Elaboration of a benzofuran scaffold and evaluation of binding affinity and inhibition of Escherichia coli DsbA: A fragment-based drug design approach to novel antivirulence compounds

Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity

“…BZFs have been shown to posses several biologically interesting activities, including anticancer and antiviral activities ( Delogu et al, 2022 ; Duncan et al, 2021 ; Era et al, 2020 ; Fais et al, 2019 ; Ferino et al, 2013 ; Galal et al, 2009 ; Geldenhuys et al, 2012 ; Jiang et al, 2008 ; Kumar et al, 2018 ; Pisani et al, 2013 ; Van Dyk et al, 2015 ; Xu et al, 2019 ). Firstly, BZFs can be isolated from natural products such as: Machilus glaucescens, Ophryosporus charua, Ophryosporus lorentzii, Krameria ramosissima, Ammi majus L., and Zanthoxylum ailanthoidoland presenting antihyperglycemic, analgesic, antiparasitic, antimicrobial, antitumor and kinase inhibitory properties ( Khanam and Shamsuzzaman, 2015 ); secondly, BZFs are included in commonly used medicines all of them showing a good bioavailability among the species tested: amiodarone, ailanthoidol, bufurarol β-adrenoceptor antagonist, opioids (i.e.…”

“…To identify novel antiviral agents and given the reported STING-agonist activity of benzothiophene ( Pan et al, 2020 ) and benzimidazole derivatives ( Zhu et al, 2021 ), we studied the activity of a new series of benzofurans derivatives (BZFs), whose scaffold is a bioisostere of both benzothiophene and benzimidazole substructures ( Barillari and Brown, 2012 ; Brown, 2012 ). Furthermore, BZF is a common moiety present in many biologically active natural and therapeutic compounds representing a suitable scaffold for the development of novel bioactive molecules ( Duncan et al, 2021 ; Khanam and Shamsuzzaman, 2015 ; Miao et al, 2019 ; Naik et al, 2015 ; Nevagi et al, 2015 ; Pan et al, 2020 ; Xu et al, 2019 ). Hence, thirteen in house BZF derivatives bearing different substituents were selected ( Delogu et al, 2022 , 2021 , 2016 ), and subjected to biological assay to assess their ability to induce IFN and to inhibit viral replication.…”

A Buried Water Network Modulates the Activity of the Escherichia coli Disulphide Catalyst DsbA

“…Five DsbA mutants, E24A, E37A, K58A, E24A/K58A and E24A/E37A/K58A, were constructed using site-directed mutagenesis. DsbA wildtype and mutants were expressed and purified as previously described [42]. CD spectroscopy wavelength scan results showed that the overall fold and distribution of secondary structural elements were not affected by the introduced mutations (Supplementary Figure S1).…”

Towards solvent regulated self-activation of N-terminal disulfide bond oxidoreductase-D

“…DsbA targeted inhibitor compounds have been designed, following the central role of enzymes in bacterial pathogenicity. 10 Later on, the identification of DsbD, an oxidoreductase assisting in the isomerization (correction of the mispaired S-S bond), which is crucial in meningitis-causing Neisseria bacteria, initiated the exploration for new disulfide bond targets. 11,12 DsbD is a multidomain enzyme in Gram-negative bacteria, with the N-terminal domain (nDsbD) acting as the redox hub.…”