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As such, there is an increasing need to find new alternative strategies. This study evaluated and validated 2 medicinal plants used in traditional medicine to treat malaria.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Inspired by their ethnobotanical reputation of being effective against malaria, <jats:italic>Ziziphus mucronata<\/jats:italic> and <jats:italic>Xysmalobium undulutum<\/jats:italic> were collected and sequentially extracted using hexane (HEX), ethyl acetate (ETA), Dichloromethane (DCM) and methanol (MTL). The resulting crude extracts were screened for their anti-malarial and cytotoxic potential using the parasite lactate dehydrogenase (pLDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, respectively. This was followed by isolating the active compounds from the DCM extract of <jats:italic>Z. mucronata<\/jats:italic> using silica gel chromatography and structural elucidation using spectroscopic techniques (NMR: <jats:sup>1<\/jats:sup>H, <jats:sup>12<\/jats:sup>C, and DEPT). The active compounds were then targeted against <jats:italic>P. falciparum<\/jats:italic> heat shock protein 70\u20131 (PfHsp70-1) using Autodock Vina, followed by in vitro validation assays using ultraviolet\u2013visible (UV\u2013VIS) spectroscopy and the malate dehydrogenase (MDH) chaperone activity assay.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The extracts except those of methanol displayed anti-malarial potential with varying IC<jats:sub>50<\/jats:sub> values, Z. mucronata HEX (11.69\u2009\u00b1\u20093.84\u00a0\u00b5g\/mL), ETA (7.25\u2009\u00b1\u20091.41\u00a0\u00b5g\/mL), DCM (5.49\u2009\u00b1\u20090.03\u00a0\u00b5g\/mL), and <jats:italic>X. undulutum<\/jats:italic> HEX (4.9\u2009\u00b1\u20090.037\u00a0\u00b5g\/mL), ETA (17.46\u2009\u00b1\u20090.024\u00a0\u00b5g\/mL) and DCM (19.27\u2009\u00b1\u20090.492\u00a0\u00b5g\/mL). The extracts exhibited minimal cytotoxicity except for the ETA and DCM of <jats:italic>Z. mucronata<\/jats:italic> with CC<jats:sub>50<\/jats:sub> values of 10.96 and 10.01\u00a0\u00b5g\/mL, respectively. Isolation and structural characterization of the active compounds from the DCM extracts revealed that betulinic acid (19.95\u2009\u00b1\u20091.53\u00a0\u00b5g\/mL) and lupeol (7.56\u2009\u00b1\u20092.03\u00a0\u00b5g\/mL) were responsible for the anti-malarial activity and had no considerable cytotoxicity (CC<jats:sub>50<\/jats:sub>\u2009&gt;\u2009\u00b5g\/mL). Molecular docking suggested strong binding between PfHsp70-1, betulinic acid (\u2212\u00a06.8\u00a0kcal\/mol), and lupeol (\u2212\u00a06.9\u00a0kcal\/mol). Meanwhile, the in vitro validation assays revealed the disruption of the protein structural elements and chaperone function.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This study proves that <jats:italic>X undulutum<\/jats:italic> and <jats:italic>Z. mucronata<\/jats:italic> have anti-malarial potential and that betulinic acid and lupeol are responsible for the activity seen on <jats:italic>Z. mucronata<\/jats:italic>. They also make a case for guided purification of new phytochemicals in the other extracts and support the notion of considering medicinal plants to discover new anti-malarials.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-024-04976-1","type":"journal-article","created":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T14:01:39Z","timestamp":1715436099000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Phytochemical evaluation of Ziziphus mucronata and Xysmalobium undulutum towards the discovery and development of anti-malarial drugs"],"prefix":"10.1186","volume":"23","author":[{"given":"Muzi N.","family":"Buthelezi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vhahangwele G.","family":"Tshililo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abidemi P.","family":"Kappo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mthokozisi B. 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