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It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which was later identified as Azomycin 1 (2-nitroimidazole) and remained in focus until now. This natural antibiotic was the starting point for synthesizing numerous analogs and regio-isomers, leading to several life-saving drugs and clinical candidates against a number of diseases, including infections (bacterial, viral, parasitic) and cancers, as well as imaging agents in medicine\/diagnosis. In the present decade, the nitroimidazole scaffold has again been given two life-saving drugs (Delamanid and Pretomanid) used to treat MDR (multi-drug resistant) tuberculosis. Keeping in view the highly successful track-record of the nitroimidazole scaffold in providing breakthrough therapeutic drugs, this comprehensive review focuses explicitly on presenting the activity profile and synthetic chemistry of functionalized nitroimidazole (2-, 4- and 5-nitroimidazoles as well as the fused nitroimidazoles) based drugs and leads published from 1950 to 2021. The present review also presents the miscellaneous examples in each class. In addition, the mutagenic profile of nitroimidazole-based drugs and leads and derivatives is also discussed.<\/jats:p>","DOI":"10.3390\/ph15050561","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T07:08:58Z","timestamp":1651475338000},"page":"561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950\u20132021 Comprehensive Overview"],"prefix":"10.3390","volume":"15","author":[{"given":"Ria","family":"Gupta","sequence":"first","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"Academy of Scientific & Innovative Research, Gaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit","family":"Sharma","sequence":"additional","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"Academy of Scientific & Innovative Research, Gaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4235-8436","authenticated-orcid":false,"given":"Rohit","family":"Singh","sequence":"additional","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"Academy of Scientific & Innovative Research, Gaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram A.","family":"Vishwakarma","sequence":"additional","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"Academy of Scientific & Innovative Research, Gaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Mignani","sequence":"additional","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"PRES Sorbonne Paris Cit\u00e9, CNRS UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, 45, rue des Saints Peres, Universit\u00e9 Paris Descartes, 75006 Paris, France"},{"name":"CQM\u2014Centro de Qu\u00edmica da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvinder Pal","family":"Singh","sequence":"additional","affiliation":[{"name":"Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Canal Road, Jammu 180001, India"},{"name":"Academy of Scientific & Innovative Research, Gaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7636","DOI":"10.1021\/acs.jmedchem.7b00143","article-title":"Nitroimidazoles: Molecular fireworks that combat a broad spectrum of infectious diseases","volume":"60","author":"Ang","year":"2017","journal-title":"J. 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