Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Manu Vanaerschot, Leonardo Lucantoni, Tao Li, Jill M. Combrinck, Andrea Ruecker, T. R.Santha Kumar, Kelly Rubiano, Pedro E. Ferreira, Giulia Siciliano, Sonia Gulati, Philipp P. Henrich, Caroline L. Ng, James M. Murithi, Victoria C. Corey, Sandra Duffy, Ori J. Lieberman, M. Isabel Veiga, Robert E. Sinden, Pietro Alano, Michael J. DelvesKim Lee Sim, Elizabeth A. Winzeler, Timothy J. Egan, Stephen L. Hoffman, Vicky M. Avery, David A. Fidock

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1403-1414
Number of pages12
JournalNature Microbiology
Issue number10
StatePublished - Oct 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


Dive into the research topics of 'Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity'. Together they form a unique fingerprint.

Cite this