Nkomba Gaofenngwe, Terre'Blanche Gisella, Janse van Rensburg Helena D, Legoabe Lesetja J
Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.
Med Chem Res. 2022;31(8):1277-1297. doi: 10.1007/s00044-022-02908-9. Epub 2022 May 24.
Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-]pyridine derivatives as non-nucleoside A agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound (thieno[2,3-]pyridine derivative), displayed good binding affinity to the rA AR ( = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (-) in relation to AR binding was also evaluated. A significant loss of activity against rA/rA ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA ARs ( < 10 nM) than rA. Compound had the best rA affinity ( = 0.076 nM). Novel compounds (, , , , , , were highly selective towards rA AR ( between 0.179 and 21.0 nM). Based on their high selectivity for A ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-]pyridines (, , ) from amino-3,5-dicyanopyridine derivatives (, , ).
由于腺苷在抑制癫痫发作中的作用，基于腺苷的疗法如腺苷受体（AR）激动剂已被研究。本研究旨在研究噻吩并[2,3 - ]吡啶衍生物作为可用于耐药性癫痫（PRE）的非核苷类A激动剂。化合物（噻吩并[2,3 - ]吡啶衍生物）对rA AR显示出良好的结合亲和力（= 61.9 nM）。这可能是进一步研究这种杂环支架作为潜在配体的一个突破。对该化合物的计算机模拟评估引发了对生物利用度的担忧，但在类药性测试中表现良好。还评估了从先导化合物氨基 - 3,5 - 二氰基吡啶衍生物（ - ）合成噻吩并[2,3 - ]吡啶过程中发生的分子内环化对AR结合的影响。结果显示，环化后对rA/rA ARs的活性显著丧失。氨基 - 3,5 - 二氰基吡啶对rA ARs的亲和力（<10 nM）高于rA。化合物具有最佳的rA亲和力（= 0.076 nM）。新型化合物（，，，，，，）对rA AR具有高度选择性（在0.179至21.0 nM之间）。基于它们对A ARs的高选择性，氨基 - 3,5 - 二氰基吡啶在经过适当的结构优化和制剂设计后，可作为PRE中的AR配体进一步研究。在从氨基 - 3,5 - 二氰基吡啶衍生物（，，）合成噻吩并[2,3 - ]吡啶（，，）的过程中，观察到分子内环化会导致rA AR亲和力降低。
