{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T20:04:23Z","timestamp":1787774663627,"version":"build-2784847793"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2017,6,1]],"date-time":"2017-06-01T00:00:00Z","timestamp":1496275200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI114671"],"award-info":[{"award-number":["AI114671"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE020607"],"award-info":[{"award-number":["DE020607"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Giardia lamblia<\/jats:named-content>\n            is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstrated\n            <jats:italic>in vivo<\/jats:italic>\n            and\n            <jats:italic>in vitro<\/jats:italic>\n            . Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative\n            <jats:named-content content-type=\"genus-species\">G. lamblia<\/jats:named-content>\n            strains showed a wide spectrum of\n            <jats:italic>in vitro<\/jats:italic>\n            activities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing &gt;100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasis\n            <jats:italic>in vivo<\/jats:italic>\n            . These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.\n          <\/jats:p>","DOI":"10.1128\/aac.02397-16","type":"journal-article","created":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T00:30:32Z","timestamp":1491870632000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia"],"prefix":"10.1128","volume":"61","author":[{"given":"Wan Jung","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith A.","family":"Korthals","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaros\u0142aw","family":"Kalisiak","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Barry","family":"Sharpless","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valery V.","family":"Fokin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Eckmann","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.watres.2011.10.013"},{"key":"e_1_3_3_3_2","first-page":"15","article-title":"Giardiasis surveillance\u2013United States, 2011-2012","volume":"64","author":"Painter JE","year":"2015","unstructured":"Painter JE GarganoJW CollierSA YoderJS. 2015. Giardiasis surveillance\u2013United States, 2011-2012. MMWR Suppl64:15\u201325.","journal-title":"MMWR Suppl"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2006.100198"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu629"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199754050-00003"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.7.1533"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/647939"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1179\/136485908X267894"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.01208"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00360-12"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.2174\/187152610791591610"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.14.1.150-164.2001"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/46.5.819"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.8.12.1885"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1086\/320886"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(96)02661-8"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00909-08"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt106"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr192"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40475-015-0051-1"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.1.344-347.2006"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm900356n"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.04.064"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302664110"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trstmh.2011.11.007"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1746.2003.03058.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00384-11"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2016.06.026"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(97)00010-9"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(01)00136-1"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(80)90031-4"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.62.8.3583-3585.1994"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2012.04.002"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2016.07.003"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr029"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.7.2116-2123.2002"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050211"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01159-06"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci000095o"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD006085.pub2"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(92)90095-T"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(88)90278-7"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2010.03.004"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.15.3.329-341.2002"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-005-8694-y"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth261"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02397-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02397-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:40:48Z","timestamp":1645476048000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02397-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1128\/AAC.02397-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.02397-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6]]},"assertion":[{"value":"2016-11-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02397-16"}}