Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.
Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.
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DOI：
10.1021/acs.jmedchem.7b00738
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发表时间：
2018-02-22
影响因子：
7.3
通讯作者：
Manetsch R
中科院分区：
文献类型：
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作者：
Neelarapu R;Maignan JR;Lichorowic CL;Monastyrskyi A;Mutka TS;LaCrue AN;Blake LD;Casandra D;Mashkouri S;Burrows JN;Willis PA;Kyle DE;Manetsch R
在过去10至15年中，疟疾死亡人数一直在下降，全球死亡率自2000年以来下降了47%。虽然世界卫生组织（世卫组织）建议使用以青蒿素为基础的联合疗法来防治疟疾，但青蒿素耐药菌株的出现突出表明有必要开发新的抗疟疾药物。历史上的抗疟药物ICI 56780最近的体内疗效有所提高，但由于其溶解度差，耐药发展迅速，该化合物需要进一步优化。利用构效关系（SAR）和构性关系（SPR）研究了一系列具有较强溶解度的含哌嗪的4(1H)-喹诺酮类药物。此外，有希望的化合物被选择用于体内侦察试验，以缩小在体内汤普森试验中测试的选择范围。最后，两种含哌嗪的4(1H)-喹诺酮类药物在常规汤普森试验中具有疗效，并且对寄生虫的肝脏阶段也显示出体内活性。
Malaria deaths have been decreasing over the last 10–15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure–activity relationship (SAR) and structure–property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.
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影响因子：
17.1
作者：
Nilsen A;LaCrue AN;White KL;Forquer IP;Cross RM;Marfurt J;Mather MW;Delves MJ;Shackleford DM;Saenz FE;Morrisey JM;Steuten J;Mutka T;Li Y;Wirjanata G;Ryan E;Duffy S;Kelly JX;Sebayang BF;Zeeman AM;Noviyanti R;Sinden RE;Kocken CHM;Price RN;Avery VM;Angulo-Barturen I;Jiménez-Díaz MB;Ferrer S;Herreros E;Sanz LM;Gamo FJ;Bathurst I;Burrows JN;Siegl P;Guy RK;Winter RW;Vaidya AB;Charman SA;Kyle DE;Manetsch R;Riscoe MK
通讯作者：
Riscoe MK
影响因子：
--
作者：
Cowley, Robin;Leung, Suet;O'Neill, Paul M.
通讯作者：
O'Neill, Paul M.
影响因子：
2.7
作者：
Bueno, Jose M.;Manzano, Pilar;Gargallo-Viola, Domingo
通讯作者：
Gargallo-Viola, Domingo
影响因子：
7.3
作者：
Cross, R. Matthew;Namelikonda, Niranjan K.;Mutka, Tina S.;Luong, Lisa;Kyle, Dennis E.;Manetsch, Roman
通讯作者：
Manetsch, Roman
影响因子：
7.3
作者：
Cross, R. Matthew;Maignan, Jordany R.;Manetsch, Roman
通讯作者：
Manetsch, Roman