Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure–Activity Relationship Studies, and Biological Assessment
Rudolf MuellerVirsinha ReddyAloysius T. NchindaFanuel M. MebrahtuDale TaylorNina LawrenceLloyd TannerMarine BarnabeCharles J. EyermannBin ZouRavinder Reddy KondreddiSuresh B. LakshminarayanaMatthias RottmannLeslie J. StreetKelly Chibale
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Abstract:
A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC50 NF54 = 0.81 μM) and its methyl-substituted analogue 2 (IC50 NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC50 NF54 = 0.062 μM) and multidrug-resistant K1 (IC50 K1 = 0.054 μM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.Keywords:
hERG
Benzimidazole
IC50
Plasmodium berghei
Human ether-a-go-go related gene(hERG) encodes α subunit of Ikr potassium channel which plays an essential role in Ⅲ phase repolarization of action potential.The expression and / or function of hERG channel could be influenced by mang factors,such as diverse drugs,low temperature or low K+,which may cause the QT interval prolongation,torsade de points and even sudden cardiac death.Therefore,the research of hERG potassium channel has significance for guiding development of new drugs and individualized treatment of arrhythmia.The hERG potassium channels as anti-arrhythmic drug treatment target which plays an important roles in new drugs safety test and development.This review summarizes recent progresses of structure and functions of hERG channel,the biosynthesis process of hERG potassium channel and regulatory elements,relationship between hERG potassium channel and long QT syndrome,and treatment for abnormal expression of hERG channel,which provides reference and basis for in-depth study of hERG channel.
hERG
Potassium channel blocker
Drug Development
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Based on the scaffold of astemizole, three novel turn-on fluorescent probes (N1-N3) for human ether-a-go-go-related gene (hERG) potassium channel were developed herein. These probes have reasonable fluorescence properties, acceptable cell toxicity, and potent inhibitory activity, all of which contribute to cell imaging at the nanomolar level. Overall, these probes have the potential for setting up a screening system for hERG channels.
hERG
Astemizole
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hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.
hERG
Cardiac action potential
Potassium channel blocker
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A novel environment-sensitive probe S2 with turn-on switch for Human Ether-a-go-go-Related Gene (hERG) potassium channel was developed herein. After careful evaluation, this fluorescent probe showed high binding affinity with hERG potassium channel with an IC50 value of 41.65 nM and can be well applied to hERG channel imaging or cellular distribution study for hERG channel blockers. Compared with other imaging techniques, such as immunofluorescence and fluorescent protein-based approaches, this method is convenient and affordable, especially since a washing procedure is not needed. Meanwhile, this environment-sensitive turn-on design strategy may provide a good example for the probe development for these targets that have no reactive or catalytic activity.
hERG
Potassium channel blocker
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To study the pharmacodynamic effect of naphthoquine phosphate and its combination with artemisinin in mice infected with Plasmodium berghei. Applying orthogonal design and 4 d suppressive test to study the optimum proportion of synergetic effect. By gradually increasing drug pressure during successive weekly passages of P. berghei infection in mice, cultivate drug-resistance of P. berghei to naphthoquine phosphate, artemisinin and its combination respectively,up to 100 passages. The optimum proportion of naphthoquine phosphate and artemisinin was 1∶50. The pharmacodynamic tests revealed that the combination of these two drugs was synergetic, the synergetic indices were 4.2 and 8.2 that calculated from chloroquine-sensitive strain of P.bergher or chloroquine-resistent strain of P.bergher, respectively. The curative effects of the combination against P.bergher in mice were superior to the drug used in single. After 100 passages, the resistant indices of naphthoquine phosphate, artemisinin and the combination were 200.3, 5.6 and 4.4 respectively. The tests confirmed that the naphthoquine phosphate and its combination with artemisinin exhibited a synergetic activity against P.bergher in mice. It was also revealed that the combination could delay the emergence of drug resistance and reduce its resistance level.
Plasmodium berghei
Combination therapy
Pharmacodynamics
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hERG
Second messenger system
Potassium channel blocker
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hERG
Antiestrogen
Potassium channel blocker
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hERG
Heteronuclear molecule
PAS domain
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Objective:To investigate the effect of panax notoginseng saponins(PNS) on hERG(human ether-a-go-go related gene) potassium channel currents.Methods: Using whole-cell voltage-clamp recording techniques,we observed the effect of various concentrations of PNS on hERG potassium channel in HEK293 cells permanently transfected with this channel.Results: PNS at 100 and 300 μg·mL-1 increased hERG currents in a time-dependent manner in the hERG-transfected cells.Conclusion: PNS can increase hERG potassium currents,which may be associated with the hERG deactivation state.
hERG
Panax notoginseng
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