Dana Srikanta, Valissery Praveesh, Kumar Sharvan, Gurung Sumiran Kumar, Mondal Neelima, Dhar Suman Kumar, Mukhopadhyay Pritam
Supramolecular and Material Chemistry Lab, School of Physical Sciences, Jawaharlal Nehru University, New Delhi - 110067, India.
Special Center for Molecular Medicine and School of Life Sciences, Jawaharlal Nehru University, New Delhi - 110067, India.
ACS Med Chem Lett. 2020 Jun 4;11(7):1450-1456. doi: 10.1021/acsmedchemlett.0c00196. eCollection 2020 Jul 9.
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 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 (-). We realized a potent chloroquinolone-ciprofloxacin-based antimalarial hybrid (, 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 at low nanomolar concentrations (IC 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.
抗疟药物耐药性是根除疟疾这一长期目标中的严重障碍。需要有强效化学药剂，能够在合理浓度下作用于耐药群体，且对宿主无任何相关毒性。通过合理药物设计，我们设想通过生成一种新型杂合药物来解决这一问题，该药物拥有两个药效基团，可作用于细胞内两个独特且独立的靶点。我们合成了一类基于环丙沙星的新型杂合分子，其已与吖啶、喹诺酮、磺酰胺和肉桂酰药效基团（-）整合。我们实现了一种基于氯喹诺酮 - 环丙沙星的强效抗疟杂合物（，CQ - CFX），其作用机制与其母体分子不同，表明有独特的生物学靶点。CQ - CFX不仅在低纳摩尔浓度下对氯喹抗性和敏感菌株有效（IC值分别为63.17 ± 1.2 nM和25.52 ± 4.45 nM），而且分别在高达20 μM和1 μM时对哺乳动物和细菌系统无毒。
