Publicação
Synthesis of Compounds Containing a 1,3-Diazo Spacer with Potential MTDL Capacity and As-sessment of their Activity on Biological Targets
| Resumo: | Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which the prevailing "One target, one drug" approach has shown limited efficacy. The Multi-Target-Directed-Ligand (MTDL) drug design strategy offers a promising alternative by devel-oping compounds capable of single-handedly modulating multiple pathological pathways. This work explores the synthesis and preliminary biological evaluation of a library of novel compounds designed as potential MTDLs for AD. The main strategy focused on the hydrolysis of bicyclic amidines (DBN and DBU), as well as the monocyclic amidine 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DmTHP) to generate a structure with a 1,3-diazo spacer. Using tacrine as the model-drug, these spacers were functionalized with aromatic moieties (e.g., anthracene, acridine, pyridine) through a one-pot reductive amination protocol to yield secondary amines, with an amide group on the second terminal of the 1,3-diazo spacer, which underwent further N-alkylation with propargyl or benzyl bromide to obtain tertiary amines. Building on previous work in our research group, the hydrolysis of DmTHP was monitored by 1HNMR spectroscopy to reveal optimal conditions for ring opening. The structures of all synthesized compounds (BB1-BB9 and their alkylated derivatives) were confirmed by spectroscopic techniques (FTIR, NMR, MS). The synthetic efficiency varied considerably, with the initial reductive amination steps generally returning high yields (47-96%), while the alkylation reactions proved challenging, resulting in low to moderate yields (10-61%) and often failing to reach completion. Preliminary enzymatic assays based on Ellman's method were conducted to assess the inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). De-spite the promising results when testing with BuChE, the assays with AChE reveal that further optimization is necessary for accurate kinetic analysis. Overall, this study successfully estab-lishes a synthetic pathway for obtaining novel 1,3-diazo spacer compounds and provides a foundation for the future development of MTDLs targeting cholinergic dysfunction and other pathologies in Alzheimer's disease. |
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| Autores principais: | Braga, Bernardo Miguel Mendonça de Medeiros |
| Assunto: | Alzheimer's Disease Multi-Target-Directed Ligands (MTDLs) Acetylcholines-terase (AChE) Butyrylcholinesterase (BuChE) Organic Synthesis 1 3-Diazo Spacer |
| Ano: | 2025 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which the prevailing "One target, one drug" approach has shown limited efficacy. The Multi-Target-Directed-Ligand (MTDL) drug design strategy offers a promising alternative by devel-oping compounds capable of single-handedly modulating multiple pathological pathways. This work explores the synthesis and preliminary biological evaluation of a library of novel compounds designed as potential MTDLs for AD. The main strategy focused on the hydrolysis of bicyclic amidines (DBN and DBU), as well as the monocyclic amidine 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DmTHP) to generate a structure with a 1,3-diazo spacer. Using tacrine as the model-drug, these spacers were functionalized with aromatic moieties (e.g., anthracene, acridine, pyridine) through a one-pot reductive amination protocol to yield secondary amines, with an amide group on the second terminal of the 1,3-diazo spacer, which underwent further N-alkylation with propargyl or benzyl bromide to obtain tertiary amines. Building on previous work in our research group, the hydrolysis of DmTHP was monitored by 1HNMR spectroscopy to reveal optimal conditions for ring opening. The structures of all synthesized compounds (BB1-BB9 and their alkylated derivatives) were confirmed by spectroscopic techniques (FTIR, NMR, MS). The synthetic efficiency varied considerably, with the initial reductive amination steps generally returning high yields (47-96%), while the alkylation reactions proved challenging, resulting in low to moderate yields (10-61%) and often failing to reach completion. Preliminary enzymatic assays based on Ellman's method were conducted to assess the inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). De-spite the promising results when testing with BuChE, the assays with AChE reveal that further optimization is necessary for accurate kinetic analysis. Overall, this study successfully estab-lishes a synthetic pathway for obtaining novel 1,3-diazo spacer compounds and provides a foundation for the future development of MTDLs targeting cholinergic dysfunction and other pathologies in Alzheimer's disease. |
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