Design, Synthesis, and Biological Evaluation of Amidobenzimidazole Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds , , and were measured by a STING competition binding assay.

Structure-based analysis and biological characterization of imatinib derivatives reveal insights towards the inhibition of wild-type BCR-ABL and its mutants.

To reveal insights into the inhibition of BCR-ABL and its mutants, structure-based computing methods, such as docking, molecular dynamics (MD) simulation, the molecular mechanics generalized born surface area (MMGBSA), and biological characterizations, were employed to analyze two main pharmacophore zones and two related regions of imatinib derivatives. The hydrophobic and halogen interactions formed by the trifluoromethyl, as well as T-shaped π-π interactions formed by the pyrimidine, were confirmed. For the imatinib derivatives, the impacts of the amide moiety (region A) and the pyridine (region B) on the formed interactions were explored.

One-Pot Synthesis of O-Heterocycles or Aryl Ketones Using an InCl/EtSiH System by Switching the Solvent.

An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using EtSiH in the presence of InCl via a sequential ionic hydrogenation reaction by switching the solvent. This methodology can be used to construct C-O bonds and to prepare conjugate reduction products, including chromans, tetrahydrofurans, tetrahydropyrans, dihydroisobenzofurans, dihydrochalcones, and 1,4-diones in a facile manner. In addition, a novel plausible mechanism involving a conjugate reduction and a tandem reductive cyclization was verified by experimental investigations.

A Computational Approach to the Study of the Binding Mode of S1PR Agonists Based on the Active-Like Receptor Model.

Sphingosine-1-phosphate receptor 1 (S1PR), a member of the G protein-coupled receptor (GPCR) family, is an attractive protein target for the treatment of autoimmune diseases, and a diverse array of S1PR agonists have been developed. Rational drug design based on S1PR remains challenging due to the limited information available on the binding mode between S1PR and its agonists. In this work, the active-like state of S1PR was modeled via Gaussian accelerated molecular dynamics (GaMD) based on its inactive form, which was further validated by docking studies with two representative S1PR agonists.

Identification and Structure-Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P).

Agonism of S1P receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P modulators. In this paper we described a series of oxadiazole-based S1P direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P receptor and favorable selectivity against S1P receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered.

Diversity-Oriented Synthesis of Heterocycles: Al(OTf)-Promoted Cascade Cyclization and Ionic Hydrogenation.

An efficient and facile method has been developed for the diversity-oriented synthesis of heterocycles. Hexahydrophenoxazines, tetrahydroquinolines, indolines, hexahydrocarbazoles, and lactones were conducted via Al(OTf)-promoted cascade cyclization and ionic hydrogenation. Furthermore, this protocol was utilized to smoothly prepare piracetam and its key intermediate as well.