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The inhibitors are designed to enhance backbone binding interactions, particularly at the S2\u2032 subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2\u2032 ligands was set by asymmetric reduction of the corresponding ketone using (<jats:italic>R<\/jats:italic>,<jats:italic>R<\/jats:italic>)\u2010 or (<jats:italic>S<\/jats:italic>,<jats:italic>S<\/jats:italic>)\u2010Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors <jats:bold>3g<\/jats:bold> and <jats:bold>3h<\/jats:bold> showed enzyme <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values of 27.9 and 49.7\u2005p<jats:sc>m<\/jats:sc> and antiviral activity of 6.2 and 3.9\u2005n<jats:sc>m<\/jats:sc>, respectively. These inhibitors also remained quite potent against darunavir\u2010resistant HIV\u20101 variants. An X\u2010ray structure of inhibitor <jats:bold>3g<\/jats:bold> in complex with HIV\u20101 protease revealed key interactions in the S2\u2032 subsite.<\/jats:p>","DOI":"10.1002\/cmdc.201700614","type":"journal-article","created":{"date-parts":[[2017,11,6]],"date-time":"2017-11-06T21:52:38Z","timestamp":1510005158000},"page":"1942-1952","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Design, Synthesis, Biological Evaluation, and X\u2010ray Studies of HIV\u20101 Protease Inhibitors with Modified P2\u2032 Ligands of Darunavir"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-1841","authenticated-orcid":false,"given":"Arun K.","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. 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