Introduction to Coumarin and SAR

Santhosh Penta,    Department of Chemistry, National Institute of Technology, Raipur, Chhattisgarh, India

Structure-based drug design is a quickly emerging field, with achievements to a large extent of anticipation in recent years. Improvements in structural information and the mechanism of biological interactions have delivered several new targets and opportunities to create new drugs, leading to discovery. In medicinal and pharmacological studies, coumarins are well known for their highly potent biological activity as well as their versatility. Structure-activity relationships (SARs) of the coumarin derivatives with different substituents in various positions reveals significant information related to the development of highly specified and potent drugs.

This chapter is intended as an overview of and introduction to coumarin and the process of drug designing as well as the application of structure-activity relationships, starting from the selection of the target to the generation and development of the lead compound.

Keywords

Coumarins; classification; structure-activity relationship (SAR); drug design; electrostatic interaction; geometric interaction; ligands; target site

Outline

1.1 What is Coumarin?

The coumarin1 (benzopyran-2-one, or chromen-2-one) ring system [1], present in natural products such as tonka beans, warfarin, and clover leaf, displays interesting pharmacological properties. The parent molecule was first isolated by Vogel2 from tonka beans. The coumarin ring can be looked upon as arising out of a fusion of a pyrone ring with a benzene nucleus. The derivatives of coumarin usually occur as secondary metabolites present in seeds, roots, and leaves of many plant species.3 More than 300 coumarins have been identified from natural sources, especially from green plants. These varying substances have disparate pharmacological, biochemical, and therapeutic applications.4 As for physical properties, coumarin is a white crystalline, volatile compound. It smells like vanilla and has a melting point of 341–344 K.

1.2 Types of Coumarin and Examples

There are various ways to classify coumarins according to their chemical structure, occurrence, or synthesis, thus it creates several classes of coumarins. Here we mention roughly categorized coumarins on the basis of their structure5 given in Table 1.1:

1.3 What is SAR?

There is an appropriate way for interaction between drugs and the respective biological site to achieve effective biological activity. A higher level of information regarding the molecular level of a drug and its mechanism of biological activity leads to better understanding for developing the drug with optimum efficiency. These structure-related properties of a drug can be resolved, either through computational method (in silico) or experimental method with in vivo and in vitro conditions. Structure-activity relationship (SAR) is an approach that is designed to find relationships between chemical structure of a ligand and biological target of studied compounds. Likewise, for all molecules it is also hypothesized that similar molecules have similar activities. This assumption is well considered as the guiding principle of SAR.

1.4 Why SAR?

The traditional methods of drug design are now modified by concise methods of SAR, which is found to be highly influential in the drug design process. The geometrical and electrostatic interaction is responsible for causing the effective biological activity. Geometrical interaction involves the complete three-dimensional spatial arrangement of target site and ligands, whereas the electrostatic interaction involves the electronic effect, hydrophobicity, solubility, and so on. However, a number of these interactions cannot be characterized in suitable numerical considerations to describe several attributes. Thus, the mechanism of chemical interaction between the ligand and targeted biological active site needs abundant information. SAR exists to explain the ways of interaction between the ligand and receptor and is applicable in optimization of ligands for better interactive behavior for highly specific and potent bioactive drugs.

1.5 Application of SAR

SARs are the traditional practices of medicinal chemistry via which we try to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structure.

Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects. This enables the identification and determination of the chemical groups responsible for evoking a target biological effect in the organism. Figure 1.1 shows the several applications of studying the SAR.

1.5.1 Pharmacokinetics Studies Via SAR

Pharmacokinetics involves four basic steps: absorption, distribution, metabolism, and excretion (ADME). Bioavailability of a drug, defined as the amount of drug that is actually available at the active site of receptor, is an important parameter of pharmacokinetics. Bioavailability of a drug mainly depends on two major steps:

Absorption depends significantly on the extent of aqueous solubility and its lipophilicity, which can be stabilized by adding an alcoholic group, an acidic group or carboxylic group, or the like in the lipophilic core moiety. In most drugs, metabolism reduces bioavailability. SAR is helpful in determining the solubility, lipophilicity, rate of reaction in metabolism, metabolites, toxicology, and interaction between drugs.

1.5.2 Drug-Receptor Interaction Studies Using SAR

Most drugs display extremely great relationship of structure besides specificity to have highly potent pharmacological activity. The interaction of drugs occurs with active sites of a biological target that has specific three-dimensional structure and protein-like properties. Drug-receptor interaction requires a minimum of three points of attachment.

The binding between the drug and its receptor occurs by either of these two ways:

Several in silico methods were developed to determine SAR for the interaction between the target receptor site and drugs, with the illustration of types of binding. They reveal the extent of binding affinity for the set of drugs.

1.5.3 Chemical, Physical Property and Formulation

SAR has arisen as an important tool for the understanding and development of chemical and physical properties and the formulation of drugs. SAR provides insight into the important aspects of molecular structure, which is effective for the potent activity. Such information may assist in devising an organized approach to drug design of lead compounds with more desired and specific potency.

1.5.4 Drug Modification

Today SAR provides several in silico methods developed for optimization and development of drugs. These include the statistical method, validation method, quantum analysis, and artificial networks modeling,...