Pharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and UGC Centre of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University, Chandigarh, India.
Faculty of Pharmacy, Philadelphia University, Amman, Jordan.
Chem Biol Drug Des. 2018 Apr;91(4):962-969. doi: 10.1111/cbdd.13155. Epub 2017 Dec 22.
A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17-19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA AR, whereas carbamoylation of the amino group at 2-position (in the presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7-10) for hA AR. Molecular dynamic simulation study of one of the most active compound 8 (K hA > 30 μm, hA = 0.65 μm, and hA = 0.124 μm) revealed the role of important amino acid residues for imparting good affinity towards hA and hA ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA AR and a homology model of hA AR to rationalize their structure-activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.
一系列含有噻吩并[2,3-d]嘧啶骨架的新分子被合成并通过有效的合成方案进行了表征。研究了骨架 2 位上有无取代的氨基以及 4 位上的氧、咪唑或 1,2,4-三唑环对腺苷受体（ARs）的亲和力和选择性的影响。在骨架 4 位上具有咪唑/1,2,4-三唑环的同时在 2 位上具有游离氨基的化合物 17-19 对 hA AR 具有选择性结合亲和力，而在骨架 4 位上的氧取代基的存在下氨基的氨甲酰化（carbamoylation）增加了某些化合物（7-10）对 hA AR 的亲和力和选择性。对最活跃的化合物 8（K hA > 30 μm，hA = 0.65 μm，和 hA = 0.124 μm）的分子动力学模拟研究揭示了重要氨基酸残基在赋予 hA 和 hA ARs 良好亲和力方面的作用。使用 hA AR 的晶体结构和 hA AR 的同源模型对其他化合物进行了分子对接研究，以合理推断它们的构效关系。分子对接结果与 ARs 的实验结合亲和力数据一致。
