Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 7, Pages 1450-1456Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00196
Keywords
Hybrid drug design; synthesis; structure activity relationship; antimalarial activity
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Funding
- Swarna Jayanti Fellowship, DSTPURSE II [DST/SJF-02/CSA-02/2013-14]
- DST-FIST
- Department of Biotechnology grant [BT/PR21569/NNT/28/1234/2017]
- DPRP, Department of Science and Technology, Government of India
- University Potential of Excellence 2 (University Grant Commission)
- UGC-SAP
- UGC
- Department of Science and Technology (DST-PURSE II)
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Antimalarial drug resistance is a serious obstacle in the persistent quest to eradicate malaria. There is a need for potent chemical agents that are able to act on drug-resistant Plasmodium falciparum populations at reasonable concentrations without any related toxicity to the host. By rational drug design, we envisaged to address this issue by generating a novel hybrid drug possessing two pharmacophores that can act on two unique and independent targets within the cell. We synthesized a new class of ciprofloxacinbased hybrid molecules, which have been integrated with acridine, quinolone, sulphonamide, and cinnamoyl pharmacophores (1-4). We realized a potent chloroquinolone-ciprofloxacin-based antimalarial hybrid (2, CQ-CFX) whose mechanism of action is unlike that of its parent molecules indicating a unique biological target. CQ-CFX is not only potent against CQ-resistant and susceptible strains of Plasmodium falciparum at low nanomolar concentrations (IC50 values are 63.17 +/- 1.2 nM and 25.52 +/- 4.45 nM, respectively) but is also not toxic to mammalian and bacterial systems up to 20 mu M and 1 mu M, respectively.
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