{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T22:21:36Z","timestamp":1770762096646,"version":"3.50.0"},"posted":{"date-parts":[[2025,10,8]]},"group-title":"Microbiology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Chemotherapeutic options for schistosomiasis, a prevalent infectious disease of poverty, are limited to just one drug, praziquantel (PZQ), and alternatives are needed. Our previous studies identified thiophen-2-yl pyrimidines (TPPs), which are structurally derived from microtubule (MT)-active phenylpyrimidines, as potent paralytics of\n                  <jats:italic>Schistosoma mansoni<\/jats:italic>\n                  . Although relatively non-toxic to mammalian cells, the progenitor compound,\n                  <jats:bold>3<\/jats:bold>\n                  , had poor aqueous solubility and was lipophilic potentially hindering preclinical advancement. To address these issues and expand on the structure-activity and structure-property relationships, 43 new TPP analogs were designed and synthesized, their lipophilicity calculated (cLogP), and their anti-schistosomal activity evaluated in culture. This effort yielded compound\n                  <jats:bold>38<\/jats:bold>\n                  , which possessed an oxetane-containing amine moiety at C5, and an\n                  <jats:italic>ortho, ortho-<\/jats:italic>\n                  difluoroaniline at C6 of the TPP scaffold. Compared to\n                  <jats:bold>3<\/jats:bold>\n                  , compound\n                  <jats:bold>38<\/jats:bold>\n                  had better aqueous solubility (46\n                  <jats:italic>vs.<\/jats:italic>\n                  &lt; 0.5 \u00b5M) and decreased lipophilicity (logP calc. 4.48\n                  <jats:italic>vs.<\/jats:italic>\n                  6.81), with toxicity CC\n                  <jats:sub>50<\/jats:sub>\n                  values &gt; 20 \u00b5M against three mammalian cell lines. Further, paralytic potency, as measured by the EC\n                  <jats:sub>50<\/jats:sub>\n                  value for adult\n                  <jats:italic>S. mansoni<\/jats:italic>\n                  motility, was increased 14.5-fold (538\n                  <jats:italic>vs.<\/jats:italic>\n                  37 nM), and plasma half-life (t\n                  <jats:sub>1\/2<\/jats:sub>\n                  ) was improved 3-fold, from 0.48 to 1.51 h for a 40% loss in maximum plasma concentration (C\n                  <jats:sub>max<\/jats:sub>\n                  ). In washout experiments,\n                  <jats:bold>38<\/jats:bold>\n                  produced a sustained paralysis of both juvenile and adult\n                  <jats:italic>S. mansoni,<\/jats:italic>\n                  possibly suggesting a broader\n                  <jats:italic>in vitro<\/jats:italic>\n                  efficacy spectrum compared to PZQ, which is inactive against the juvenile parasite. Also, the two other medically important species,\n                  <jats:italic>Schistosoma haematobium<\/jats:italic>\n                  and\n                  <jats:italic>Schistosoma japonicum,<\/jats:italic>\n                  were susceptible to\n                  <jats:bold>38<\/jats:bold>\n                  . Finally, to identify potential protein targets, we synthesized a TPP photoaffinity labeling (PAL) probe that labeled several\n                  <jats:italic>S. mansoni<\/jats:italic>\n                  proteins by SDS-PAGE fluorescence analysis, although, notably, not tubulin, suggesting that the antischistosomal activity of\n                  <jats:bold>38<\/jats:bold>\n                  is a function of engaging other targets. Future work with the TPP series will aim to decrease toxicity further while improving PK properties to better support\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy testing.\n                <\/jats:p>","DOI":"10.1101\/2025.10.07.681061","type":"posted-content","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T21:00:11Z","timestamp":1759957211000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure-Activity Relationship and Target Investigation of Thiophen-2-yl-Pyrimidines against\n                  <i>Schistosoma<\/i>\n                  species"],"prefix":"10.64898","author":[{"given":"Karol R.","family":"Francisco","sequence":"first","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bobby","family":"Lucero","sequence":"additional","affiliation":[{"name":"Department 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