title: Exploration of thiaheterocyclic hHDAC6 inhibitors as potential antiplasmodial agents.
abstract: The recurring resistance of the malaria parasite to many drugs compels the design of innovative chemical entities in antimalarial research. Pan-histone deacetylase inhibitors (pan-HDACis) have recently been presented in the literature as powerful novel antimalarials, although their application is hampered due to toxic side effects. This drawback might be neutralized by the deployment of isoform-selective HDACis.
  
  
  
  In this study, 42 thiaheterocyclic benzohydroxamic acids, 17 of them being potent and selective hHDAC6 inhibitors, were tested to investigate a possible correlation between hHDAC6 inhibition and antiplasmodial activity.
  
  
  
  Four hHDAC6 inhibitors showed submicromolar potency against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with high selectivity indices, pointing to the relevance of exploring hHDAC6 inhibitors as potential new antiplasmodial agents.
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry & Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Rob De
authors.initials: R
authors.lastname: Vreese
authors.affiliation: Division of Pharmacology, Department of Medicine, University of Cape Town, K45, OMB Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Carmen de
authors.initials: C
authors.lastname: Kock
authors.affiliation: Division of Pharmacology, Department of Medicine, University of Cape Town, K45, OMB Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: South African Medical Research Council Drug Discovery & Development Research Unit, Department of Chemistry & Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry & Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002738:Chloroquine / Q000494:pharmacology; D003412:Cricetulus; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D002738:Chloroquine; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C006696:benzohydroxamic acid
keywords: HDAC6; Plasmodium falciparum; benzohydroxamic acids; malaria; thiaheterocycles