Natural product inspired library synthesis - Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis

Abstract

A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.

Regio‐ and Diastereoselective Organo‐Zinc‐Promoted Arylation of trans‐2,3‐Diaryloxiranes by Arylboronic Acids: Stereoselective Access to trans‐2,3‐Diphenyl‐2,3‐dihydrobenzofuran

“…The NMR spectra of the products were compared with those described in literature and confirmed the stereochemistry of both. Thus, the relative stereochemistry of all the intermediates 2b , 2c , 8a and 8b was indirectly confirmed as well…”

“…Even a chemo‐enzymatic approach exploiting the laccase‐mediated oxidative (homo)coupling of ( E )‐4‐styrylphenols was used for the synthesis of 2,3‐dihydrobenzofuran scaffolds . Recently several 2,3‐diaryl‐2,3‐dihydrobenzofurans were prepared utilizing Pd catalyzed one‐pot multicomponent reactions and ruthenium‐catalyzed intramolecular carbenoid C–H insertions, affording to cis/trans racemic mixtures, which were resolved by HPLC …”

Exploring the Multi–Target Neuroprotective Chemical Space of Benzofuran Scaffolds: A New Strategy in Drug Development for Alzheimer’s Disease

“…Thus, synthetic efforts in conjunction with the development of benzofuran based chemical libraries would provide the necessary collection of molecules to efficiently explore the multi-target neuroprotective chemical space of this scaffold, facilitating the discovery of effective pharmaceuticals against AD. Chemical libraries, which can be inspired by natural products or synthetic scaffolds, are collections of chemicals often used in high-throughput screening (Shelat and Guy, 2007;Grabowski et al, 2008;Quinn et al, 2008;Galloway et al, 2010;Gu et al, 2013;Saleeb et al, 2018). The development of chemical libraries relies on well-known and robust chemical transformations in which practitioners of organic chemistry can generate a number of variations on a defined molecular scaffold or backbone.…”

Red Fluorescent Chlamydia trachomatis Applied to Live Cell Imaging and Screening for Antibacterial Agents

“…The screening protocol could be further automated given that the biosafety aspects are properly addressed for example by using liquid handling automation placed inside safety cabinets or closed systems. Screening using Chlamydia immunostaining protocols has been validated for different Chlamydia species (Osaka et al, 2012) and has identified different classes of anti-chlamydial compounds such as salicylacylidene acylhydrazides (Muschiol et al, 2006; Wolf et al, 2006; Ur-Rehman et al, 2012; Bao et al, 2014), 8-hydroxyquinoline based inhibitors (Enquist et al, 2012), N -acylated derivatives of sulfamethoxazole and sulfafurazole (Marwaha et al, 2014), salicylacylidene acylhydrazide sulfonamide hybrids (Sunduru et al, 2015), the Chlamydia protease inhibitor-peptide Boc-Val-Pro-ValP(OPh2) (JO146) (Gloeckl et al, 2013; Ong et al, 2015), the isoflavone biochanin A (Hanski et al, 2014), dibenzocyclooctadiene lignans (Hakala et al, 2015), 2-pyridones (Engström et al, 2014; Good et al, 2016, 2017) and 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors (Saleeb et al, 2018). Screening protocols without immunostaining have also been developed previously, for example a protocol using a fluorescent lipid, 6{ N -[(7-nitrobenzo-2-oxa-1,3-diazol-4-yl)-amino]caproylsphingosine}(WHO, 2018) (C6-NBD-ceramide) that is converted to fluorescent sphingomyelin and accumulates in Chlamydia inclusions (Sandoz et al, 2012).…”