Heterocyclic drugs, literature

This series in heterocyclic chemistry is being introduced to collectively make available critically and comprehensively reviewed literature scattered in various journals as papers and review articles. All sorts of heterocyclic compounds originating from synthesis, natural products, marine products, insects, etc. will be covered. Several heterocyclic compounds play a significant role in maintaining life. Blood constituent hemoglobin and purines as well as pyrimidines, are constituents of nucleic acid (DNA and RNA) are also heterocyclic compounds. Several amino acids, carbohydrates, vitamins, alkaloids, antibiotics, etc. are also heterocyclic compounds that are essential for life. Heterocyclic compounds are widely used in clinical practice as drugs, but all applications of heterocyclic medicines can not be discussed in detail. In addition to such applications, heterocyclic compounds also find several applications in the plastics industry, in photography as sensitizers and developers, and in dye industry as dyes, etc. 

It is estimated that far more than 50% of the published chemical literature concerns heterocyclic structures. One striking structural feature inherent to heterocycles, which continues to be exploited to great advantage by the drug industry, lies in their ability to manifest substituents around a core scaffold in a defined three-dimensional representation, thereby allowing for far fewer degrees of conformational freedom than the corresponding conceivable acyclic structures. 

AO has been shown to be responsible for the primary metabolism of several drugs that contain an aromatic nitrogen heterocycle [72,88,159,160]. In general, when drug structures contain aromatic nitrogen heterocycles, a role for AO should be considered in preclinical and in vitro tests. The contribution of this enzyme to drug clearance can be defined by examining metabolism of an NCE by cytosolic preparations and inhibition by either menadione or raloxifene [161, 162], DDIs with AO have not yet been reported in the literature. 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

The drug reference books by Mashkovskiy (2008) and Negwer (Negwer and Scharnow 2001) comprise 89 benzimidazole derivatives used in medicine. However, only 11 of them (Fig. 6.2) include other heterocyclic rings directly fused with the benzimidazole system. Probably, this is due to the fact that such compounds are hardly accessible. Indeed, the analysis of the literature data shows that the methods of synthesis of such compounds involve many steps, are laborious, and the total yields of products never exceed 20 25 %. 

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