{"id":{"repo_id":"soton","oai_identifier":"oai:eprints.soton.ac.uk:193149"},"canonical_url":"https://search.dev.ndltd.org/etd/soton/oai:eprints.soton.ac.uk:193149","repository":{"repo_id":"soton","name":"University of Southampton","base_url":"https://eprints.soton.ac.uk/cgi/oai2"},"display":{"title":"Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors","abstract":"HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described","abstract_html":"HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described","abstract_has_math":false,"creators":["Hohlfeld, Konrad"],"institution":"University of Southampton","degree_name":"Ph.D.","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Linclau, Bruno"],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-05","date_published":"2011-05","updated_at":"2026-07-24T04:36:28Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Linclau, Bruno"]},{"key":"dc:creator","label":"Author","values":["Hohlfeld, Konrad"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011-05-25"]},{"key":"dc:date.issued","label":"Date","values":["2011-05"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Chemistry (pre 2011 reorg)","Chemistry"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Southampton"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://eprints.soton.ac.uk/193149/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Ph.D."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://eprints.soton.ac.uk/193149/1/Thesis_Konrad_Hohlfeld.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described"]},{"key":"dc:format","label":"Dc Format","values":["text"]},{"key":"dc:title","label":"Title","values":["Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors"]}]}],"canonical_facts":{"dc:contributor.advisor":["Linclau, Bruno"],"dc:creator":["Hohlfeld, Konrad"],"dc:date":["2011-05-25"],"dc:date.issued":["2011-05"],"dc:description.abstract":["HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described"],"dc:format":["text"],"dc:identifier.uri":["https://eprints.soton.ac.uk/193149/1/Thesis_Konrad_Hohlfeld.pdf"],"dc:publisher.department":["Chemistry (pre 2011 reorg)","Chemistry"],"dc:publisher.institution":["University of Southampton"],"dc:relation.isreferencedby":["https://eprints.soton.ac.uk/193149/"],"dc:title":["Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["Ph.D."]},"updated_at":"2026-07-24T04:36:28Z"}