RESUMO
A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88⯵g/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16⯵g/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells.
Assuntos
Alcinos/farmacologia , Antibacterianos/farmacologia , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Pirimidinas/farmacologia , Alcinos/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Bases de Mannich/química , Bases de Mannich/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxidiazóis/química , Células PC12 , Pseudomonas aeruginosa/efeitos dos fármacos , Pirimidinas/química , Ratos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The purpose of our study was to understand the protective effects of a partial reduction of dynamin-related protein 1 (Drp1) in Alzheimer's disease (AD) progression and pathogenesis. Increasing evidence suggests that phosphorylated Tau and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline, in patients with AD. In the current study, we investigated whether a partial reduction of Drp1 protect neurons from phosphorylated Tau-induced mitochondrial and synaptic toxicities in AD progression. We crossed Drp1+/− mice with Tau transgenic mice (P301L line) and created double mutant (TauXDrp1+/−) mice. Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamicsDrp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesisNrf1, Nrf2, PGC1α and TFAM and synapticsynaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month-old Drp1+/−, Tau, TauXDrp1+/− and wild-type mice. Using biochemical and immunoblotting methods, mitochondrial function and phosphorylated Tau were measured. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1+/− mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1+/− mice relative to Tau mice. Phosphorylated Tau found to be reduced in TauXDrp1+/− mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the production of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice. Findings of this study may have implications for the development of Drp1 based therapeutics for patients with AD and other tauopathies.