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Within this context, the biphenyl subunit has been identified as a highly versatile privileged structure capable of interacting with diverse protein targets via hydrophobic and \u03c0-interactions. The purpose of this study is to review the pharmacological potential of biphenyl-based compounds, focusing on their application as anti-infective agents. We comprehensively analyzed recent literature and rational design strategies concerning biphenyl derivatives, examining structure-activity relationships, molecular docking insights, and structural optimizations aimed at enhancing both pharmacodynamics and pharmacokinetics. The reviewed studies demonstrate that incorporating biphenyl moieties yields compounds with potent antifungal and antiviral activities. Specifically, optimized biphenyl derivatives exhibit strong inhibitory effects against resistant Candida strains and crucial viral targets, including mutant variants of the HIV-1 reverse transcriptase and protease enzymes. Furthermore, strategic modifications, such as scaffold hopping and the introduction of specific substituents, successfully mitigated cytotoxicity and improved metabolic stability against cytochrome P450 enzymes. Biphenyl serves as a robust and adaptable scaffold for drug design. Its rational structural optimization provides a viable pathway to overcome drug resistance and develop effective, metabolically stable anti-infective therapeutics.<\/jats:p>","DOI":"10.3390\/molecules31071109","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T12:45:53Z","timestamp":1774615553000},"page":"1109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Biphenyl as a Privileged Structure in Medicinal Chemistry: Advances in Anti-Infective Drug Discovery"],"prefix":"10.3390","volume":"31","author":[{"given":"Marilia Oliva","family":"Gandi","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal, Instituto de Ci\u00eancias Biom\u00e9dicas\u2014ICB, Universidade Federal do Rio de Janeiro\u2014UFRJ, Rio de Janeiro 21941-902, Brazil"},{"name":"Laborat\u00f3rio de S\u00edntese de F\u00e1rmacos\u2014LASFAR, Departamento de S\u00edntese de F\u00e1rmacos e Bioativos\u2014DSFB, Instituto de Tecnologia em F\u00e1rmacos\u2014Farmanguinhos, Funda\u00e7\u00e3o Oswaldo Cruz\u2014Fiocruz, Rio de Janeiro 21041-250, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-8016","authenticated-orcid":false,"given":"Rodolfo Rodrigo Florido","family":"Fran\u00e7a","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de F\u00e1rmacos\u2014LASFAR, Departamento de S\u00edntese de F\u00e1rmacos e Bioativos\u2014DSFB, Instituto de Tecnologia em F\u00e1rmacos\u2014Farmanguinhos, Funda\u00e7\u00e3o Oswaldo Cruz\u2014Fiocruz, Rio de Janeiro 21041-250, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederico Silva","family":"Castelo-Branco","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de F\u00e1rmacos\u2014LASFAR, Departamento de S\u00edntese de F\u00e1rmacos e Bioativos\u2014DSFB, Instituto de Tecnologia em F\u00e1rmacos\u2014Farmanguinhos, Funda\u00e7\u00e3o Oswaldo Cruz\u2014Fiocruz, Rio de Janeiro 21041-250, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-2218","authenticated-orcid":false,"given":"Nubia","family":"Boechat","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese de F\u00e1rmacos\u2014LASFAR, Departamento de S\u00edntese de F\u00e1rmacos e Bioativos\u2014DSFB, Instituto de Tecnologia em F\u00e1rmacos\u2014Farmanguinhos, Funda\u00e7\u00e3o Oswaldo Cruz\u2014Fiocruz, Rio de Janeiro 21041-250, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1021\/jm00120a002","article-title":"Methods for drug discovery: Development of potent, selective, orally efeective cholecytokinin antagonist","volume":"31","author":"Evans","year":"1988","journal-title":"J. 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