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Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

ABSTRACT: Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC50) = 4.31 ?M) against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC50 = 24.77 ?M) and edaravin (EC50 = 5.62 ?M). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t-Butyloxy carbonyl (boc)-protected derivatives.

SUBMITTER: Jia X

PROVIDER: S-EPMC6832219 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

Jia Xiaohui X Jia Menglu M Yang Yuqin Y Wang Di D Zhou Fei F Zhang Wenxi W Huang Xuemei X Guo Wenbo W Cai Desheng D Chen Hongshan H Qi Jinchai J Zhou Shuqi S Ren Haomiao H Xu Bing B Ma Tao T Wang Penglong P Lei Haimin H

Molecules (Basel, Switzerland) 20191009 20

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (<i>Scutellaria altissima</i> L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neur ...[more]

PMID: 31601055

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Project description:Background and purposeAlthough pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives.Experimental approachIn this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds. 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds.Findings/resultsMost of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds.Conclusion and implicationsRacecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

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Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

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Synthesis of Novel Baicalein Amino Acid Derivatives and Biological Evaluation as Neuroprotective Agents.

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