Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate |
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| Affiliation: | 1. Department of Science and Technology, University of Sannio, via Francesco de Sanctis snc, Benevento 82100, Italy;2. Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, I-80134 Napoli, Italy |
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| Abstract: | A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action. |
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| Keywords: | Organic synthesis Thiazinoquinones Antimalarial DFT calculations Reactive radical species Redox-based mechanism of action RBCs" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" red blood cells SARs" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" structure-activity relationships DFT" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" density functional theory DHA" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" dihydroartemisinin NAC" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" N-acetyl-" },{" #name" :" small-caps" ," _" :" l" },{" #name" :" __text__" ," _" :" -cysteine CAN" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" cerium ammonium nitrate HMEC-1" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" human microvascular endothelial cells line 1 SI" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," _" :" selectivity index BMDM" },{" #name" :" keyword" ," $" :{" id" :" k0130" }," $$" :[{" #name" :" text" ," _" :" bone marrow-derived macrophages THP-1" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," _" :" human monocytic leukaemia cells MD" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," _" :" molecular dynamics SA" },{" #name" :" keyword" ," $" :{" id" :" k0160" }," $$" :[{" #name" :" text" ," _" :" Simulated annealing MM" },{" #name" :" keyword" ," $" :{" id" :" k0170" }," $$" :[{" #name" :" text" ," _" :" molecular mechanics GM" },{" #name" :" keyword" ," $" :{" id" :" k0180" }," $$" :[{" #name" :" text" ," _" :" global minimum C-PCM" },{" #name" :" keyword" ," $" :{" id" :" k0190" }," $$" :[{" #name" :" text" ," _" :" conductor-like polarizable continuum model RMSD" },{" #name" :" keyword" ," $" :{" id" :" k0200" }," $$" :[{" #name" :" text" ," _" :" root mean square deviation LUMO" },{" #name" :" keyword" ," $" :{" id" :" k0210" }," $$" :[{" #name" :" text" ," _" :" lowest unoccupied molecular orbital NBO" },{" #name" :" keyword" ," $" :{" id" :" k0220" }," $$" :[{" #name" :" text" ," _" :" natural bond orbitals GSH" },{" #name" :" keyword" ," $" :{" id" :" k0230" }," $$" :[{" #name" :" text" ," _" :" glutathione iRBCs" },{" #name" :" keyword" ," $" :{" id" :" k0240" }," $$" :[{" #name" :" text" ," _" :" infected red blood cells ACT" },{" #name" :" keyword" ," $" :{" id" :" k0250" }," $$" :[{" #name" :" text" ," _" :" artemisinin-based combination therapy |
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