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Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity

Relitti, Nicola; Federico, Stefano; Pozzetti, Luca; Butini, Stefania; Lamponi, Stefania; Taramelli, Donatella; D'Alessandro, Sarah; Martin, Rowena; Shafik, Sarah; Summers, Robert; Babij, Simone; Habluetzel, Annette; Tapanelli, Sofia; Caldelari, Reto; Gemma, Sandra; Campiani, Giuseppe

Description

Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite’s digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to...[Show more]

dc.contributor.authorRelitti, Nicola
dc.contributor.authorFederico, Stefano
dc.contributor.authorPozzetti, Luca
dc.contributor.authorButini, Stefania
dc.contributor.authorLamponi, Stefania
dc.contributor.authorTaramelli, Donatella
dc.contributor.authorD'Alessandro, Sarah
dc.contributor.authorMartin, Rowena
dc.contributor.authorShafik, Sarah
dc.contributor.authorSummers, Robert
dc.contributor.authorBabij, Simone
dc.contributor.authorHabluetzel, Annette
dc.contributor.authorTapanelli, Sofia
dc.contributor.authorCaldelari, Reto
dc.contributor.authorGemma, Sandra
dc.contributor.authorCampiani, Giuseppe
dc.date.accessioned2023-02-08T23:56:13Z
dc.identifier.issn0223-5234
dc.identifier.urihttp://hdl.handle.net/1885/285095
dc.description.abstractDue to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite’s digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.
dc.description.sponsorshipFinancial contribution from MIUR is kindly acknowledged (Project PRIN 20154JRJPP)
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherElsevier
dc.rights© 2021 Elsevier Masson SAS
dc.sourceEuropean Journal of Medicinal Chemistry
dc.subjectMalaria
dc.subjectPlasmodium falciparum
dc.subjectChloroquine resistance
dc.subjectPfCRT
dc.subjectChemosensitization
dc.subjectLiver-stage antimalarial
dc.subjectXenopus oocytes
dc.titleSynthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume215
dc.date.issued2021
local.identifier.absfor310702 - Infectious agents
local.identifier.absfor310100 - Biochemistry and cell biology
local.identifier.ariespublicationa383154xPUB17646
local.publisher.urlhttps://www.elsevier.com/en-au
local.type.statusPublished Version
local.contributor.affiliationRelitti, Nicola, University of Siena
local.contributor.affiliationFederico, Stefano, University of Siena
local.contributor.affiliationPozzetti, Luca, University of Siena
local.contributor.affiliationButini, Stefania, University of Siena
local.contributor.affiliationLamponi, Stefania, University of Siena
local.contributor.affiliationTaramelli, Donatella, University of Milan
local.contributor.affiliationD'Alessandro, Sarah, University of Milan
local.contributor.affiliationMartin, Rowena, RSCH Research & Innovation Portfolio, ANU
local.contributor.affiliationShafik, Sarah, College of Science, ANU
local.contributor.affiliationSummers, Robert, College of Science, ANU
local.contributor.affiliationBabij, Simone, College of Science, ANU
local.contributor.affiliationHabluetzel, Annette, University of Camerino
local.contributor.affiliationTapanelli, Sofia, University of Camerino
local.contributor.affiliationCaldelari, Reto, University of Bern
local.contributor.affiliationGemma, Sandra, Università di Siena
local.contributor.affiliationCampiani, Giuseppe, University of Siena
local.description.embargo2099-12-31
local.bibliographicCitation.startpage1
local.bibliographicCitation.lastpage16
local.identifier.doi10.1016/j.ejmech.2021.113227
dc.date.updated2023-12-17T07:16:03Z
local.identifier.scopusID2-s2.0-85101867879
local.identifier.thomsonIDWOS:000634820600005
CollectionsANU Research Publications

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