Applications of Combinatorial Chemistry in Pharmaceutical Synthesis

COMBINATORIAL CHEMISTRY(part 1) Mr. A. Rajendiran (Sr. Lecturer) Uni. Inst. of Pharmacy, C.S.J.M. University, Kanpur-24

UNIT 5: Concept and applications of combinatorial chemistry(CC); Solid phase and solution phase synthesis Introduction combinatorial chemistry(CC) is the new synthetic approach in which a very large number of chemical entities (libraries)are synthesized by condensing small number of chemical compounds together in all combinations defined by a small set of chemical reactions. Phases in combinatorial chemistry: Making a combinatorial library Finding active compound (lead discovery) 1. 2. 2

Types of Combinatorial Libraries Types of Combinatorial Libraries Scaffold-based Libraries: Core-structure, which is common to all compounds of the library. Several single building blocks can consist of Scaffold. Ex: Amino acid and Amino Benzophenone. Backbone-based Libraries Ex: Nucleic acid and Carbohydrate. Two approaches to generate libraries are 1. Random libraries and 2. Focused libraries. 3

Methods introduces in 1980s and applied even outside chemistry also Two important methods included in CC. a). Solid phase Synthesis b. Solution phase synthesis A) Solid Phase Technique Solid-phase synthesis is a method used to streamline the synthesis of molecules. It is often used in combinatorial chemistry(a technique used to prepare a large number of molecules in a short period of time), to generate libraries of compounds due to the ease of purification, and overall chemical synthesis. Reactants are bound to a polymeric surface and modified whilst still attached. Final product is released at the end of the synthesis. 4

B . Solution phase synthesis The use of solution phase techniques has been explored as an alternative to solid-phase chemistry approaches for the preparation of arrays of compounds in the drug discovery process. Solution-phase work is free from some of the constraints of solid-phase approaches but has disadvantages with respect to purification. It was first used for easily synthesized compound classes (amides, sulfonamides, Ureas, Heterocycles (Thiazole)). Presently, solution-phase combinatorial synthesis is attracting more interest because of some advantages. Many more reactions are optimized in solution-phase - All reactive groups of the starting materials are available - No limitations of the thermal or chemical stability of the resin - Synthesis is shorter by one or two steps - Reactions in solution often need considerably less time - Reactions that involve insoluble components are confined to solution phase -Reactions can be followed conveniently by simple means (TLC, NMR, UV) - In general, the reaction volumes in relation to the amount of product are smaller 5