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作为透皮前药候选物的美金刚衍生席夫碱

Memantine-Derived Schiff Bases as Transdermal Prodrug Candidates.

作者信息

Araujo de Oliveira Ana P, Romero Colmenares Victoria C, Diniz Renata, Freitas Jennifer T J, da Cruz Clara M, Lages Eduardo B, Ferreira Lucas A M, Vieira Rafael P, Beraldo Heloisa

机构信息

Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.

Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.

出版信息

ACS Omega. 2022 Mar 28;7(14):11678-11687. doi: 10.1021/acsomega.1c06571. eCollection 2022 Apr 12.

DOI:10.1021/acsomega.1c06571
PMID:35449959
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9017104/
Abstract

Condensation reactions of salicylaldehyde, 2-pyridinecarboxaldehyde, and pyridoxaldehyde with memantine () produced novel memantine-derived Schiff bases (-). Speciation predictions and calculations of Log P, Log D, and of the percentage (%) of neutral species for (-) were carried out. In comparison with , the Schiff bases presented increased log P and log D in all cases and pH values, suggesting higher hydrophobicity. The determined solubilities in -octanol were 34.7 mg/mL for memantine hydrochloride and 67.3 mg/mL for (). According to the molecular weights and calculated logP, compounds (-) are suitable for transdermal administration, especially compound (). In addition, hydrolysis of with the release of pyridoxal, a daily cofactor in human metabolism, was observed. The results suggested that is the most promising compound and that formation of the pyridoxal Schiff base with might be an effective strategy to obtain a prodrug candidate with increased lipophilicity, which would be able to passively cross biological barriers during transdermal delivery and might have applications in the treatment of Alzheimer's disease and other neurological disorders.

摘要

水杨醛、2-吡啶甲醛和吡哆醛与美金刚（）的缩合反应生成了新型的美金刚衍生席夫碱（-）。进行了物种形成预测以及对（-）的Log P、Log D和中性物种百分比（%）的计算。与相比，在所有情况和pH值下，席夫碱的log P和log D均有所增加，表明疏水性更高。测定的盐酸美金刚在正辛醇中的溶解度为34.7 mg/mL，而（）为67.3 mg/mL。根据分子量和计算出的logP，化合物（-）适用于透皮给药，尤其是化合物（）。此外，观察到（）会水解并释放出人体新陈代谢中的日常辅助因子吡哆醛。结果表明（）是最有前景的化合物，与（）形成吡哆醛席夫碱可能是获得具有增加亲脂性的前药候选物的有效策略，该前药在透皮给药过程中能够被动穿过生物屏障，可能在治疗阿尔茨海默病和其他神经疾病方面有应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/ca4e36336a60/ao1c06571_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/3b117cfb345a/ao1c06571_0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/f5a20ba9af8f/ao1c06571_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/bbf5d52e1f9e/ao1c06571_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/c7be7ba37263/ao1c06571_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/3706a216da96/ao1c06571_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/7b702e35b105/ao1c06571_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/ca4e36336a60/ao1c06571_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/3b117cfb345a/ao1c06571_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/22a5a33fc0cd/ao1c06571_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/f5a20ba9af8f/ao1c06571_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/bbf5d52e1f9e/ao1c06571_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/c7be7ba37263/ao1c06571_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/3706a216da96/ao1c06571_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/7b702e35b105/ao1c06571_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0828/9017104/ca4e36336a60/ao1c06571_0009.jpg

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