Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials
Combining 4-Aminoquinoline- and Clotrimazole-Based Pharmacophores toward Innovative and Potent Hybrid Antimalarials
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DOI：
10.1021/jm801352s
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发表时间：
2009-01-22
影响因子：
7.3
通讯作者：
Fattorusso, Caterina
中科院分区：
文献类型：
--
作者：
Gemma, Sandra;Campiani, Giuseppe;Fattorusso, Caterina
抗疟疾药物在结构上基于新的药效团，通过低成本的合成过程合成，并且具有低抗药性的特点，因此迫切需要。最近，我们开发了一类创新的基于多芳香族药效团的抗疟疾药物。将已知的抗疟药的4-氨基喹啉或9-氨基吖啶系统与克霉唑类药效基团进行杂交，我们在这里描述了一类独特的抗疟药(4a-L和5a-c)的发展，它们选择性地与游离血红素相互作用，并干扰恶性疟原虫(PF)的血红素代谢。能够形成和稳定自由基中间体的聚芳甲基体系与4(9)-氨基喹啉-(吖啶)体系的铁络合和共轭介导的电子转移特性相结合，在体外导致了有效的抗疟疾药物对氯喹敏感和耐药的PF菌株。在所合成的化合物中，4G在口服后对沙鲍迪和伯氏假单胞菌具有体内活性，并具有良好的药代动力学特性，是进一步临床前开发的候选化合物。
Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline-(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.