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dc.contributor.authorFelicetti, T
dc.contributor.authorBurali, MS
dc.contributor.authorGwee, CP
dc.contributor.authorKi Chan, KW
dc.contributor.authorAlonso, S
dc.contributor.authorMassari, S
dc.contributor.authorSabatini, S
dc.contributor.authorTabarrini, O
dc.contributor.authorBarreca, ML
dc.contributor.authorCecchetti, V
dc.contributor.authorVasudevan, SG
dc.contributor.authorManfroni, G
dc.date.accessioned2021-06-08T05:29:50Z
dc.date.available2021-06-08T05:29:50Z
dc.date.issued2021
dc.identifier.issn0223-5234
dc.identifier.doi10.1016/j.ejmech.2020.112992
dc.identifier.urihttp://hdl.handle.net/10072/405000
dc.description.abstractThe mosquito-borne viruses belonging to the genus Flavivirus such as Dengue virus (DENV) and Zika virus (ZIKV) cause human infections ranging from mild flu-like symptoms to hemorrhagic fevers, hepatitis, and neuropathies. To date, there are vaccines only for few flaviviruses while no effective treatments are available. Pyridobenzothiazole (PBTZ) derivatives are a class of compounds endowed with a promising broad-spectrum anti-flavivirus activity and most of them have been reported as potent inhibitors of the flaviviral NS5 polymerase. However, synthesis of PBTZ analogues entails a high number of purification steps, the use of hazardous reagents and environmentally unsustainable generation of waste. Considering the promising antiviral activity of PBTZ analogues which require further exploration, in this work, we report the development of a new and sustainable three-component reaction (3CR) that can be combined with a basic hydrolysis in a one-pot procedure to obtain the PBTZ scaffold, thus reducing the number of synthetic steps, improving yields and saving time. 3CR was significantly explored in order to demonstrate its wide scope by using different starting materials. In addition, taking advantage of these procedures, we next designed and synthesized a new set of PBTZ analogues that were tested as anti-DENV-2 and anti-ZIKV agents. Compound 22 inhibited DENV-2 NS5 polymerase with an IC50 of 10.4 μM and represented the best anti-flavivirus compound of the new series by inhibiting DENV-2- and ZIKV-infected cells with EC50 values of 1.2 and 5.0 μM, respectively, that translates into attractive selectivity indexes (SI - 83 and 20, respectively). These results strongly reaffirm PBTZ derivatives as promising anti-flavivirus agents that now can be synthesized through a convenient and sustainable 3CR in order to obtain more potent compounds for further pre-clinical development studies.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherElsevier BV
dc.relation.ispartofpagefrom112992
dc.relation.ispartofjournalEuropean Journal of Medicinal Chemistry
dc.relation.ispartofvolume210
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3405
dc.subject.fieldofresearchcode3214
dc.subject.keywordsAntiviral agents
dc.subject.keywordsDengue inhibitors
dc.subject.keywordsNS5 polymerase
dc.subject.keywordsOne-pot procedure
dc.subject.keywordsThree-component reaction (3CR)
dc.titleSustainable, three-component, one-pot procedure to obtain active anti-flavivirus agents
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationFelicetti, T; Burali, MS; Gwee, CP; Ki Chan, KW; Alonso, S; Massari, S; Sabatini, S; Tabarrini, O; Barreca, ML; Cecchetti, V; Vasudevan, SG; Manfroni, G, Sustainable, three-component, one-pot procedure to obtain active anti-flavivirus agents, European Journal of Medicinal Chemistry, 2021, 210, pp. 112992
dcterms.dateAccepted2020-11-02
dc.date.updated2021-06-08T03:03:42Z
gro.hasfulltextNo Full Text
gro.griffith.authorVasudevan, Subhash


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