The aim of this application is to produce pilot-scale libraries for evaluation via the Molecular Library Screening Network (MLSCN). It is expected that the output from MLSCN screening of these """"""""designer collections"""""""" will help enable the promise of chemical biology, unearthing quality small molecule probes to elucidate physiological roles of proteins of unknown function. 25 libraries will be targeted, comprising 25-80 characterized compounds (>10mg, >90% pure). To this end, effective file enhancement requires complementary skill sets in multiple functional areas and as such, the collective investigators have proposed a multitude of potentially robust medicinally relevant protocols and possess a depth of expertise in high-throughput medicinal chemistry and drug design principles spanning both academic and industrial settings. The combined infrastructures of the collaborative parties further strengthen this application, with ready access to state of the art screening, structural biology, high-throughput instrumentation and core chemistry facilities. The notion of scaffold uniqueness will be evaluated using measurements of molecular dissimilarity based on observed substructure patterns and their frequency of occurrence in PubChem and vendor databases. Evaluation tools will include but are not limited to standard diverse subset and hierarchical chemotype-based analyses. Selected scaffolds will also have a strong biological rational, often taking advantage of crucial molecular recognition motifs of multiple target families. All scaffolds are unique and viewed as structurally compelling. Resupply and future SAR studies will be facilitated by selection of scaffolds possessing 'High Iterative Efficiency Potential'that 1) improve the iterative speed of the medicinal chemist navigating the 'hypothesis-synthesis-screening'loop and 2) reduce the number of required iterations for milestone progression. Designer libraries detailed herein will be presenting opportunities for therapeutic advances in multiple indications.

Public Health Relevance

An immense opportunity has been created to improve human health and longevity. Roles of a plethora of new macromolecules in disease progression may now be investigated by preparation of collections of potential molecular probes detailed herein. Once identified, these small molecules may ultimately be the precursors to disease modifying drugs that address currently unmet medical needs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-R (50))
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Schools of Pharmacy
United States
Zip Code
Xu, Zhigang; Martinez-Ariza, Guillermo; Cappelli, Alexandra P et al. (2015) (Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction. J Org Chem 80:9007-15
Martinez-Ariza, Guillermo; Ayaz, Muhammad; Medda, Federico et al. (2014) Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions. J Org Chem 79:5153-62
Medda, Federico; Hulme, Christopher (2014) Exploiting the Divalent Nature of Isonitriles: a novel Pictet-Spengler Amidination process. Tetrahedron Lett 55:3328-3331
Bell, Christan E; Shaw, Arthur Y; De Moliner, Fabio et al. (2014) MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines. Tetrahedron 7:54-59
Gunawan, Steven; Hulme, Christopher (2013) Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity. Org Biomol Chem 11:6036-46
Xu, Zhigang; De Moliner, Fabio; Cappelli, Alexandra P et al. (2013) Aldol reactions in multicomponent reaction based domino pathways: a multipurpose enabling tool in heterocyclic chemistry. Org Lett 15:2738-41
Martinez-Ariza, Guillermo; Ayaz, Muhammad; Hulme, Christopher (2013) A simple one-pot 2-step N-1-alkylation of indoles with ?-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles. Tetrahedron Lett 54:
Gunawan, Steven; Hulme, Christopher (2013) Construction of functionalized tricyclic dihydropyrazino-quinazolinedione chemotypes via an Ugi/N-acyliminium ion cyclization cascade. Tetrahedron Lett 54:4467-4470
Gunawan, Steven; Petit, Joachim; Hulme, Christopher (2012) Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles. ACS Comb Sci 14:160-3
Xu, Zhigang; Ayaz, Muhammad; Cappelli, Alexandra A et al. (2012) General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity. ACS Comb Sci 14:460-4

Showing the most recent 10 out of 20 publications