ArticleNature microbiology2017
Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity.
Article in Nature microbiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 53 citations in OpenAlex.
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- De Novo Molecular Design and Bioactivity Prediction of Novel Hexahydroquinolines asBioinformatics and biology insights · 2026Article
- Emerging insights into chemistry and therapeutic potentials of functionalized hexahydroquinolines.Frontiers in chemistry · 2026Review
- Heme processing in the malaria parasite, Plasmodium falciparum: a time-dependent basal-level analysis.Communications biology · 2025Article
- Systematic in vitro evolution inScience (New York, N.Y.) · 2024Article
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- Optimization of diastereomeric dihydropyridines as antimalarials.European journal of medicinal chemistry · 2024Article
- Catalyst-free synthesis of highly functionalized triazole hexahydroquinoline carbohydrazide scaffolds via four-component cyclocondensation reaction.Molecular diversity · 2024Article
- Employing Hexahydroquinolines asAdvances and applications in bioinformatics and chemistry : AABC · 2024Article
- Isoliensinine from Cissampelos pariera rhizomes exhibits potential gametocytocidal and anti-malarial activities against Plasmodium falciparum clinical isolates.Malaria journal · 2023Article
- Identification and characterisation of the haemozoin of Haemonchus contortus.Parasites & vectors · 2023Article
- Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex.Frontiers in cellular and infection microbiology · 2022Article
- Quantifying Reductions inFrontiers in immunology · 2022Article
- Protecting future antimalarials from the trap of resistance: Lessons from artemisinin-based combination therapy (ACT) failures.Journal of pharmaceutical analysis · 2021Review
- Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials.Trends in parasitology · 2021Review
- The antimalarial MMV688533 provides potential for single-dose cures with a high barrier toScience translational medicine · 2021Article
- Heme Detoxification in the Malaria Parasite: A Target for Antimalarial Drug Development.Accounts of chemical research · 2021Review
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26 authors at 9 institutions in 7 countries.
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Abstract
Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.