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dc.contributor.authorLei, Xiangyangen_US
dc.date.accessioned2014-07-22T18:46:46Z
dc.date.available2014-07-22T18:46:46Z
dc.date.created2006en_US
dc.date.issued2006en_US
dc.identifieretd-08012006-092058en_US
dc.identifiercat-001289819en_US
dc.identifier.urihttps://repository.tcu.edu:443/handle/116099117/3932
dc.descriptionTitle from dissertation title page (viewed Sept. 12, 2006).en_US
dc.descriptionIncludes abstract.en_US
dc.descriptionThesis (Ph.D.)--Texas Christian University, 2006.en_US
dc.descriptionDepartment of Chemistry; advisor, Manfred G. Reinecke.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.descriptionText (electronic thesis) in PDF.en_US
dc.descriptionThe human immunodeficiency virus type 1 (HIV-1) causes the acquired immune deficiency syndrome (AIDS). Three essential enzymes are necessary for HIV-1 replication: reverse transcriptase (RT), integrase (IN), and protease (PR). Current drugs target RT and PR, but there is substantial interest in inhibitors targeted at IN, which catalyzes the integration of the proviral DNA into the host cell's DNA. The only two reported classes of compounds considered lead molecules for clinically useful HIV IN inhibitors are the dicaffeoyltartaric acids, of which L-chicoric acid (L-CA) is the lead compound, and the second are the aryl diketo acids (DKAs). These compounds prevent proviral DNA integration and inhibit HIV-1 replication at non-toxic concentrations in cell culture.^Our research focused on: 1) scaffold modification of L-CA; 2) catechol modification of L-CA; and 3) synthesis of hybrid DKA/catechol molecules.In the first part, three conformationally restricted cyclopentane analogues of L-CA were synthesized and tested against HIV IN, and HIV replication. Several showed good anti-HIV IN activity, with the isomer having caffeoyl groups on the opposite side of the ring from the carboxyl group being the most active, thus suggesting this preferred conformation in the IN active site. Neither the rigid analogues nor a synthesized open-chain analogue had significant anti-HIV replication activity.^In the second part, six 2-pyridone analogues of L-CA were synthesized, but only one had moderate anti-HIV IN and anti-HIV activity supporting the conclusion that catechols are required for anti-HIV and anti-HIV IN activity and that simple 2-pyridones are not bioisosteres of catechols.In the third part, six synthesized DKA/catechol hybrids were potent IN inhibitors with the compound with the diketo acid and catechol moiety in a meta-orientation being the most active, even more so than L-CA and some DKA drug candidates. Against HIV replication, only two compounds showed moderate activity, but less so than either L-CA or simple DKAs. The results suggest that caffeoyl are preferred to simple catechol groups and one caffeoyl group is sufficient for inhibition of either HIV IN or HIV replication. Methyl esters in all the above series were less active than their corresponding acids in both assays.en_US
dc.format.mediumFormat: Onlineen_US
dc.language.isoengen_US
dc.publisherFort Worth, Tex. : Texas Christian University,en_US
dc.relation.ispartofTexas Christian University dissertationen_US
dc.relation.ispartofUMI thesis.en_US
dc.relation.requiresMode of access: World Wide Web.en_US
dc.relation.requiresSystem requirements: Adobe Acrobat reader.en_US
dc.subject.lcshHIV (Viruses)en_US
dc.subject.lcshAIDS (Disease)en_US
dc.subject.lcshVirus inhibitors.en_US
dc.subject.lcshAntiviral agents.en_US
dc.subject.lcshDrugs Design.en_US
dc.titleDesign, syntheses and biological activities of L-chicoric acid analogues as HIV-1 integrase inhibitors [electronic resource] /en_US
dc.typeTexten_US
etd.degree.departmentDepartment of Chemistry
etd.degree.levelDoctoral
local.academicunitDepartment of Chemistry and Biochemistry
local.subjectareaChemistry and Biochemistry


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