Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor (Ki = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.

Imidazoles are heterocycles with five-member ring structure heterocyclic compounds have gained very remarkable place in recent years because of their exceptional pharmacological activities. The imidazole nucleus is a main synthetic strategy in drug discovery. Imidazole is a planar five-member ring system having N atom at 1 and 3 positions. The systemic name for the compound is 1, 3 diazoles, one of the N bear an H atom and other to be termed as a pyrrole type N. Imidazole was first named as glyoxaline. It is amphoteric in nature, and it has susceptibility to be attacked by electrophile and nucleophile. It is a constituent of the purine nucleus and histidine amino acid, 4-amino imidazole-5-carboxamide found naturally as a riboside. This interesting group of heterocyclic compounds has wide range biological activities such as, analgesic, anti-inflammatory anticancer, antiviral, anthelmintic, anticonvulsant, antiulcer, antimicrobial, anti-allergic activity etc. Various methods employed for the synthesis of imidazole's and their chemical structure reactions offer enormous scope in the field of medicinal chemistry.