Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat 382355, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Opposite Air Force Station, Palaj, Gandhinagar, Gujarat 382355, India.
Bioorg Med Chem Lett. 2021 Jun 15;42:127999. doi: 10.1016/j.bmcl.2021.127999. Epub 2021 Apr 9.
Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid β aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid β aggregation (IC of 4.6 μM) through selective binding with Amyloid β at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu, Zn and Fe) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.
阿尔茨海默病是多因素的，炎症在疾病进展和严重程度中起着主要作用。金属和活性氧（ROS）是与阿尔茨海默病相关炎症状态的主要介质。除了多因素性质外，开发新药的主要挑战是分子穿过血脑屏障（BBB）的能力。我们设计并合成了含有三唑的多靶标导向己烷醇，以抑制淀粉样β聚集，同时螯合细胞外空间中过量的金属并清除 ROS，从而减轻炎症状态。从筛选的化合物文库中，发现化合物 1c 具有很强的活性和安全性。它通过与淀粉样 β 在成核部位的选择性结合（从分子对接中得到证实）来抑制淀粉样 β 聚集（IC 为 4.6 μM）。它还能螯合金属（Cu、Zn 和 Fe）并显著清除 ROS。由于分子中存在六氟丁烷部分，它可能有助于穿透 BBB 并改善药代动力学性质。化合物 1c 的体外结果表明，含有六氟丁烷的三唑酰胺支架作为多靶标导向治疗阿尔茨海默病的药物具有混杂性。
