Open AccessFunctionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights
Author(s) -
. Shalini,
Jenny Legac,
Adebayo A. Adeniyi,
Prishani Kisten,
Philip J. Rosenthal,
Parvesh Singh,
Vipan Kumar
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00521
Subject(s) - conjugate , chemistry , cytotoxicity , combinatorial chemistry , docking (animal) , titration , ic50 , stereochemistry , density functional theory , chloroquine , in vitro , biochemistry , computational chemistry , organic chemistry , biology , malaria , medicine , mathematical analysis , mathematics , nursing , immunology
A 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 IC 50 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 IC 50 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.