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A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3\u2032-azido-2\u2032,3\u2032-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.<\/jats:p>","DOI":"10.3390\/molecules27238502","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T07:07:31Z","timestamp":1670224051000},"page":"8502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-3252","authenticated-orcid":false,"given":"Maria da Concei\u00e7\u00e3o Avelino Dias","family":"Bianco","sequence":"first","affiliation":[{"name":"Programa de Pos-Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal, Instituto de Ci\u00eancias Biom\u00e9dicas\u2014ICB, Universidade Federal do Rio de Janeiro\u2014UFRJ, Av. 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Carlos Chagas Filho, 373, Bloco L, Rio de Janeiro 21941-902, Brazil"},{"name":"Laboratorio de Sintese de Farmacos\u2014LASFAR\u2014Fundacao Oswaldo Cruz, Instituto de Tecnologia em Farmacos\u2014Farmanguinhos\u2014Fiocruz, Rua Sizenando Nabuco, 100\u2014Manguinhos, Rio de Janeiro 21041-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1021\/acsmedchemlett.9b00039","article-title":"Harnessing Polypharmacology with Medicinal Chemistry","volume":"10","author":"Bolognesi","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_2","unstructured":"Barreiro, E.J., and Fraga, C.A.M. (2015). Qu\u00edmica Medicinal: As Bases Moleculares Da A\u00e7\u00e3o Dos F\u00e1rmacos, Artmed. 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