Hameed Abdul, Zehra Syeda T, Shah Syed J A, Khan Khalid M, Alharthy Rima D, Furtmann Norbert, Bajorath Jürgen, Tahir Muhammad N, Iqbal Jamshed
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
Chem Biol Drug Des. 2015 Nov;86(5):1115-20. doi: 10.1111/cbdd.12579. Epub 2015 May 28.
Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3'-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3'-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3'-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.
胆碱酯酶，即乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE），在胆碱能缺陷中起作用，而胆碱能缺陷显然会导致阿尔茨海默病（AD）。用小分子抑制胆碱酯酶是AD治疗中一种有吸引力的策略。本研究展示了吡啶并[2,3 - b]吡嗪（6a - 6q）系列的合成、它们对两种胆碱酯酶AChE和BChE的抑制活性以及分子对接研究。吡啶并[2,3 - b]吡嗪的生物活性数据表明，3 - （3'-硝基苯基）吡啶并[2,3 - b]吡嗪6n是该系列中对AChE和BChE的强效双重抑制剂，IC50值分别为0.466±0.121和1.89±0.05μm。发现类似物3 - （3'-甲基苯基）吡啶并[2,3 - b]吡嗪6c和3 - （3'-氟苯基）吡啶并[2,3 - b]吡嗪6f分别对BChE和AChE有选择性抑制作用，IC50值分别为0.583±0.052μm和0.899±0.10μm。活性化合物的分子对接研究表明了它们与胆碱酯酶的假定结合模式。该系列中的强效化合物有可能成为开发新型胆碱酯酶抑制剂的良好先导物。
