Lead optimisation of dehydroemetine for repositioned use in malaria

Panwar, P; Burusco, KK; Abubaker, M; Matthews, H; Gutnov, A; Fernández-Álvaro, E; Bryce, RA; Wilkinson, JA; Nirmalan, NJ

Abstract

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.]

Citation

Panwar, P., Burusco, K., Abubaker, M., Matthews, H., Gutnov, A., Fernández-Álvaro, E., …Nirmalan, N. (2020). Lead optimisation of dehydroemetine for repositioned use in malaria. Antimicrobial Agents and Chemotherapy, 64(4), 1-10. https://doi.org/10.1128/AAC.01444-19

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2019
• Online Publication Date: Jan 21, 2020
• Publication Date: Mar 24, 2020
• Deposit Date: Feb 5, 2020
• Publicly Available Date: Feb 5, 2020
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Volume: 64
• Issue: 4
• Pages: 1-10
• DOI: https://doi.org/10.1128/AAC.01444-19
• Publisher URL: https://doi-org.salford.idm.oclc.org/10.1128/AAC.01444-19
• Related Public URLs: https://aac.asm.org/
• Additional Information: Additional Information : ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1098-6596 **Article IDs: pubmed: 31964796; pii: AAC.01444-19 **History: published 21-01-2020; Access Information : "For its primary-research journals, ASM posts online PDF versions of manuscripts that have been peer reviewed and accepted but not yet copyedited. Accepted manuscripts are pub-lished online as soon as possible after acceptance, on a weeklybasis, before the copyedited, typeset articles are published. They are posted “as is” (i.e., as submitted by the authors at themodification stage) and do not reflect ASM editorial changes."; Projects : Pump Priming Award