Rapid Generation of Privileged Substructure-Based Compound Libraries with Structural Diversity and Drug-Likeness Lei Zhang, † Mingyue Zheng, † Fei Zhao, Yun Zhai, and Hong Liu* CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China * S Supporting Information ABSTRACT: A library of privileged-substructure-based, heterocyclic compounds was constructed by a sequence of Ugi four- component reactions incorporating the indole motif and microwave-assisted cyclizations in branched pathways. Cheminformatic analysis confirmed that the library exhibited a high degree of structural diversity and good drug-likeness. KEYWORDS: indole, diversity-oriented synthesis, drug-like, privileged structure, microwave ■ INTRODUCTION An increasing number of therapeutic targets have been identified due to the rapid advances in genomics and proteomics. This has created a tremendous need to develop more efficient methods to generate new chemical libraries used for drug screening. 1 It is recognized that molecular skeletons are more important than the appendices for high-throughput screening, and a compound library featuring a high degree of skeletal diversity can effectively increase the occupation of “chemical space”, thus improving the hit rates for diverse biological targets in “biological space”. 2 However, the hit rates of most of current combinatorial libraries are far from satisfactory. This is often attributed to the lack of structural diversity in these libraries which traditionally yield similar molecular skeletons decorated with different substituents. In addition to diversity, high-quality compound libraries are expected to display good drug-like properties. 3 A diverse library created with little consideration of drug-like properties may be subjected to more absorption, distribution, metabolism, excretion, and toxicity (ADME/T) problems during the drug discovery process. The concept of diversity-oriented synthesis 4 around privileged structures, defined as rational DOS or privileged-substructure-based DOS (pDOS), has been proven as a powerful tool to construct high-quality compound libraries. 5 Even though, the development of robust strategies to create diverse molecular architectures embedded with privileged structures remains a demanding challenge and is highly desirable for improving the success of biological screenings. 6 We herein introduce an efficient strategy which allows rapid access to pDOS libraries encompassing molecular complexity, structural diversity, and drug-like properties. ■ RESULTS AND DISCUSSION Library Construction. Multicomponent reactions (MCRs) provide an efficient complexity-generating approach to easily transform three or more starting materials into a single product in an atom- and step-economical way. 7 Privileged structures offer an ideal source of lead compounds for drug discovery due to their inherent affinity for diverse biological targets. 8 Microwave heating can speed up a broad range of organic reactions compared to conventional heating conditions. 9 Combining these ideas, we proposed a sequential procedure of a versatile MCR incorporating a privileged structural motif in the modular inputs, and subsequent branched post-MCR transformations under microwave heating. This may serve as a flexible and robust strategy to rapidly access diverse and drug- like libraries. As a demonstration, we selected the Ugi reaction 10 as the MCR, indole as the privileged structure, and microwave- assisted intramolecular cyclizations as the post-transformations (Scheme 1). Indole motifs represent one of the most prominent privileged structures and are ubiquitous in natural products and pharmaceutical compounds. 11 More importantly, from the point of view of diversity, there are at least three reactive sites in the indole structure, with the potential for Received: October 5, 2013 Revised: January 4, 2014 Published: February 13, 2014 Research Article pubs.acs.org/acscombsci © 2014 American Chemical Society 184 dx.doi.org/10.1021/co4001309 | ACS Comb. Sci. 2014, 16, 184-191