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Trying to Copy the Nature–the Amide Bond

May 9, 2023 - 9:10
Trying to Copy the Nature–the Amide Bond

Dr. Stanimir Manolov
Department of Organic Chemistry, Faculty of Chemistry, University ofPlovdiv “PaisiiHilendarski”, Plovdiv, Bulgaria

The amide bond is almost ubiquitous in pharmaceutical chemistry as it offers high chemical stability, a fixed geometry, together with hydrogen-bond donor and acceptor sites [1]. Amides are abundant in nature, including proteins, peptides, and numerous amide-bond containing biomolecules, as well as many synthetic compounds with different applications, such as pharmaceutically active chemicals or synthetic polymers.Amides are of particular importance in organic chemistry due to their high stability and polarity, as well as their structural diversity.The synthesis of amides is very important for the pharmaceutical industry. Various amides are present in about 25% of the best-selling pharmaceutical products and in many other important medicinal compounds [2].

The majority of biological amide bonds originate in ribosomes, where complex proteins are built amino acid by amino acid. Furthermore, many smaller biomolecules, including as nonribosomally encoded peptides, critical metabolites, and natural products, include amide linkages [3].

As can be seen from the examples of the drugs used in clinical practice, these drugs range from relatively simple molecules like paracetamol, which has a strong analgesic and antipyretic effect, to more complex molecules like Ceftazidime, a third-generation cephalosporin antibiotic used to treat a wide range of bacterial infections (Figure 1).



Figure 1.Structural formulas of Paracetamol and Ceftazidime

Compounds containing amide function have a wide range of biological activity.In fact, they are all around us. Black pepper’s pungency, for example, is caused by the alkaloid piperine and its isomer chavicine (Figure 2).



Figure 2.Structural formulas of Piperine and Chavicine.

Another amide representative is Anandamide, which is responsible for some of the joyful sensations associated with chocolate consumption(Figure 3) [4].


Figure 3. Structural formula of Anandamide

One of the most significant chemical reactions is the creation of amide bonds.Amides can be prepared by a wide variety of chemical reactions. Three of the most efficient methods for the synthesis of amides are nucleophilic acyl substitution, partial hydrolysis of nitriles, and reaction of amines with carboxylic acids in the presence of DCC, EDC, or other “dehydrating” reagents.

Amides are most often synthesized by reacting an acid chloride with amines.In addition, an amide function can be synthesized in a similar manner by reacting a carboxylic acid and an amine with a coupling agent such as DCC. By reacting an acid anhydride with an amine, simple amides can be created.Direct synthesis of amines is possible by combining an amine with a carboxylic acid as well (Scheme 1).

Scheme 1.Synthetic pathways for amide bond formation

Because amides are the building blocks of many other, more complicated organic compounds, organic chemists are still looking for better and more efficient ways to “build” them.

Except the classic well known methodsfor amide bond formation mentioned above many other have been reported varying the reaction conditions using microwave irradiation [5], electrosynthesis [6], enzymatic catalyzed reaction [7,8], in ionic liquids [9], metal-catalyzed approaches [10, 11],and many others.

Recently we developed a new series of amide derivatives – amfens, using the classic Schoten- Baumann reaction, with excellent yields. Amfens (Figure 4) are hybrid molecules between amphetamine (given in blue colour) and profens (given in red colour) [12].

Figure 4. Structural formula of amfens

Amphetamine is a psychoactive substance that induces feelings of cheerfulness, strength, and lightness in people who are severely physically exhausted. Also, the compound and its derivatives are used to treat depression, narcolepsy, and obesity [13]. Profens from other site are used worldwide to treat pain and inflammation [14]. Using an amide bond we’ve managed to connect amphetamine with profens in order to combine the powerful central nervous system stimulant actions of amphetamine with the strong analgesic properties of profens due to their anti-inflammatory effect [12].

This topic is quite current, and continues to excite many scientists around the world. Both in the search for new active pharmaceutical ingredients and in the search for new, more effective methods for their preparation.


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