Optimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzi

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dc.citation.volume171pt_BR
dc.contributor.authorVarela, Marina T. [UNIFESP]
dc.contributor.authorAmaral, Maiara
dc.contributor.authorRomanelli, Maiara M.
dc.contributor.authorLevatti, Erica V. de Castro
dc.contributor.authorTempone, Andre G.
dc.contributor.authorFernandes, João Paulo dos Santos [UNIFESP]
dc.contributor.authorLatteshttp://lattes.cnpq.br/7259164526317967pt_BR
dc.date.accessioned2022-05-30T16:33:56Z
dc.date.available2022-05-30T16:33:56Z
dc.date.issued2022
dc.description.abstractTrypanosoma cruzi is the causing agent of Chagas disease, a parasitic infection without efficient treatment for chronic patients. Despite the efforts, no new drugs have been approved for this disease in the last 60 years. Molecular modifications based on a natural product led to the development of a series of compounds (LINS03 series) with promising antitrypanosomal activity, however previous chemometric analysis revealed a significant impact of excessive lipophilicity and low aqueous solubility on potency of amine and amide derivatives. Therefore, this work reports different modifications in the core structure to achieve adequate balance of the physicochemical properties along with biological activity. A set of 34 analogues were designed considering predicted properties related to lipophilicity/hydrosolubility and synthesized to assess their activity and selective toxicity towards the parasite. Results showed that this strategy contributed to improve the drug-likeness of the series while considerable impacts on potency were observed. The rational analysis of the obtained data led to the identification of seven active piperazine amides (28–34, IC50 8.7 to 35.3 µM against intracellular amastigotes), devoid of significant cytotoxicity to mammalian cells. The addition of water-solubilizing groups and privileged substructures such as piperazines improved the physicochemical properties and overall drug-likeness of these compounds, increased potency and maintained selectivity towards the parasite. The obtained results brought important structure-activity relationship (SAR) data and new lead structures for further modifications were identified to achieve improved antitrypanosoma compounds.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipIDFAPESP: 2021/04464–8
dc.description.sponsorshipIDFAPESP: 2020/03637–3
dc.description.sponsorshipIDFAPESP: 2019/24028–8
dc.description.sponsorshipIDFAPESP: 2019/14167–0
dc.description.sponsorshipIDFAPESP: 2018/03918–2
dc.format.extent106114pt_BR
dc.identifierhttps://doi.org/10.1016/j.ejps.2021.106114pt_BR
dc.identifier.doi10.1016/j.ejps.2021.106114pt_BR
dc.identifier.urihttps://hdl.handle.net/11600/63910
dc.languageengpt_BR
dc.publisherElsevierpt_BR
dc.relation.ispartofEuropean Journal of Pharmaceutical Sciencespt_BR
dc.rightsAcesso abertopt_BR
dc.subjectPhysicochemical propertiespt_BR
dc.subjectPiperazinept_BR
dc.subjectStructure-property relationshippt_BR
dc.subjectTrypanosoma cruzipt_BR
dc.subjectAntitrypanosomal compoundspt_BR
dc.titleOptimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzipt_BR
dc.typeArtigopt_BR
unifesp.campusInstituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF)pt_BR
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