the parent compound for a large group of synthetic chemotherapeutic agents—the sulfonamides, sharing the general formula:

One of the hydrogen atoms of the amino group located at position 4 can also be substituted with various radicals.

The combination of the sulfonamide drug sulfamethoxazole and the diaminopyrimidine derivative trimethoprim in co-trimoxazole (Biseptol, Bactrim) enhances its bactericidal effect (from the Greek cido, meaning to kill).

Substituting one of the hydrogen atoms attached to the amino group at carbon 4 with radicals led to The Development of enteric sulfonamide drugs (such as phthalazol, used to treat dysentery, enterocolitis, and colitis).

There are also combination medications whose chemical structures are azo compounds of sulfapyridine (sulfasalazine) and sulfapyridazine.

Combinations of sulfadimethoxine (salazopyridazine, salazodimethoxine) with salicylic acid exert antibacterial and anti-inflammatory effects through the gradual release of 5-aminosalicylic acid from the sulfonamide components.

If the amino group at position 4 in the sulfonamide molecule is replaced by another group, the drug loses its antimicrobial activity. Antimicrobial activity is likewise absent in the ortho and meta isomers of streptocide. The same phenomenon is observed when additional substituents are introduced into the benzene ring of sulfonamides. Sulfonamides are structurally similar to PABA:

The antimicrobial action of sulfonamides is explained by the fact that they compete in the body with structurally similar PABA during the synthesis of pteroic acid, forming the compound shown below (acting as a PABA antimetabolite):

As a result, the synthesis of folic acid is halted, leading to the death of the microorganisms.

Scientists have isolated relatively simple compounds from most natural products that are responsible for their pleasant and characteristic aromas. Some of these flavoring agents are heterocyclic in nature:

Often, the aroma and flavor of natural products are determined not by a single substance, but by a mixture of several.

Carboxylic acid esters are known for their pleasant fragrances:

Certain representatives of aldehydes and phenols also possess pleasant aromas:

Complete the tasks and check your Answers against the answer keys

Task No. 1

In a living Organism, the amino alcohol colamine is formed from:

Serine.

Alanine.

Glycine.

D. Glycerol.

Hydrolysis of novocaine leads to The formation of:

p-Aminophenol.

p-Aminobenzoic acid.

Sulfanilic acid.

D. Additional information is required.

In the body, adrenaline is synthesized from:

Phenylalanine.

Serine.

Valine.

D. Alanine.

Answer keys: 1-A; 2-B; 3-A.