The practice of medicinal chemistry is concerned with the discovery and development of new agents or drugs for treating diseases at molecular level. Medicinal chemistry is also called as Pharmaceutical, Therapeutic and Pharmacochemistry.
Most of the activities in the discipline of medicinal chemistry is direct to formation of new synthetic or natural organic compounds.
Pharmacological activities shown by the organic compounds are very specific so they are predominant over the natural compounds. The resent advances in computer science and molecular biology plays important role in drug design, development and production.
The process of drug development is very complex. It requires talents of people from various disciplines like chemistry (organic chemistry, chemistry of natural compounds, biochemistry etc.), physiology, pharmacology, pharmaceuticals and medicine. Medicinal chemistry links between chemical structure and biological activity and also pharmacokinetic and pharmacodynamic behavior of drug to the physicochemical properties of therapeutic agents. There is considerable overlap between medicinal chemistry and pharmacology.
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While searching ahead on a new drug development or research on preclinical drugs condition, medicinal chemist and biologist have dominating activity of finding the biochemical pathways by which drug shows beneficial activities.
The other areas which are collaborated with medicinal chemistry are biology, computer aided drug design (CAD), x-ray crystallography, metabolism and pharmacokinetics also legal and regulatory affairs, clinical trial managements, pharmaceutics and process research activity.
Together all these teams uses sophisticated analytical techniques for development of new drug products and most effective ecofriendly production procedures.
Majority of pharmacological active compounds in medicinal chemistry has the heterocyclic ring system. Benzimidazole is also one among them which is having pronounce Biological activities.
The benzimidazole is a heterocyclic compound. In its structure six membered benzene ring is fused with five membered imidazole ring.
Firstly benzimidazole discovered as a part of Vit.B12 structure. It is in the form of 5,6-dimethyl benzimidazole. It has two nitrogen atoms at 1 and 3 position.
In general benzimidazole are crystalline compounds having fairly high melting points, substitution at 1 position lowers the melting point.
Benzimidazoles are having very less solubility in water. Sometimes they may be recrystallised with hot water also. Many of benzimidazole having good solubility in aqueous alkali and also in aqueous acids.
Benzimidazole possess both characteristics i.e. acidic and basic. The ââ‚¬"NH- group present in it is having strongly acidic and relatively very weakly basic characteristics. Due to itââ‚¬â„¢s acidic nature they form N-metallic compounds when dissolved in acids. As Benzimidazole are weakly basic, it is having pka value of 5-3 to 12-3. Under suitable benzimidazoles may be protonated at pka 5-6 and it may be deprotonated at pka12.
SYNTHESIS OF BENZIMIDAZOLES
The benzimidazole synthesis starts with Benzene derivatives, which is having nitrogen containing functions at ortho position to each other.
FROM CARBOXYLIC ACIDS.
2-substituted benzimidazole usually in very good yield is obtained by reacting o-phenylenediamines with most carboxylic acids.
Phillips1 reported the synthesis of 2-substituted benzimidazoles. He introduced an important modification in this reaction, when o-phenylenediamines reacts with organic acids in presence dilute mineral acid (usually about 4N Hydrochloric Acid), it gives substituted benzimidazoles. The yield obtained with aliphatic acids and aromatic acids are good.
After studying reaction mechanism Phillips concluded that, for the reaction to proceed monoacyl derivative was the necessary intermediate. On heating dilute mineral acid with the monoacyl derivatives, Monoacyl derivatives readily passed into the corresponding benzimidazoles. At similar reaction conditions diacyl-orthophenylenediamine also give benzimidazoles, but it was concluded that due to the hydrolysis of acyl derivative to the monoacyl derivatives better reaction involved as the first step.
Hydrochloric acid shows the catalytic activity in the reaction. It activates the carboxyl group by addition of a proton to oxygen which leads to formation of a carbonium ion, with electron deficiency at carbon atom. Due to the entry of unshared electron pair present on one of nitrogen to the carbonium ion of the acid radical, the intermediate formed in the reaction is the additional product.
Dibasic acids are also reacted with o-phenylenediamine to form substituted benzimidazole derivatives. The product formed in this reaction is depends upon the mole ratio of the reactants and also on the experimental conditions. When one mole of dibasic acid heated with the two or more moles of o-phenylenediamine, product formed in most of the cases are benzimidazoles2.
By using microwave irradiations
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Synthesis of 2-substituted benzimidazole by using microwave irradiation requires less time and less solvent. The yield obtained by this method is also more.
K. Niknam et al;3 synthesized substituted benzimidazole by using microwave irradiations. In this o-phenylenediamine reacted with different aromatic and aliphatic carboxylic acids in presence of alumina-methanesulfonic acid at microwave power of 20% for 4-10 mins.
By using high temperature and supercritical water as solvent
The application of the green chemistry is the main challenge for researchers. Above 3740C and 221bar (22.1mPa) water is become supercritical fluid. At this point the physicochemical properties such as hydrogen bonding, degree of ionization, dielectric constant and also density can be finally tuned by using temperature and pressure. This means without changing the solvent chemical environment can also be changed.
In some of the cases water also plays role of solvent, reactant and catalyst.
Joan Fragra-Dubreuil et al;4 synthesized 2-substituted benzimidazole in high temperature water (HTW) by using high pressure mini autoclave. He synthesized these compounds by using o-phenylenediamine and different carboxylic acids.
The compounds formed by the double dehydration and intramolecular cyclization.
The best yield was obtained at 3500C and 20 MPa (90%).