In vitro activity of rhinacanthin analogues against drug resistant Plasmodium falciparum isolates from Northeast Thailand
Issued Date
2023-12-01
Resource Type
eISSN
14752875
Scopus ID
2-s2.0-85150896792
Pubmed ID
36959593
Journal Title
Malaria Journal
Volume
22
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Malaria Journal Vol.22 No.1 (2023)
Suggested Citation
Chaorattanakawee S., Kosaisavee V., Bunsermyos W., Aonsri C., Imaram W., Suwannasin K., Kunasol C., Thamnurak C., Boonyalai N., Saunders D., Dondorp A.M., Mungthin M., Imwong M. In vitro activity of rhinacanthin analogues against drug resistant Plasmodium falciparum isolates from Northeast Thailand. Malaria Journal Vol.22 No.1 (2023). doi:10.1186/s12936-023-04532-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81392
Title
In vitro activity of rhinacanthin analogues against drug resistant Plasmodium falciparum isolates from Northeast Thailand
Author's Affiliation
Faculty of Tropical Medicine, Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
Kasetsart University
Armed Forces Research Institute of Medical Sciences, Thailand
Mahidol University
Nuffield Department of Medicine
Phramongkutklao College of Medicine
Uniformed Services University of the Health Sciences
Mahidol Oxford Tropical Medicine Research Unit
Kasetsart University
Armed Forces Research Institute of Medical Sciences, Thailand
Mahidol University
Nuffield Department of Medicine
Phramongkutklao College of Medicine
Uniformed Services University of the Health Sciences
Other Contributor(s)
Abstract
Background: New anti-malarial drugs are needed urgently to address the increasing challenges of drug-resistant falciparum malaria. Two rhinacanthin analogues containing a naphthoquinone moiety resembling atovaquone showed promising in-vitro activity against a P. falciparum laboratory reference strain (K1). The anti-malarial activity of these 2 compounds was further evaluated for P. falciparum field isolates from an area of multi-drug resistance in Northeast Thailand. Methods: Using a pLDH enzyme-linked immunosorbent assay, four P. falciparum isolates from Northeast Thailand in 2018 were tested for in vitro sensitivity to the two synthetic rhinacanthin analogues 1 and 2 as well as established anti-malarials. Mutations in the P. falciparum cytochrome b gene, a marker for atovaquone (ATQ) resistance, were genotyped in all four field isolates as well as 100 other clinical isolates from the same area using PCR-artificial Restriction Fragment Length Polymorphisms. Pfkelch13 mutations, a marker for artemisinin (ART) resistance, were also examined in all isolates. Results: The 50% inhibitory concentrations (IC50) of P. falciparum field isolates for rhinacanthin analogue 1 was 321.9–791.1 nM (median = 403.1 nM). Parasites were more sensitive to analogue 2: IC50 48.6–63.3 nM (median = 52.2 nM). Similar results were obtained against P. falciparum reference laboratory strains 3D7 and W2. The ART-resistant IPC-5202 laboratory strain was more sensitive to these compounds with a median IC50 45.9 and 3.3 nM for rhinacanthin analogues 1 and 2, respectively. The ATQ-resistant C2B laboratory strain showed high-grade resistance towards both compounds (IC50 > 15,000 nM), and there was a strong positive correlation between the IC50 values for these compounds and ATQ (r = 0.83–0.97, P < 0.001). There were no P. falciparum cytochrome b mutations observed in the field isolates, indicating that P. falciparum isolates from this area remained ATQ-sensitive. Pfkelch13 mutations and the ring-stage survival assay confirmed that most isolates were resistant to ART. Conclusions: Two rhinacanthin analogues showed parasiticidal activity against multi-drug resistant P. falciparum isolates, although less potent than ATQ. Rhinacanthin analogue 2 was more potent than analogue 1, and can be a lead compound for further optimization as an anti-malarial in areas with multidrug resistance.