Planejamento racional de compostos antitripanosoma: modulação das propriedades físico-químicas associadas à seletividade e melhor perfil farmacocinético in vitro
Data
2022-11-24
Autores
Varela, Marina Themoteo [UNIFESP]
Orientadores
Fernandes, João Paulo dos Santos [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A expansão da série LINS03 teve como objetivo obter compostos anti-T. cruzi equipotentes ou superiores aos análogos conhecidos da série, com maior hidrossolubilidade e menor citotoxicidade. Para tanto, subestruturas que pudessem aumentar a solubilidade em água (como grupos piperazina e vinila) foram introduzidas na cadeia lateral, ao mesmo tempo mantendo características estruturais presentes em compostos ativos. Desta forma, 46 novos análogos foram preparados e isolados com rendimentos de 31 a 84% e pureza adequada. A atividade anti-T. cruzi foi determinada em formas tripomastigotas e amastigotas bem como sua citotoxicidade contra células mamíferas. Em paralelo, foram realizados ensaios para determinação de logD7,4 e solubilidade e de propriedades farmacocinéticas in vitro. Foram obtidos 14 análogos ativos e seletivos contra formas amastigotas de T. cruzi, sendo a introdução da piperazina uma modificação importante para o ganho de atividade. Predições in silico indicaram um bom balanço entre solubilidade e lipofilicidade, confirmado para alguns análogos experimentalmente. O composto 34 (CE50 8,7 μM) foi o mais ativo da série e com melhores características de drug-likeness e eficiência lipofílica (LLE). Destaca-se também o composto 29 (CE50 13,9 μM) com alta solubilidade (> 200 μM) e permeabilidade (Papp > 100 nm/s), e estável a microssomas humanos isolados (5,2 mL/min/g) e em células hepáticas (0,5 mL/min/g) em estudos in vitro. Em suma, as modificações propostas levaram a obtenção de compostos ativos e seletivos, com melhor hidrossolubilide e drug-likeness.
The expansion of LINS03 series aimed to obtain anti-T. cruzi compounds equipotent or superior to known analogues of the series, with improved hydrosolubility and lower cytotoxicity. Therefore, substructures that could increase water solubility (such as piperazine and vinyl) were introduced to the side chain, maintaining structural features present in active analogues. Thus, 46 new analogues were prepared and isolated with adequate purity and yields from 31 to 84%. These anti-T cruzi was determined in trypomastigotes and amastigotes as well as its cytotoxicity against mammalian cells. Additionally, studies were conducted to determine logD7,4 and solubility as well as in vitro pharmacokinetic properties. 14 active and selective for the amastigotes of T. cruzi analogues were obtained, with the addition of the piperazine being an important modification to gain activity. In silico predictions indicated a good balance between solubility and lipophilicity, confirmed experimentally for some analogues. Compound 34 (EC50 8.7 μM) was the most active of the series, with the best drug-likeness characteristics and lipophilic efficiency (LLE). Compound 29 is also highlighted (EC50 13.9 μM), with high aqueous solubility (> 200 μM) and permeability (Papp > 100 nm/s), as well as stable against human liver microsomes (5.2 mL/min/g) and human hepatocytes (0,5 mL/min/g) in in vitro studies. In short, the proposed modifications led to active and selective compounds, with improved hydrosolubility and drug-likeness.
The expansion of LINS03 series aimed to obtain anti-T. cruzi compounds equipotent or superior to known analogues of the series, with improved hydrosolubility and lower cytotoxicity. Therefore, substructures that could increase water solubility (such as piperazine and vinyl) were introduced to the side chain, maintaining structural features present in active analogues. Thus, 46 new analogues were prepared and isolated with adequate purity and yields from 31 to 84%. These anti-T cruzi was determined in trypomastigotes and amastigotes as well as its cytotoxicity against mammalian cells. Additionally, studies were conducted to determine logD7,4 and solubility as well as in vitro pharmacokinetic properties. 14 active and selective for the amastigotes of T. cruzi analogues were obtained, with the addition of the piperazine being an important modification to gain activity. In silico predictions indicated a good balance between solubility and lipophilicity, confirmed experimentally for some analogues. Compound 34 (EC50 8.7 μM) was the most active of the series, with the best drug-likeness characteristics and lipophilic efficiency (LLE). Compound 29 is also highlighted (EC50 13.9 μM), with high aqueous solubility (> 200 μM) and permeability (Papp > 100 nm/s), as well as stable against human liver microsomes (5.2 mL/min/g) and human hepatocytes (0,5 mL/min/g) in in vitro studies. In short, the proposed modifications led to active and selective compounds, with improved hydrosolubility and drug-likeness.