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Inhibitors bearing <jats:italic>bis<\/jats:italic>\u2010THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2\u2032 ligands, showed very potent HIV\u20101 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide\u2010derived inhibitors which showed good antiviral IC<jats:sub>50<\/jats:sub> value. Boronic acid derived inhibitor with <jats:italic>bis<\/jats:italic>\u2010THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2\u2010<jats:italic>Crn<\/jats:italic>\u2010THF ligand also showed potent enzyme <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug\u2010resistant HIV\u20101 variants. One of the inhibitors maintained good antiviral activity against HIV<jats:sub>DRV<\/jats:sub><jats:sup>R<\/jats:sup><jats:sub>P20<\/jats:sub> and HIV<jats:sub>DRV<\/jats:sub><jats:sup>R<\/jats:sup><jats:sub>P30<\/jats:sub> viruses. We have determined high resolution X\u2010ray structures of two synthetic inhibitors bound to HIV\u20101 protease and obtained molecular insight into the ligand\u2010binding site interactions.<\/jats:p>","DOI":"10.1002\/cmdc.201900508","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T22:04:09Z","timestamp":1569276249000},"page":"1863-1872","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Potent HIV\u20101 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein\u2010Ligand X\u2010ray Structural Studies"],"prefix":"10.1002","volume":"14","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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilei","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Kovela","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Department of Medicinal Chemistry Purdue University  West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Kneller","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute  Bethesda MD 20892 USA"},{"name":"Department of Refractory Viral Infections National Center for Global Heath and Medicine Research Institute  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Department of Refractory Viral Infections National Center for Global Heath and Medicine Research Institute  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene T.","family":"Weber","sequence":"additional","affiliation":[{"name":"Departments of Biology and Chemistry, Molecular Basis of Disease Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases Kumamoto University School of Medicine  Kumamoto 860-8556 Japan"},{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute  Bethesda MD 20892 USA"},{"name":"Department of Refractory Viral Infections National Center for Global Heath and Medicine Research Institute  Shinjuku Tokyo 162-8655 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,10,4]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/9783527665211.ch15","volume-title":"Structure-Based Design of Drugs and Other Bioactive Molecules: Tools and Strategies","author":"Ghosh A. 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