Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli NIPER, Raebareli, Uttar Pradesh 226002, India.
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli NIPER, Raebareli, Uttar Pradesh 226002, India.
J Org Chem. 2023 Aug 4;88(15):10494-10500. doi: 10.1021/acs.joc.3c00446. Epub 2023 Jul 18.
Kynurenic acid (KYNA) is an endogenous molecule, which is a non-selective antagonist of ionotropic glutamate receptors and has been found to have neuroprotective activity. A supplement of KYNA may be applicable for the treatment of neurodegenerative disease, but it does not cross the blood-brain barrier due to its polar nature. Therefore, its different esters and amide derivatives were explored as a prodrug, which can cross blood-brain barrier and transform into KYNA in situ. However, many esters and amide derivatives of KYNA are synthesized via coupling reaction or multi-step synthesis using different organic or metallic catalysts. Herein, we developed a novel one-pot, catalyst-free, convenient synthesis of KYNA ethyl esters using aniline and diethyl acetylene dicarboxylate in DMF under heating. We also explored the synthesis of KYNA and KYNA amide derivative in a simple manner with overall good yields via hydrolysis and condensation, respectively.
犬尿酸（KYNA）是一种内源性分子，是离子型谷氨酸受体的非选择性拮抗剂，已被发现具有神经保护活性。KYNA 的补充剂可能适用于治疗神经退行性疾病，但由于其极性，它不能通过血脑屏障。因此，人们探索了其不同的酯和酰胺衍生物作为前药，这些前药可以穿过血脑屏障，并在原位转化为 KYNA。然而，KYNA 的许多酯和酰胺衍生物是通过使用不同的有机或金属催化剂的偶联反应或多步合成来合成的。在此，我们开发了一种使用苯胺和二乙基乙炔二羧酸酯在 DMF 中加热一锅法、无催化剂、简便的 KYNA 乙酯合成方法。我们还通过水解和缩合，分别以简单的方式探索了 KYNA 和 KYNA 酰胺衍生物的合成，总收率良好。
