Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies

Dziwornu Godwin Akpeko; Coertzen Dina; Leshabane Meta; Korkor Constance M.; Cloete Cleavon K.; Njoroge Mathew; Gibhard Liezl; Lawrence Nina; Reader Janette; van der Watt Mariette; Wittlin Sergio; Birkholtz Lyn-Marie; Chibale Kelly

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Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies

机译：掺入酚类植物碱基侧链的抗疟苯并咪唑衍生物抑制微管和血液沸蛋白形成：结构 - 活性关系和体内口腔疗效研究

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A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the H-1-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the H-1-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 x 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.

机译：本文报道了一系列新的抗疟苯并咪唑衍生物，其C2位含有酚曼尼希碱侧链，具有双重无性血液和性阶段活性。构效关系研究表明，1-苄基苯并咪唑类似物具有亚微摩尔无性血期和性期活性，而H-1-苯并咪唑类似物仅对无性血期（ABS）寄生虫有效。此外，前者在ABS寄生虫中表现出微管抑制活性，但在II/III期配子体中更为显著。H-1-苯并咪唑类似物除了是血红素形成的真正抑制剂外，还显示出对微管的抑制作用。对伯氏疟原虫感染小鼠的体内药效研究表明，当以4 x 50 mg/kg的剂量口服时，先导化合物41表现出较高的药效（寄生虫血症降低98%）。一般来说，这些化合物对哺乳动物细胞没有细胞毒性。

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《Journal of Medicinal Chemistry》 |2021年第8期|共18页
作者
Dziwornu Godwin Akpeko; Coertzen Dina; Leshabane Meta; Korkor Constance M.; Cloete Cleavon K.; Njoroge Mathew; Gibhard Liezl; Lawrence Nina; Reader Janette; van der Watt Mariette; Wittlin Sergio; Birkholtz Lyn-Marie; Chibale Kelly;
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作者单位

Univ Cape Town Dept Chem ZA-7701 Rondebosch South Africa;

Univ Pretoria Inst Sustainable Malaria Control Dept Biochem Genet &

Microbiol ZA-0028 Hatfield South Africa;

Univ Pretoria Inst Sustainable Malaria Control Dept Biochem Genet &

Microbiol ZA-0028 Hatfield South Africa;

Univ Cape Town Dept Chem ZA-7701 Rondebosch South Africa;

Univ Cape Town Dept Chem ZA-7701 Rondebosch South Africa;

Univ Cape Town Drug Discovery &

Dev Ctr H3D Dept Med Div Clin Pharmacol ZA-7925 Cape Town South Africa;

Univ Cape Town Drug Discovery &

Dev Ctr H3D Dept Med Div Clin Pharmacol ZA-7925 Cape Town South Africa;

Univ Cape Town Drug Discovery &

Dev Ctr H3D Dept Med Div Clin Pharmacol ZA-7925 Cape Town South Africa;

Univ Pretoria Inst Sustainable Malaria Control Dept Biochem Genet &

Microbiol ZA-0028 Hatfield South Africa;

Univ Pretoria Inst Sustainable Malaria Control Dept Biochem Genet &

Microbiol ZA-0028 Hatfield South Africa;

Swiss Trop &

Publ Hlth Inst CH-4002 Basel Switzerland;

Univ Pretoria Inst Sustainable Malaria Control Dept Biochem Genet &

Microbiol ZA-0028 Hatfield South Africa;

Univ Cape Town Inst Infect Dis &

Mol Med Dept Chem ZA-7701 Rondebosch South Africa;

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正文语种 eng
中图分类药学;
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Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies

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