Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora, Minas Gerais, CEP: 36036-900, Brazil.
Núcleo de Pesquisa Em Química Biológica, Universidade Federal de São João Del Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG, 35501-296, Brazil.
Eur J Med Chem. 2021 Apr 5;215:113271. doi: 10.1016/j.ejmech.2021.113271. Epub 2021 Feb 8.
Chloroquine (CQ) has been the main treatment for malaria in regions where there are no resistant strains. Molecular hybridization techniques have been used as a tool in the search for new drugs and was implemented in the present study in an attempt to produce compound candidates to treat malarial infections by CQ-resistant strains. Two groups of molecules were produced from the 4-aminoquinoline ring in conjugation to hydrazones (HQ) and imines (IQ). Physicochemical and pharmacokinetic properties were found to be favorable when analyzed in silico and cytotoxicity and antiplasmodial activity were assayed in vitro and in vivo showing low cytotoxicity and selectiveness to the parasites. Candidates IQ5 and IQ6 showed important values of parasite growth inhibition in vivo on the 5th day after infection (IQ5 15 mg/kg = 72.64% and IQ6 15 mg/kg = 71.15% and 25 mg/kg = 93.7%). IQ6 also showed interaction with ferriprotoporphyrin IX similarly to CQ. The process of applying condensation reactions to yield imines is promising and capable of producing molecules with antiplasmodial activity.
氯喹（CQ）一直是无耐药株地区治疗疟疾的主要药物。分子杂交技术已被用作寻找新药的工具，并在本研究中实施，试图通过 CQ 耐药株产生治疗疟疾感染的化合物候选物。两组分子由 4-氨基喹啉环与腙（HQ）和亚胺（IQ）共轭产生。通过计算机模拟分析发现，物理化学和药代动力学性质良好，体外和体内的细胞毒性和抗疟原虫活性测定显示低细胞毒性和对寄生虫的选择性。候选物 IQ5 和 IQ6 在感染后第 5 天在体内显示出重要的寄生虫生长抑制值（IQ5 15mg/kg=72.64%，IQ6 15mg/kg=71.15%和 25mg/kg=93.7%）。IQ6 还表现出与 ferriprotoporphyrin IX 的类似 CQ 的相互作用。应用缩合反应生成亚胺的过程很有前途，能够产生具有抗疟原虫活性的分子。
