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Functionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights
journal contribution
posted on 2020-01-10, 14:44 authored by Shalini, Jenny Legac, Adebayo A. Adeniyi, Prishani Kisten, Philip J. Rosenthal, Parvesh Singh, Vipan KumarA series
of 25 conjugates has been synthesized to evaluate their
antiplasmodial potency and cytotoxicity against the chloroquine resistant
(CQR) W2 strain of P. falciparum and Vero kidney
cell lines, respectively. Most of the compounds showed IC50 values in the lower nM range and proved to be many fold more active
than chloroquine (CQ). The studies were extended to decipher modes
of action using techniques including UV–vis absorption, NMR
titrations, and mass spectrometry, and conclusions were strengthened
by docking and density functional theory (DFT) simulations. The most
active compound, with IC50 15 nM and selectivity index
>4000, proved to be an interesting template for antimalarial drug
discovery. To the best of our knowledge this is the first report of
a potent naphthalimide based antiplasmodial conjugate.
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UVcompoundseriesselectivityPromising Antiplasmodialsantiplasmodial potency25 conjugatesmass spectrometrysimulationFunctionalized Naphthalimide -4-aminoquinoline Conjugatesdockingdensityabsorptionantimalarial drug discoverytechniqueNMR titrationstemplateIC 50 15 nMnM rangeIC 50 valuesCQconclusionchloroquineDFTMechanistic InsightsnaphthalimideVero kidney cell linesCQRfalciparumcytotoxicityW 2 strainantiplasmodial conjugatemode
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