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Development of new drug leads for tuberculosis

2022-05Doctoral thesis Open access
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorLopes, Francisca Conceição
dc.contributor.advisorMoreira, Rui Ferreira Alves
dc.contributor.advisorWarner, Digby Francis
dc.contributor.authorCampaniço, André Filipe da Silva
dc.date.accessioned2022-10-25T17:57:11Z
dc.date.available2025-06-01T00:31:12Z
dc.date.issued2022-05
dc.date.submitted2022-02
dc.description.abstractTuberculosis (TB) is a deadly disease caused by a single infectious agent, Mycobacterium tuberculosis (M. tuberculosis). The complexity and duration of the treatment lead to misuse and low compliance by patients, increasing disease burden and the appearance of multidrug-resistant strains of M. tuberculosis. Thus, new antibiotics active against drug-resistant M. tuberculosis and useful for short period therapeutic regimens at lower required doses are urgently needed. A family of azaaurone-based derivatives, from a chemical library developed in iMed.ULisboa, revealed to be active against M. tuberculosis, including multidrug- and extensively drug-resistant clinical isolates, at a submicromolar level. [3] Despite the promising activities, this new scaffold displayed poor ADME properties. In this thesis, we report the complete SAR exploration and ADME profiling of newly synthesized derivatives. All chemical sites of the azaaurone scaffold were extensively explored. More metabolically stable moieties were introduced, generating compounds with improved in vitro half-lives. More hydrophilic groups were inserted and nonaromatic heterocycles were introduced to disrupt the scaffold planarity, two strategies to improve overall solubility. The double bond within the scaffold was also reduced to a single bond, generating a new family of saturated analogues of azaaurones. The new synthesized derivatives displayed improved potency against M. tuberculosis and retained its activity on drug-resistant isolates, remaining non-cytotoxic and selective for the bacteria. Identification of the target was attempted through isolation of resistant mutants, but it was not successful as no azaaurone-resistant isolates were found. Final azaaurones are typically obtained as mixtures of E/Z isomers. The isomers were isolated and differentially studied. Both display similar antitubercular activity. Furthermore, azaaurone isomers were found to isomerize in the presence of mouse liver microsomes (MLM) and under the influence of light. Concerning photoisomerization, it was concluded that this family of azaaurones does not display the optimal characteristics to be used as a photoswitch system.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2022-10-12T14:45:46Z No. of bitstreams: 1 scnd740024_td_André_Campaniço.pdf: 6913147 bytes, checksum: 4d648acba090866f9f05acf5b48dd7da (MD5)en
dc.description.provenanceMade available in DSpace on 2022-10-25T17:57:11Z (GMT). No. of bitstreams: 1 scnd740024_td_André_Campaniço.pdf: 6913147 bytes, checksum: 4d648acba090866f9f05acf5b48dd7da (MD5) Previous issue date: 2022-05en
dc.identifier.tid101617429pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/54905
dc.language.isoengpt_PT
dc.relationDevelopment of new drug leads for tuberculosis
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.subjectazaauronaspt_PT
dc.subjectMycobacterium tuberculosispt_PT
dc.subjectmelhoria de propriedades farmacocinéticaspt_PT
dc.subjecttuberculose resistentept_PT
dc.subjectfotoisomerizaçãopt_PT
dc.subjectazaauronespt_PT
dc.subjectMycobacterium tuberculosispt_PT
dc.subjectADME improvementpt_PT
dc.subjectdrug-resistant tuberculosispt_PT
dc.subjectphotoisomerizationpt_PT
dc.titleDevelopment of new drug leads for tuberculosispt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleDevelopment of new drug leads for tuberculosis
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F131896%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FMED-FAR%2F30266%2F2017/PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream9471 - RIDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.contributor.authoremailrepositorio@reitoria.ulisboa.pt
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication941814d8-7490-490b-a27f-effcd605f7c3
relation.isProjectOfPublicationbb00962c-ed82-4d7a-bc37-61df49767d93
relation.isProjectOfPublicationa21e6964-b01b-421e-9356-1ff6579cdd5c
relation.isProjectOfPublicatione4e75623-bed4-4b63-851d-45ca8fa6794a
relation.isProjectOfPublication.latestForDiscovery941814d8-7490-490b-a27f-effcd605f7c3
thesis.degree.nameTese de doutoramento, Farmácia (Química Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2022pt_PT

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