A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC50 =0.16 µM, EC50 =0.3 µM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

Hydrogenations at room temperature and atmospheric pressure with mesoionic carbene-stabilized borenium catalysts.

1,2,3-Triazolylidene-based mesoionic carbene boranes have been synthesized in a convenient one-pot protocol from the corresponding 1,2,3-triazolium salts, base, and borane. Borenium ions are obtained by hydride abstraction and serve as catalysts in mild hydrogenation reactions of imines and unsaturated N-heterocycles at ambient pressure and temperature.

Highly selective directed arylation reactions via back-to-back dehydrogenative C-H borylation/arylation reactions.

Dimeric rhodium N-heterocyclic carbene complexes are demonstrated to be effective catalyst precursors for directed C-H borylation reactions at room temperature. The reactions are highly selective for mono-borylation and can be combined with a one-pot Suzuki-Miyaura coupling to give C-H arylation products with exclusive selectivity for mono-arylation without the requirement for steric blocking groups.

Ultra stable self-assembled monolayers of N-heterocyclic carbenes on gold.

Since the first report of thiol-based self-assembled monolayers (SAMs) 30 years ago, these structures have been examined in a huge variety of applications. The oxidative and thermal instabilities of these systems are widely known, however, and are an impediment to their widespread commercial use. Here, we describe the generation of N-heterocyclic carbene (NHC)-based SAMs on gold that demonstrate considerably greater resistance to heat and chemical reagents than the thiol-based counterparts. This increased stability is related to the increased strength of the gold-carbon bond relative to that of a gold-sulfur bond, and to a different mode of bonding in the case of the carbene ligand. Once bound to gold, NHCs are not displaced by thiols or thioethers, and are stable to high temperatures, boiling water, organic solvents, pH extremes, electrochemical cycling above 0 V and 1% hydrogen peroxide. In particular, benzimidazole-derived carbenes provide films with the highest stabilities and evidence of short-range molecular ordering. Chemical derivatization can be employed to adjust the surface properties of NHC-based SAMs.

Dioxygen adducts of rhodium N-heterocyclic carbene complexes.

Rhodium complexes functionalized by N-heterocyclic carbene ligands react with dioxygen to form adducts. Depending on the specifics of the ancillary ligands, oxygen binds to Rh either as a peroxide to form a fully oxidized Rh(III) complex, or as singlet dioxygen in a Rh(I) square planar complex. We have shown through analysis of a series of compounds, some previously published and some novel, that the presence of additional ligands that would support the formation of an octahedral geometry, as typically found with Rh(III) complexes, is critical for formation of the peroxide. In addition, we have demonstrated through DFT studies, that the potential energy surface with regard to the O-O bond length is relatively shallow, which provides a rationale for the distribution of bond lengths observed for apparently similar complexes analyzed by crystallography.

Heteroleptic rhodium NHC complexes with pyridine-derived ligands: synthetic accessibility and reactivity towards oxygen.

The synthesis, structure determination and oxidative stability of novel Rh-NHC complexes which feature pyridine-derived ligands have been described. All complexes described herein were synthesized from common dinuclear precursors of general structure [Rh(NHC)(L)Cl](2), where L is a monodentate olefin. We demonstrate that the use of these precursors is critical for the formation of all complexes since related cyclooctadiene containing precursors ([Rh(NHC)(COD)Cl]) were completely unreactive under identical conditions. We further demonstrate that complexes with the general formula [Rh(NHC)(olefin)(Py)Cl] or ([Rh(NHC)(BiPy/Phen)Cl]) are extremely sensitive to oxygen, reacting initially to give an adduct with dioxygen, and then decomposing further. The series of compounds and their oxidation products gave a remarkable range of colours which may be useful in the preparation of colourometric oxygen sensors.

Double single-crystal-to-single-crystal transformation and small-molecule activation in rhodium NHC complexes.

Three gases, one crystal: rhodium NHC complexes undergo back-to-back single-crystal-to-single-crystal transformations by selective nonreversible ligand exchange reactions. Slow diffusion of O(2) converts a dinitrogen complex into a dioxygen complex, and CO subsequently replaces O(2).