Ribeiro João L P, Costa Inês, Silva Renata, Lopes Susana M M, Saraiva Lucília, Pinho E Melo Teresa M V D
University of Coimbra, Coimbra Chemistry Centre-Institute of Molecular Sciences, and Department of Chemistry, 3004-535 Coimbra, Portugal.
UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, Porto University, Porto, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, Porto University, Porto, Portugal.
Bioorg Med Chem. 2024 Sep 1;111:117841. doi: 10.1016/j.bmc.2024.117841. Epub 2024 Jul 18.
3-Tetrazolyl-β-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that β-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-β-carbolines as potential neuroprotective agents against Parkinson's disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1H-tetrazol-5-yl)-1-(p-dimethylaminophenyl)-β-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-β-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-β-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson's disease.
3-四唑基-β-咔啉是通过皮克特-施彭格勒方法，使用色氨酸类似物作为构建模块制备的，其中羧酸被生物电子等排体四唑基团取代。鉴于β-咔啉通常与精神药理作用相关，对3-四唑基-β-咔啉作为抗帕金森病潜在神经保护剂进行了研究。对其针对1-甲基-4-苯基吡啶鎓（MPP）诱导的细胞毒性的神经保护作用进行评估，从而鉴定出具有相关神经保护活性的化合物。一种衍生物，3-(1-苄基-1H-四唑-5-基)-1-(对二甲氨基苯基)-β-咔啉，因其低细胞毒性和出色表现脱颖而出，可防止这种神经毒素诱导的细胞死亡。还对最有前景的化合物针对铁（III）诱导的细胞毒性的神经保护特性进行了评估。然而，只有一种3-四唑基-β-咔啉衍生物略微降低了铁诱导的细胞毒性。总体而言，已证明3-四唑基-β-咔啉具有神经保护特性，这一发现可能有助于开发帕金森病的新疗法。
