Exploiting Chemical Toolboxes for the Expedited Generation of Tetracyclic Quinolines as a Novel Class of PXR Agonists

Abstract

The discovery of lead compounds relies on the iterative generation of structure−activity relationship data resulting from the synthesis and biological evaluation of hit analogues. Using traditional approaches, a significant time delay may occur from compound design to results, leading to slow and expensive hit-to-lead explorations. Herein, we have exploited the use of chemical toolboxes to expedite lead discovery and optimization. In particular, the integration of flow synthesizers, automation, process analytical technologies, and computational chemistry has provided a prototype system enabling the multicomponent flow synthesis, in-line analysis, and characterization of chiral tetracyclic quinolines as a novel class of PXR agonists. Within 29 compounds, a novel template 19b (3aS,11R,11aS) was identified with an EC 50 of 1.2 μM (efficacy 119%) at the PXR receptor.

Flow Synthesis of Biologically-Relevant Compound Libraries

“…This combined system allowed the synthesis of 22 products that have displayed biological activity in preliminary in vitro essays. As a continuation of this work, a study on the synthesis of tetracyclic quinolines, to be tested as ligands of the Pregnane X receptor (PXR), was performed by the same authors [34]. The choice of using PEG300 as co-solvent made the purification procedure more complex, but, on the other hand, it was essential as it prevented the precipitation of the aniline chlorohydrates inside the system.…”

“…This combined system allowed the synthesis of 22 products that have displayed biological activity in preliminary in vitro essays. As a continuation of this work, a study on the synthesis of tetracyclic quinolines, to be tested as ligands of the Pregnane X receptor (PXR), was performed by the same authors [34].…”

Meroterpene-Like α-Glucosidase Inhibitors Based on Biomimetic Reactions Starting from β-Caryophyllene

“…To assign the absolute configurations (ACs) of those newly formed chiral carbons (C-4 and C-5) unambiguously, we carried out ECD calculations [36,37] and compared the calculated curves with the experimental ones. The skeletons 1 and 2 possess the same planar structures but inverse chiralities at C-4 and C-5.…”

“…The ACs of 3a and 4a were also determined by ECD associated with the calculated spectra ( Figure 1b). The halogen (Cl or Br)-substituted products b and c in the series 1-4 had the same Cotton effect as the To assign the absolute configurations (ACs) of those newly formed chiral carbons (C-4 and C-5) unambiguously, we carried out ECD calculations [36,37] and compared the calculated curves with the experimental ones. The skeletons 1 and 2 possess the same planar structures but inverse chiralities at C-4 and C-5.…”

Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines

“…Herein, we would like to disclose a novel interrupted Ugi reaction, exploiting for the first time the imidazole ring, as a soft nucleophile able to intramolecularly intercept the nascent nitrilium ion. This intermediate enables the formation of otherwise synthetically challenging substituted imidazopyrazines, in excellent yields and under mild reaction conditions (r.t. in MeOH) Multicomponent reactions represent a powerful chemical tool to expedite medicinal chemistry and early drug discovery programs [29], especially when combined with automation and flow synthesis [30,31,32].…”