Chemical database

Chemical databases are an essential part of modern drug development during all stages of it. Those databases allow quick access to the information about the compound of interest as well as to group several chemical compounds by structural and physico-chemical properties. This in turn can help during lead determination and optimization in research projects.

What are exactly chemical databases? These are databases designed for storing information about chemical compounds. This concept includes both popular, open-source chemical databases and highly specialized commercial collections. Examples of the first category are PubChem and ProteinDataBank which contain a wealth of information about every known substance. The second category of chemical databases is usually needed for specific drug discovery compound collections.

One of the examples for the chemical database designed for applications in medicinal chemistry is the chemical database of building blocks - chemical reagents, fragments and intermediates. Components of such a database can be used in research projects in the field of medicinal chemistry, design of the novel combined compound libraries, lead optimization, etc.

Let’s take a closer look at some examples of such chemical database components and their properties in terms of building blocks.

Table 1. Characterization of the first 6 classes of the chemical database

Name	Aldehydes	Alkyl Halides	Alcohols	Phenols	Primary Amines	Secondary Amines
Functional group		X = F, Cl, B, I			X = any atom but carbon	X = any atom but carbon

First group of compounds in the chemical database is aldehydes (Table 1). They are used as intermediates in the synthesis of antihistamines, antipsychotics, and antibiotics. Synthesis of one of the most common antibiotic drugs - penicillin - involves the reaction of an aldehyde with a nucleophile, such as amines or hydroxyl groups, to form a beta-lactam ring, which is the core structure of penicillin [1]. Moreover, alkyl halides (another group of compounds from the chemical database) are also a part of this synthesis: an alkyl halide reacts with a nucleophile (such as an amine) to form an amide intermediate, which is then hydrolyzed to form the final product. Unique properties of the second group of building blocks are used not only in the production of antibiotics but also in the production of antivirals.

The next class of building blocks called alcohols is known for its applications in the production of various drugs. Intermediates obtained from reactions of an alcohol with different bases and acids take part in the formation of sedatives (diazepam) and painkillers (aspirin). Development of painkillers such as aspirin also includes phenol derivatives [2]. Those derivatives find application in the development of drugs for the treatment of cancer.

Both primary and secondary amines are used in the development of drugs for various therapeutic areas, including cancer, infectious diseases, and neurological disorders. For example, primary amines are used in the synthesis of anti-cancer drugs such as cyclophosphamide and doxorubicin. Secondary amines are used in the development of antidepressants such as fluoxetine and sertraline.

Table 2. Characterization of the next 6 classes of the chemical database

Name	Aryl Halides	Boronic acids	Carboxylic acids	Hydrazines	Isocyanates	Isothiocyanates
Functional group	X = F, Cl, B, I		X = a carbon group or a hydrogen atom

An interesting application for aryl halides as a part of this chemical database is coupling partners in cross-coupling reactions. These reactions involve the formation of a carbon-carbon bond between two aryl groups, and are widely used in organic synthesis. The most commonly used cross-coupling reaction is the Suzuki-Miyaura reaction (Fig. 1), which involves the use of a palladium catalyst.

Figure 1. Suzuki-Miyaura reaction scheme [3]

One of the key advantages of boronic acids and esters building blocks is their ability to form reversible covalent bonds with certain biological targets. This property has been exploited in the design of drugs that target specific enzymes or receptors involved in disease processes.

Carboxylic acids and their derivatives (halides, esters, hydrazines) have been used in the development of drugs for a variety of diseases, including hypertension, diabetes, and cancer. For instance, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen are derived from carboxylic acids. Moreover, these building blocks can participate in the synthesis of complex drug molecules, as well as hydrazines. The functional group of hydrazines allows them to have a high specificity for the biological target. Isocyanates and isothiocyanates, another two classes of substances in the chemical database, can also increase specificity and therefore optimize the pharmacological profiles of potential drugs.

Table 3. Characterization of the final 6 classes of the chemical database

Name	Ketones	Nitriles & isonitriles	Nitro compounds	Amidoximes	Sulfonic acids	Thiols
Functional group

The following class of building blocks - ketones - has shown to possess a wide range of pharmacological activities, including antiviral, antibacterial, antifungal, and anticancer properties. In addition to that, ketones can be easily synthesized from a wide range of starting materials, making them readily available for drug development. Nitriles, as well as ketones, have a lot of ways of implementation in drug discovery. Isonitriles, however, have an even more interesting application: they are able to form stable complexes with metal ions, which can be used for imaging and therapeutic purposes. For example, isonitrile derivatives have been used as radiotracers for positron emission tomography (PET) imaging and as metal chelators for cancer therapy [4].

Let us briefly list applications for the remaining groups of building blocks. Thiol-containing compounds can target specific enzymes or receptors in the body and can be used to improve drug delivery and bioavailability. Antibiotics such as nitrofurantoin (used to treat urinary tract infections) contain a nitro group, while sulfonamide antibiotics (derivatives of sulfonic acids) are widely known for the treatment of many more bacterial infections. Finally, amidoxime derivatives of ribavirin are potent inhibitors of hepatitis C virus replication.

Overall, all building blocks listed above play an important role in the development of new chemical compounds and applications. Their applications are diverse and continue to expand as new compounds are synthesized. The unique properties and reactivity make those substances an essential tool for organic chemists working in a wide range of fields. The chemical database of building blocks contains information about its components that is crucial for their efficient use in chemical synthesis and application development. As research in this field continues, we can expect to see new and innovative building blocks being added to the database to increase a variety of usage possibilities.

References

1. “Derivatives of 6-Aminopenicillanic Acid. VII.1 Synthesis of Penicillin Aldehydes by a Novel Method” W. J. Gottstein, G. E. Bocian, L. B. Crast, Kathleen Dadabo, J. M. Essery, J. C. Godfrey, and L. C. Cheney. The Journal of Organic Chemistry, 1966, 31 (6), 1922-1924

2. “A Greener Approach to Aspirin Synthesis Using Microwave Irradiation” Ingrid Montes, David Sanabria, Marilyn García, Joaudimir Castro, and Johanna Fajardo. Journal of Chemical Education, 2006 83 (4), 628

3. “Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds” Norio Miyaura and Akira Suzuki. Chemical Reviews 1995 95 (7), 2457-2483

4. “Isonitrile complexes of osmium and their reactions to give hydride, amine, and carbene complexes” Journal of the Chemical Society, Dalton Trans., 1973, 1433-1439