Hit-to-lead optimization of pharmaceutical interesting tryptophanol-derived scaffolds

• Autor(a) principal: Barcherini, Valentina
• Data de Publicação: 2016
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/84243
• topic: indole; p53; hit-to-lead optimization; tryptophanol; stability-profile; liver-stage malaria; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química

The indole nucleus is the core structure of many natural and synthetic molecules. In fact, indole-based compounds have been described with different biological activities, ranging from antitumor to antimalarials. Recent studies made by our research group led to the discovery of one enantiopure tryptophanol-derived oxazoloisoindolinone as novel activator of wild-type p53 and reactivator of mutant-type p53. The first objective of this thesis was centered on the hit-to-lead optimization of this specific derivative. Several alkyl substituents with increasing size and electron withdrawing/donating groups were selected for the protection of the indole nitrogen to assemble a library of new analogues for biological screening. A study of the activity based on chirality revealed one compound to be more active than the hit compound 34. Particularly, compound 34d restores the wt-like growth inhibitory effect to mut p53R280K in a percentage of 86.8%. Finally, the stability-profile of this chemical family was evaluated using compounds 34 and 34e as models. The second main goal of this thesis was the investigation of new leads as promising antimalarials, based on the recent report that a library of enantiopure indolizinoindolones exhibits in vitro activity against erythrocytic and liver-stages of malaria parasite. Structural derivatization of the hit-compounds was carried out using an enantioselective two-step route, involving an intramolecular cyclization to assemble the final polycyclic indolizinoindolones derivatives. In vitro screening of these tryptophanol-derived tricyclic compounds permitted the identification of two indolizinoindolone small molecules as the most active compounds.