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Clinically, the disease manifests with symptoms such as fever, anemia, jaundice, and hemoglobinuria, with <jats:italic>B. microti<\/jats:italic> being the most prevalent of these species. Our previous research has shown that <jats:italic>B. microti<\/jats:italic> primarily relies on lactate dehydrogenase (LDH)-mediated anaerobic glycolysis, rather than the tricarboxylic acid cycle (TCA cycle), to generate ATP for its intracellular survival. Because LDH is a promising drug target, it can be inhibited by compounds such as gossypol and 3,5-dihydroxy-2-naphthoxylic acid (DHNA). In this study, we conduct a structure-based optimization of DHNA, leading to the development of a novel library of compounds derived from its structure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Two compounds were identified and synthesized through molecular docking, on the basis of the crystal structure of <jats:italic>Babesia microti<\/jats:italic> lactate dehydrogenase (BmLDH). The effects of these compounds were evaluated using several methods, including surface plasmon resonance (SPR) assays, enzyme activity inhibition tests, in vitro growth inhibition assays against <jats:italic>B. microti<\/jats:italic>, and mammalian cytotoxicity tests.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Compounds target A (TA) (\u221236.0) and B (TB) (\u221243.8), both exhibiting low CDOCKER energy values, achieved final purities of 96.6% and 97.5%, respectively. Surface plasmon resonance (SPR) experiments showed that TA and TB had comparable dissociation constant (<jats:italic>K<\/jats:italic>\n              <jats:sub>D<\/jats:sub>) values of 11.3\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup> M and 13.2\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup> M, respectively. However, enzyme activity inhibition assays indicated that TB was more potent, with an half-maximal inhibitory concentration (IC<jats:sub>50<\/jats:sub>) value of 23.8\u00a0\u03bcM, compared with TA\u2019s IC<jats:sub>50<\/jats:sub> of 71.6\u00a0\u03bcM. Additionally, TB demonstrated a strong ability to inhibit the in vitro growth of <jats:italic>B. microti<\/jats:italic>, with an IC<jats:sub>50<\/jats:sub> value of 111.7\u00a0\u03bcM.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In this study, two compounds capable of inhibiting the growth of <jats:italic>B. microti<\/jats:italic> were obtained. Although both compounds showed moderate inhibitory activity against recombinant BmLDH (rBmLDH) and the growth of <jats:italic>B. microti<\/jats:italic>, there is potential to enhance their efficacy through further structural modifications, particularly of compound TB.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s13071-024-06623-9","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T07:29:46Z","timestamp":1740295786000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Design and screening of novel molecular compounds targeting lactate dehydrogenase of Babesia microti"],"prefix":"10.1186","volume":"18","author":[{"given":"Wanxin","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidan","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"6623_CR1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.7326\/0003-4819-155-8-201110180-00362","volume":"155","author":"BL Herwaldt","year":"2011","unstructured":"Herwaldt BL, Linden JV, Bosserman E, Young C, Olkowska D, Wilson M. 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