Naturally drug-like compound

Learn from Naturally Drug-Like Compounds... 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

Natural Products and Synthetic Drug-like Compounds... 

Mother nature is a good resource for new molecules over 10000 natural products are isolated each year [ 1 ]. Historically, natural products have provided a good number of leads for the development of new drugs [2], However, since natural products are commonly screened as an extraction mixture, deconvolution of an active component and structural characterization are difficult tasks. In addition, isolation of natural products has a long cycle time and is considered expensive [3], These limitations have prompted efforts to synthesize natural product analogues and natural-product-like compounds for biological screening and quantitative structure-activity relationship (QSAR) studies. 

FMS of Natural Products and Drug-like Compounds and Libraries... 

New approaches to source novel compounds from untapped areas of biodiversity coupled with the technical advances in analytical techniques (such as microcoil NMR and linked LC-MS-NMR) have removed many of the difficulties when using natural products in screening campaigns. As the chemical space occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections, synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds. A renaissance of drug discovery inspired by natural products can be predicted.2... 

The quinoline scaffold and derivatives occur in a large number of natural products and drug-like compounds. A method for microwave-assisted synthesis of 2-aminoquinolines has been described by Wilson et al. [62]. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines, then addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives (Scheme 10.27). Purification of the products was accomplished in a streamlined manner by using solid-phase extraction techniques to produce the desired compounds in high yields and purity. Direct comparison of the reaction under thermal and microwave conditions, using identical stoichiometry and sealed reaction vessels, showed the latter resulted in improved yield. 

The incorporation of fluorine into a molecule has been widely used to alter the pharmacokinetic properties and overall drug-like properties of compounds. This includes affecting the metabolism, oral absorption, and brain penetration of these molecules [18]. Metabolism can be affected by addition of fluorine directly at or adjacent to the site of metabolism. In addition, substitution with fluorine can increase the lipophilicity of compounds which has been shown to dramatically affect both oral absorption and brain penetration. Finally, the electron-withdrawing characteristic of fluorine has been exploited to lower the P-gp liability of compounds and modulate the pKa of adjacent groups which resulted in increased brain exposure. In the following section, representative examples will highlight the powerful nature of fluorine to modulate overall drug-like properties. 

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