{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T09:13:58Z","timestamp":1788513238036,"version":"build-2803163510"},"reference-count":33,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T00:00:00Z","timestamp":1437004800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI080968"],"award-info":[{"award-number":["AI080968"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM070855"],"award-info":[{"award-number":["GM070855"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Computer Aided Drug Design Center, University of Maryland, School of Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series. While 4-desmethyl telithromycin (6) was found to be equipotent with telithromycin (2) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal 6 adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of 6 with E. coli ribosomes confirmed 6 is indeed binding the ribosome.<\/jats:p>","DOI":"10.1021\/ml5002097","type":"journal-article","created":{"date-parts":[[2014,7,17]],"date-time":"2014-07-17T07:10:29Z","timestamp":1405581029000},"page":"1021-1026","source":"Crossref","is-referenced-by-count":16,"title":["Desmethyl Macrolides: Synthesis and Evaluation of\n4-Desmethyl Telithromycin"],"prefix":"10.1021","volume":"5","author":[{"given":"Ian","family":"Glassford","sequence":"first","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miseon","family":"Lee","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharat","family":"Wagh","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkata","family":"Velvadapu","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapas","family":"Paul","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Sandelin","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"DeBrosse","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Klepacki","sequence":"additional","affiliation":[{"name":"University of Illinois , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meagan C.","family":"Small","sequence":"additional","affiliation":[{"name":"University of Maryland , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Alexander D.","family":"MacKerell","sequence":"additional","affiliation":[{"name":"University of Maryland , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo B.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Temple University , , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,7,16]]},"reference":[{"key":"2026090402161182200_cit1","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/S1473-3099(13)70318-9","article-title":"Antibiotic resistance-the\nneed for global solutions","volume":"13","author":"Laxminarayan","year":"2013","journal-title":"Lancet Infect. 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Lett."},{"key":"2026090402161182200_cit5","doi-asserted-by":"crossref","first-page":"7516","DOI":"10.1021\/jo201319b","article-title":"Total synthesis of (\u2212)-4,8,10-tridesmethyl\ntelithromycin","volume":"76","author":"Velvadapu","year":"2011","journal-title":"J. Org. Chem."},{"key":"2026090402161182200_cit6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1021\/ml200254h","article-title":"Desmethyl macrolides: synthesis and\nevaluation of 4,10-didesmethyl telithromycin","volume":"3","author":"Velvadapu","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"2026090402161182200_cit7","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1021\/ml300230h","article-title":"Desmethyl\nmacrolides: synthesis and evaluation of 4,8-didesmethyl telithromycin","volume":"3","author":"Wagh","year":"2012","journal-title":"ACS Med. Chem. 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Chem. Theory Comput."},{"key":"2026090402161182200_cit32","doi-asserted-by":"crossref","first-page":"e1003113","DOI":"10.1371\/journal.pcbi.1003113","article-title":"Impact of ribosomal modification\non the binding of\nthe antibiotic telithromycin using a combined grand canonical monte\ncarlo\/molecular dynamics simulation approach","volume":"9","author":"Small","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"2026090402161182200_cit33","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1128\/AAC.49.8.3367-3372.2005","article-title":"Fluorescence polarization method\nto characterize macrolide-ribosome\ninteractions","volume":"49","author":"Yan","year":"2005","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["ACS Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/ml5002097","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/amclct\/article-pdf\/5\/9\/1021\/16231089\/ml5002097.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/amclct\/article-pdf\/5\/9\/1021\/16231089\/ml5002097.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T08:25:10Z","timestamp":1788510310000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/amclct\/article\/5\/9\/1021\/1518891\/Desmethyl-Macrolides-Synthesis-and-Evaluation-of-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,16]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2014,7,16]]},"published-print":{"date-parts":[[2014,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/ml5002097","relation":{},"ISSN":["1948-5875"],"issn-type":[{"value":"1948-5875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,16]]}}}