Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C. S. Lee, Sergio Wittlin, Diogo Rodrigo Magalhães Moreira, Lyn-Marie Birkholtz and Kelly Chibale*,
{"title":"阿司咪唑的新型氮杂苯并咪唑类似物的 hERG、疟原虫生命周期和交叉耐药性分析","authors":"Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C. S. Lee, Sergio Wittlin, Diogo Rodrigo Magalhães Moreira, Lyn-Marie Birkholtz and Kelly Chibale*, ","doi":"10.1021/acsmedchemlett.3c00496","DOIUrl":null,"url":null,"abstract":"<p >Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC<sub>50</sub> = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound <b>1</b> (<i>Pf</i> NF54 IC<sub>50</sub> = 0.012 μM; hERG IC<sub>50</sub> = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound <b>11</b> retained <i>in vitro</i> multistage antiplasmodium activity (ABS <i>Pf</i>NF54 IC<sub>50</sub> = 0.017 μM; gametocytes <i>Pf</i>iGc/<i>Pf</i>LGc IC<sub>50</sub> = 1.24/1.39 μM, and liver-stage <i>Pb</i>HepG2 IC<sub>50</sub> = 2.30 μM), good microsomal metabolic stability (MLM CL<sub>int</sub> < 11 μL·min<sup>–1</sup>·mg<sup>–1</sup>, <i>E</i><sub>H</sub> < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to <b>1</b> and AST, respectively. Despite the excellent <i>in vitro</i> antiplasmodium activity profile, <i>in vivo</i> efficacy in the <i>Plasmodium berghei</i> mouse infection model was diminished, attributable to suboptimal oral bioavailability (<i>F</i> = 14.9%) at 10 mg·kg<sup>–1</sup> resulting from poor permeability (log <i>D</i><sub>7.4</sub> = −0.82). No cross-resistance was observed against 44 common <i>Pf</i> mutant lines, suggesting activity via a novel mechanism of action.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.3c00496","citationCount":"0","resultStr":"{\"title\":\"hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole\",\"authors\":\"Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C. S. 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It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to <b>1</b> and AST, respectively. Despite the excellent <i>in vitro</i> antiplasmodium activity profile, <i>in vivo</i> efficacy in the <i>Plasmodium berghei</i> mouse infection model was diminished, attributable to suboptimal oral bioavailability (<i>F</i> = 14.9%) at 10 mg·kg<sup>–1</sup> resulting from poor permeability (log <i>D</i><sub>7.4</sub> = −0.82). 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hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint < 11 μL·min–1·mg–1, EH < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg–1 resulting from poor permeability (log D7.4 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.