Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure–Activity Relationship Studies, and Biological Assessment

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.

Synthesis and Evaluation of Chalcone-Quinoline Based Molecular Hybrids as Potential Anti-Malarial Agents

“…The solutions were analyzed by means of HPLC-DAD (Agilent1200 Rapid Resolution HPLC with a diode array detector). Best fit calibration curves were constructed using the calibration standards, which were used to determine the aqueous samples’ solubility [ 1 , 37 ].…”

“…The plates were kept in the dark for about 10 min to fully develop, and absorbance was measured at 620 nm on a microplate reader. Raw data were exported to Microsoft Excel for dose-response analysis [ 1 , 37 ].…”

“…Malaria is a life-threatening disease caused by the Plasmodium parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes [ 1 ]. Pregnant women, children under the age of 5 years, and people with weakened immune system are most likely to succumb to the morbidity and transience of the disease [ 2 , 3 ].…”

“…However, large scale use of CQ soon led to the emergence of CQ-resistant parasite strains [ 2 ]. Many other alternative drugs followed, including artemisinin combined therapies (ACTs), which for some time became one of the most effective, especially against P. falciparum , allowing millions of patients to be cured [ 1 , 2 , 3 , 6 , 7 , 8 ]. However, recent evidence of resistance to artemisinin reported in South Asia and along the Cambodia–Thailand border threatens this strategy [ 9 ].…”

Benzimidazole as a Promising Antiviral Heterocyclic Scaffold: A Review

“…Lerisetron 6 acts as an antihistaminic agent. It also shows effective antiemetic and clinical studies against nausea related to cancer chemotherapy [25].…”