Synthesis of Novel Ciprofloxacin-Based Hybrid Molecules toward Potent Antimalarial Activity

• Published in: ACS medicinal chemistry letters Vol. 11; no. 7; pp. 1450 - 1456
• Main Authors: Dana, Srikanta, Valissery, Praveesh, Kumar, Sharvan, Gurung, Sumiran Kumar, Mondal, Neelima, Dhar, Suman Kumar, Mukhopadhyay, Pritam
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.07.2020; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; synthesis; Hybrid drug design; structure activity relationship; antimalarial activity; ANTIBIOTICS; DESIGN; PROTEIN; MODE; CHLOROQUINE; DRUGS; PARASITE PLASMODIUM-FALCIPARUM; BINDING; ORGANELLE
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.0c00196

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 ciprofloxacin-based 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 μM and 1 μM, respectively.