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To address this, we designed a rigid triple\u2010connected heterocyclic scaffold locking stereochemical geometry, enabling reliable separation and unambiguous assignment. From a library of cis\/trans oxadiazole derivatives, cis compound 6 emerged as the most potent anti\u2010Toxoplasma agent, displaying superior selectivity, lower cytotoxicity, and enhanced intracellular parasite clearance compared to its trans counterpart and reference drug spiramycin. Mechanistic investigations revealed compound 6 induces pronounced oxidative stress, evidenced by elevated NO\/ROS and GSH depletion. Complementary in silico studies, including docking and 100\u2010ns MD simulations, supported a stereospecific binding mode within\n                    <jats:italic>Tg<\/jats:italic>\n                    NTPDase, with cis\u20106 forming dual hydrogen bonds that the trans isomer cannot access; the simulation further demonstrated stable protein\u2013ligand interactions with backbone RMSD 0.235 \u00b1 0.043\u00a0nm and minimum distance 0.15\u20130.22\u00a0nm throughout. ADMET predictions indicated improved solubility, slower clearance, and lower hERG risk for cis\u20106, consistent with its better selectivity. Collectively, this work establishes the rigid tris\u2010heterocyclic core as a versatile stereochemically predictable platform for isomer\u2010resolved drug design, positioning compound 6 as a promising lead for anti\u2010toxoplasmosis therapy.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.71617","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:38:36Z","timestamp":1787312316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unlocking Anti\u2010Toxoplasma Activity: The Essential Role of a Cis\u2010Configured Vinyl Linker"],"prefix":"10.1002","volume":"23","author":[{"given":"Jieqiong","family":"Wang","sequence":"first","affiliation":[{"name":"College of Pharmacy Yanbian University  Yanji P. R. 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