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About Authors:
Arvind Negi1*, Balraj Singh Gill2
1Centre for Chemical and Pharmaceutical Sciences, Central University of Punjab, Bathinda- 151001
2Centre for Biosciences, Central University of Punjab, Bathinda-151001

Stereochemistry of clinical agents play a key role in their success to become drugs. Tautomerism is a structural isomerism, playing a key role in the orientation of organic compounds and also found significant in distinctive base pairing in nucleic acids. Keto-enol form usually occurs and found prominently among different types of tautomers. The enol form ionizes in the physiological solution into enolate and alter the biological activity. So, how this enolate form brings modification in pharmacokinetics and pharmacodynamics of a drug is very important and quite interesting to know. As this form is ionic in nature so it increases the interaction with the concerning receptors, enzymes, ion channels or functional proteins. In this review we cover and compile success, role and the significance of the enolate form of clinical agents which succeed to become drugs!


PharmaTutor (ISSN: 2347 - 7881)

Volume 1, Issue 2

Received On: 13/11/2013; Accepted On: 23/11/2013; Published On: 20/12/2013

How to cite this article: Negi A, Gill BS, Success Stories of Enolate Form of Drugs, PharmaTutor, 2013, 1(2), 45-53

Usually therapeutic molecule has some sort of structural peculiarity in terms of its stereo-geometric forms. Thestereo-geometric forms give rise to various geometric forms known as isomers.  Isomers are mainly present in paired form and can be of different types: Cis-Trans, R-S, Syn-Anti, E-Z or tautomers[1]. These tautomers are the constitutional isomers that can be easily interconvert into their forms through a concerning phenomena, called tautomerization and this sort of isomerism is known as tautomerism[2].

Tautomerism is a kind of isomerization resulted from the intramolecular migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. However, this isomerism is a special case of structural isomerism and also found significant in distinctive base pairing in nucleic acid[3].

In tautomerism, there is chemical equilibrium between the tautomers and the proportionality of tautomers depend on several factors preferentially solvent, temperature, and pH of the solution[4, 5]. Tautomerism can be of different types, elucidated in the following section.

Most common tautomeric pairs are:
Amide - imidic acid, e.g., Nitrile hydrolysis

Anomers of reducing sugars in solution interconvert through an intermediate open chain form.

Enamine - enamine, e.g., during pyridoxalphosphate-catalyzed enzymatic reactions and has biological significance in some diseases[6, 7].

Enamine - imine

Ketene - ynol, e.g., for ethenone, (triphenylphosphoranylidene) ethenone

Keto– enol, e.g., especially in ketones

Lactam - lactim, antimetabolites drugs (purine and pyrimidine analogs and penicillins)

Among tautomers, keto-enol form is most studied and common, which can be easily seen in a number of FDA approved drugs.The ionic form of enol is enolates possessing an alkene(-C=C-) with a hydroxyl group(-OH group) located on one of the carbon atom of the same alkene, see in fig.1.

Fig.1.Enolate formation: Keto form interconverted into enol form via proton migration, which is followed by the abstraction of a proton (deprotonation) to achieve the ionic form of enol, “enolate”.

This property of forming keto-enol form is exclusively attributed by the ketones, aldehyde and α-unsaturated alcohols. This type of tautomers often occurs in nature and even in the human body which is prominently manifested viaacid or base-assisted catalysis. Usually it has been observed that the 'keto' form of the compound is more stable, but in certain physiological conditions, the 'enol' form can also be the stable in nature.

Keto-Enol tautomerism:
Keto-enoltautomerism refers to a chemical equilibrium betweenketo form (ketone or an aldehyde) and an enol (an alcohol with conjugated unsaturation). Simply it clearly indicates the interconversion relationship between “enol and keto forms are said to be tautomers [8]. The interconversion of the two forms involves the migration of a proton and the shifting of bonding electrons (see in fig.2.); hence, the isomerism qualifies as tautomerism and therefore mainly affected by the pH of the medium.

Mechanistically, a compound containing a carbonyl group (C=O) is normally in rapid equilibrium with an enol tautomer, which contains a pair of doubly bonded carbon atoms adjacent to a hydroxyl (−OH) group(C=C-OH, linear representation of enol form). In general, the keto form predominates at equilibrium for most ketones. Furthermore, the deprotonated intermediate-II in the inter-conversion of the two forms, referred as an enolate anion[9], which is significant in carbonyl chemistry, see in fig. 2.

Fig.2.Mechanistic pathway of enolate formation.

keto-enoltautomerization governs thermodynamically but favored in keto form as compared to enol form. This can illustrated by classical example of vinyl alcohol and acetaldehyde [10].

What makes enolates so much interesting and how they are important in biological systems?

Enolates are the ionic product of enol form. In other words, it is deprotonated form having oxygen atom with un-bonded electron pair which finally makes it a strong nucleophile and having ability to bring necessary physiological reactions.

Enolate Implication in Medicinal chemistry

Enolate implication in Antiepileptic Drug
Antiepileptic drug act against convulsions, tremors,seizures and neuro-electrophysiological disorders where patient become motionless like a statue[11].

Hydratoin is canonical class of antiepileptics which contain phenytoin, mephenytoin, ethotoin (See fig.2.).Out of these, phenytoinis effective against all types of partial and tonic-clonic seizures but failed against the absence seizures[12]. Its superior neuro-pharmacological role exerted antiseizure activity without causing general CNS depression. But intoxic doses, it aggravate the excitatory signs while lethal dosing causes a type of decerebrate rigidity[13].Its mechanism of action revealed a special mechanism which restrict the repetitive firing of action potentials, evoked by a sustained depolarization and mediated by a slowing rate of recovery of voltage-activated Na+ channels from inactivation[13].

Phenytoin is majorly (95%) metabolized by hepatic cytochrome enzymes. The principal metabolite is para-hydroxyphenol derivative which is inactive and its concentration cause saturation in further metabolism of the remaining drug. Whereas the intravenous use is restricted by its low aqueous solubility.Its water soluble prodrug, Fosphenytoin,achieve the higher status of success as it can rectify the limitation of intravenous use as it reaches in blood, it then rapidly converted into phenytoin by erythrocytes and phosphatases in liver.Fosphenytoinhave higher affinity for plasma proteins, primarily albumin and this binding is saturable in respect to displaced phenytoin from binding sites. Fosphenytoin is useful for adults with partial or generalized seizures when intravenous or intramuscular administration is indicated. Suggestively the water solubility or intravenous accessibility of these drugs can be attributed by ability of the hydratoin scaffold to form the enolate (see in fig.3.)[14-16].



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