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Introduction to Medicinal Chemistry1
Medicinal chemistry is a multidisciplinary subject involving Organic chemistry, Pharmacology, Biochemistry, Physiology, Microbiology, Toxicology, Genetics and Computer modeling. It explains the design and production of compounds that can be used for prevention, treatment or cure of human or animal diseases. More recently the IUPAC have recommended the following description for the Medicinal chemistry term; "Medicinal Chemistry is a chemistry based discipline, also involving aspects of Biological, Medical and Pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and construction of structure activity relationship (SAR).
The chemical knowledge of isolated compounds gave a way for many synthetic substances. Hundreds and thousands of new organic chemicals are prepared annually throughout the world and many of them are entered into pharmacological screens to determine whether they have useful biological activity or not. This process of random screening has been considered inefficient, but it has resulted in the identification of new 'lead compound' whose structure has been optimized to produce clinical agents.
In recent years, there has been growing interest pertaining to the synthesis of bio active compounds in the field of organic chemistry. Among the family of heterocyclic compounds, nitrogen containing heterocycles especially benzimidazole presumably gaining considerable importance owing to their varied biological properties such as, Anti-ulcer, Anti-inflammatory, Anti-microbial, Anti-tubercular, Anti-cancer, Anthelmintic, Anti-proliferative, Anti-hypertensive, Anti-allergic and Anti-oxidant.
Benzimidazole is a fused aromatic ring system in which benzene ring is fused to 4 and 5 position of an imidazole ring.It is a heterocyclic aromatic organic compound.They are also called as benziminazoles and 1,3-benzodiazoles. It is an important group of heterocyclic compounds and discovered as a part of vitamin B12 structure in the form of 5,6-dimethyl benzimidazole. Benzimidazoles show both acidic and basic characteristics and also possess the capacity to form salts. In benzimidazole, the =NH group present shows strongly acidic and basic characteristics.
IUPAC - 1H-benzimidazole.
Synonym- BI; 3-benzodiazole; benzoglyoxaline; azindole; 3-azaindole; BZI; 1,3-diazaindene.
Physical and Chemical Properties
Benzimidazoles are having high melting point heterocyclic compounds and substitution at 1 position lowers the melting point. Benzimidazoles when treated with acids, results in the formation of N-metallic compounds. These are weakly basic with a pKa value of 5-3 to 12-13. Benzimidazoles are poorly soluble in water, but dissolved in organic solvents such as chloroform, propylene glycon and polyethxylated caster oil. They are harmful if swallowed, inhaled or absorbed through the skin.
Synthesis of Benzimidazoles
The synthesis of benzimidazole derivatives starts with the benzene derivatives having nitrogen at ortho position to each other. The most commonly used starting material is orthophenylenediamine (OPDA).
Benzimidazole is prepared from O-phenylenediamine which is treated with formic acid in presence of alkali. The o-phenylenediamine reacts with formic acid to give benzimidazoles.
The reaction involves dehydration followed by cyclisation.
O-phenylenediamine Formic acid Benzimidazole
Phillips3 reported the synthesis of 2-substituted benzimidazole derivatives by treating o-phenylenediamine with organic acids in the presence of dilute mineral acid (about 4N Hydrochloric acid) to give benzimidazoles.
The mechanism of reaction of organic acid with OPDA has been studied. Philips concluded that the monoacyl derivative was the necessary intermediate for the reaction.
Amines4 are widely distributed in plants and animals and many amines have physiological activity. Volatile amines have very distinctive and usually offensive odors. Methylamine has an odor similar to that of ammonia.
The lone pair of aniline is basic in nature. The basicity of anilines can be compared by comparing the pKa of the conjugated acid. A low pKa for the conjugate acid indicates a weak base, while the large pKa value for the conjugate acid indicate strong base. The low pKa of aniline (Ph-NH2) is 4.6.
Anilines are colorless to pale yellow crystalline solid with a weak amine like odor, soluble in alcohols and acids, melts at 60C. The aniline is less basic than an alkyl amine because the lone pair is delocalized. This makes the lone pair less available and hence, less basic. The electron withdrawing groups make the nitrogen less basic while electron donors make it more basic. The three commercially available isomers of anilines are p-nitro aniline, m-nitro aniline and o-nitro aniline. The aniline possesses the activity like anti-bacterial, fungicidal and cytotoxic activities.
Preparation of Aromatic Diazonium Salt5
These are prepared by the diazotization reaction. The formation of aromatic diazoniun salt by the action of nitrous acid at 0-50C in strong acid medium is called diazotization reaction since a two-azo (nitrogen: French azote) system is bonded to the nuclear C by the process.
The above reaction shows that 2 moles of mineral acid is required to diazotize 1 mole of an aromatic primary amine. In practice, however, 1 equivalent of the amine is dissolved in 2.5 to 3 equivalents of dilute hydrochloric acid or sulphuric acid and cooled to 0-50C. To the cold solution, an aqueous dilute solution of sodium nitrite (NaNO2) is added gradually during the course of about 5 min. and mixture is allowed to stand for additional 5 to 10 min. Throughout the process the temperature is kept preferably above 00C and below 50C at which the speed of reaction is appreciable as well as the diazonium ion is fairly stable and does not decompose to nitrogen. The diazonium salt so formed remains in solution and is used as such in situ.
The N-Nitroso compounds results from reactions involving other chemical called alkylamines. At room temperature, N-Nitroso compounds are yellow liquids. They do not have a distinct odor. Industry makes small amounts of N-Nitroso compounds for research. They can also be formed as a side reaction when other products are made.
The Nitroso-di-n-propylamine (NDPA) is used in some cosmetic and toiletory products and in cleansers. Some Nitroso compounds were once used to make rocket fuel, but this manufacture ended when high levels of the compounds were found in air, water and soil near a rocket fuel plant.
The low levels of N-Nitroso compounds can be found in air, water and food products treated with nitrite. Such food products include cheeses, fish and cured meats.