Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 16 St., 31-530 Krakow, Poland.
Molecules. 2022 Dec 28;28(1):238. doi: 10.3390/molecules28010238.
The multitarget-directed ligands demonstrating affinity to histamine H receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound with a high affinity for HR ( = 8 nM) and significant inhibitory activity toward BuChE (IC = 172 nM and 1.16 µM for BuChE and BuChE, respectively). Further in vitro studies revealed that compound (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (P) of 6.3 × 10 cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound in the Passive Avoidance Test and the Formalin Test. While compound did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED = 20.9 mg/kg) and inflammatory (ED = 17.5 mg/kg) pain.
具有组胺 H 受体亲和力和额外胆碱酯酶抑制活性的多靶点配体代表了研究阿尔茨海默病有效治疗方法的有前途的策略。在这项研究中，设计并合成了一系列新型苯甲酮衍生物。在这些衍生物中，我们确定了化合物 对 HR 具有高亲和力（= 8 nM），并且对 BuChE 具有显著的抑制活性（对 BuChE 和 BuChE 的 IC 分别为 172 nM 和 1.16 µM）。进一步的体外研究表明，化合物 （4-氟苯基）（4-（5-（哌啶-1-基）戊基）氧基）苯基）甲酮）在小鼠肝微粒体中显示出中等的代谢稳定性，具有良好的渗透性，渗透系数（P）值为 6.3 × 10 cm/s，并且在 HepG2 细胞系中对肝毒性的安全性得到了证实。因此，我们研究了化合物 在被动回避试验和福马林试验中的体内活性。虽然化合物 对记忆和学习没有显示出统计学上的显著影响，但它在急性（ED = 20.9 mg/kg）和炎症（ED = 17.5 mg/kg）疼痛中均表现出镇痛作用。
