{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:09:44Z","timestamp":1790262584876,"version":"4.1.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2010,5,1]],"date-time":"2010-05-01T00:00:00Z","timestamp":1272672000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2010,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            In this paper, we present the biochemical and biological evaluation of\n            <jats:italic>N<\/jats:italic>\n            -arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of\n            <jats:italic>Trypanosoma vivax<\/jats:italic>\n            inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form\n            <jats:italic>Trypanosoma brucei brucei<\/jats:italic>\n            , only one inhibitor,\n            <jats:italic>N<\/jats:italic>\n            -(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-\n            <jats:sc>d<\/jats:sc>\n            -ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC\n            <jats:sub>50<\/jats:sub>\n            ] \u00b1 standard error, 0.49 \u00b1 0.31 \u03bcM). Validation in an\n            <jats:italic>in vivo<\/jats:italic>\n            model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against\n            <jats:italic>T. b. brucei<\/jats:italic>\n            IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on\n            <jats:italic>T. vivax<\/jats:italic>\n            IAG-NH. Second, to verify the uptake of these compounds by\n            <jats:italic>T. b. brucei<\/jats:italic>\n            , their affinities for the nucleoside P1 and nucleoside\/nucleobase P2 transporters of\n            <jats:italic>T. b. brucei<\/jats:italic>\n            were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of\n            <jats:italic>T. b. brucei<\/jats:italic>\n            displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic\n            <jats:italic>T. b. brucei<\/jats:italic>\n            (IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of\n            <jats:italic>T. b. brucei<\/jats:italic>\n            and that, therefore, it is possible that UAMC-00363 acts on an additional target.\n          <\/jats:p>","DOI":"10.1128\/aac.01787-09","type":"journal-article","created":{"date-parts":[[2010,3,2]],"date-time":"2010-03-02T04:54:26Z","timestamp":1267505666000},"page":"1900-1908","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis"],"prefix":"10.1128","volume":"54","author":[{"given":"Maya","family":"Berg","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Kohl","sequence":"additional","affiliation":[{"name":"Muse\u0301um National d'Histoire Naturelle, USM 504-EA3335, Biologie Fonctionnelle des Protozoaires, 61 Rue Buffon, CP52, Paris Cedex 05 75231, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Van der Veken","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgen","family":"Joossens","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed I.","family":"Al-Salabi","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Life Sciences, Division of 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