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The increasing prevalence of multidrug\u2010resistant strains of the causative pathogen, <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (<jats:styled-content style=\"fixed-case\">CPX<\/jats:styled-content>) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent <jats:italic>Mtb<\/jats:italic> H37Rv strain in vitro. The small propionyl analogue <jats:bold>11<\/jats:bold> (<jats:styled-content style=\"fixed-case\">MIC<\/jats:styled-content><jats:sub>90<\/jats:sub> 1.6\u00a0\u03bcM; <jats:styled-content style=\"fixed-case\">SI<\/jats:styled-content>\u00a0&gt;\u00a061) and the large cholesteryl hybrid <jats:bold>32<\/jats:bold> (<jats:styled-content style=\"fixed-case\">MIC<\/jats:styled-content><jats:sub>90<\/jats:sub> 2.0\u00a0\u03bcM; <jats:styled-content style=\"fixed-case\">SI<\/jats:styled-content>\u00a0&gt;\u00a06) were the most active derivatives, comparable to CPX (<jats:styled-content style=\"fixed-case\">MIC<\/jats:styled-content><jats:sub>90<\/jats:sub> 1.8\u00a0\u03bcM). However, the slightly less active but non\u2010cytotoxic <jats:italic>para<\/jats:italic>\u2010fluorobenzyl hybrid <jats:bold>28<\/jats:bold> (<jats:styled-content style=\"fixed-case\">MIC<\/jats:styled-content><jats:sub>90<\/jats:sub> 3.7\u00a0\u03bcM; <jats:styled-content style=\"fixed-case\">SI<\/jats:styled-content> 27) was more selective toward bacteria than <jats:bold>32<\/jats:bold>. Thus, the <jats:styled-content style=\"fixed-case\">CPX<\/jats:styled-content> derivatives <jats:bold>11<\/jats:bold> and <jats:bold>28<\/jats:bold> were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models.<\/jats:p>","DOI":"10.1111\/cbdd.13534","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T18:50:45Z","timestamp":1556563845000},"page":"1518-1536","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Design, synthesis, and antimycobacterial activity of novel ciprofloxacin derivatives"],"prefix":"10.1111","volume":"94","author":[{"given":"Pieter","family":"Cilliers","sequence":"first","affiliation":[{"name":"Pharmaceutical Chemistry School of Pharmacy North\u2010West University Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronnett","family":"Seldon","sequence":"additional","affiliation":[{"name":"SAMRC Drug Discovery and Development Research Unit University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans J.","family":"Smit","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (PHARMACEN) North\u2010West University Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Aucamp","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (PHARMACEN) North\u2010West University Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Jordaan","sequence":"additional","affiliation":[{"name":"SAMRC\/NHLS\/UCT Molecular Mycobacteriology Research Unit Department of Pathology and Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-0930","authenticated-orcid":false,"given":"Digby F.","family":"Warner","sequence":"additional","affiliation":[{"name":"SAMRC\/NHLS\/UCT Molecular Mycobacteriology Research Unit Department of Pathology and Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town South Africa"},{"name":"Wellcome Centre for Clinical Infectious Diseases Research in Africa University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-0551","authenticated-orcid":false,"given":"David D.","family":"N'Da","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (PHARMACEN) North\u2010West University Potchefstroom South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/asia.201100432"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkg212"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-8579(00)00192-8"},{"key":"e_1_2_9_5_1","first-page":"1518","article-title":"A mini review on the study of new broad\u2010spectrum antimicrobial fluoroquinolone JNJ\u2010Q2","volume":"1","author":"Asif M.","year":"2014","journal-title":"Journal of Chemistry and Applications"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0ob00199f"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1201\/b19978"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2008.12.026"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.64.070195.000333"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2007.00865.x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/21.Supplement_1.S66"},{"key":"e_1_2_9_12_1","unstructured":"CDC. 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