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Two rhinacanthin analogues containing a naphthoquinone moiety resembling atovaquone showed promising in-vitro activity against a <jats:italic>P. falciparum<\/jats:italic> laboratory reference strain (K1). The anti-malarial activity of these 2 compounds was further evaluated for <jats:italic>P. falciparum<\/jats:italic> field isolates from an area of multi-drug resistance in Northeast Thailand.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Using a pLDH enzyme-linked immunosorbent assay, four <jats:italic>P. falciparum<\/jats:italic> 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 <jats:italic>P. falciparum<\/jats:italic> 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. <jats:italic>Pfkelch13<\/jats:italic> mutations, a marker for artemisinin (ART) resistance, were also examined in all isolates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The 50% inhibitory concentrations (IC<jats:sub>50<\/jats:sub>) of <jats:italic>P. falciparum<\/jats:italic> field isolates for rhinacanthin analogue 1 was 321.9\u2013791.1\u00a0nM (median\u2009=\u2009403.1\u00a0nM). Parasites were more sensitive to analogue 2: IC<jats:sub>50<\/jats:sub> 48.6\u201363.3\u00a0nM (median\u2009=\u200952.2\u00a0nM). Similar results were obtained against <jats:italic>P. falciparum<\/jats:italic> reference laboratory strains 3D7 and W2. The ART-resistant IPC-5202 laboratory strain was more sensitive to these compounds with a median IC<jats:sub>50<\/jats:sub> 45.9 and 3.3\u00a0nM for rhinacanthin analogues 1 and 2, respectively. The ATQ-resistant C2B laboratory strain showed high-grade resistance towards both compounds (IC<jats:sub>50<\/jats:sub>\u2009&gt;\u200915,000\u00a0nM), and there was a strong positive correlation between the IC<jats:sub>50<\/jats:sub> values for these compounds and ATQ (r\u2009=\u20090.83\u20130.97, P\u2009&lt;\u20090.001). There were no <jats:italic>P. falciparum<\/jats:italic> cytochrome b mutations observed in the field isolates, indicating that <jats:italic>P. falciparum<\/jats:italic> isolates from this area remained ATQ-sensitive. <jats:italic>Pfkelch13<\/jats:italic> mutations and the ring-stage survival assay confirmed that most isolates were resistant to ART.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Two rhinacanthin analogues showed parasiticidal activity against multi-drug resistant <jats:italic>P. falciparum<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-023-04532-3","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T07:04:11Z","timestamp":1679555051000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In vitro activity of rhinacanthin analogues against drug resistant Plasmodium falciparum isolates from Northeast Thailand"],"prefix":"10.1186","volume":"22","author":[{"given":"Suwanna","family":"Chaorattanakawee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varakorn","family":"Kosaisavee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Watanyu","family":"Bunsermyos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaiyawat","family":"Aonsri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witcha","family":"Imaram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanokon","family":"Suwannasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanon","family":"Kunasol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chatchadaporn","family":"Thamnurak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonlawat","family":"Boonyalai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjen M.","family":"Dondorp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathirut","family":"Mungthin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallika","family":"Imwong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"4532_CR1","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/S1473-3099(19)30391-3","volume":"19","author":"RW van der Pluijm","year":"2019","unstructured":"van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, et al. 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