Dihydrofolate reductase inhibitory potential of 1H-indole-based-meldrum linked 1H-1,2,3-triazoles as new anticancer derivatives: In-vitro and in-silico studies

Article

作者: Avula, Satya Kumar ; Gibbons, Simon ; Anwar, Muhammad U ; Ebrahimi, Amirhossein ; Al-Harrasi, Ahmed ; Halim, Sobia Ahsan ; Khan, Ajmal ; Csuk, René ; Ullah, Saeed ; Rostami, Ali

In this present work, we describe the syntheses of a new series of 32 1H-indole-based-meldrum linked 1H-1,2,3-triazole derivatives (2-13, 15a-15f, 16a-16f, 17a-17f and 19a, 19b, 20a), which constitute a new class of 1H-1,2,3-triazoles. Compounds 15a-15f, 16a-16f, 17a-17f have been prepared by employing "click" reactions between substituted 1H-indole-based meldrum alkynes (11, 12 and 13) and substituted aromatic azides (14a-14f) in the presence of copper iodide (CuI) and Hünig's base. Then, the synthesis of compounds 19, 20 through decomposition of meldrum moiety. The resulting compounds have been screened for their dihydrofolate reductase (DHFR) inhibition activity. All the newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR (spectroscopy when applicable), and HR-ESI-MS spectroscopy techniques. The X-ray crystallography studies have unambiguously confirmed the structure of compounds 6, 11 and 13. Furthermore, their DHFR-inhibitory activity was evaluated in-vitro. The results obtained from the DHFR-inhibitory assay revealed that all the synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole derivatives were highly potent inhibitors, with IC₅₀ values in the range 3.48 ± 0.16-30.37 ± 1.20 μM. Ten compounds (15c-15f, 16c-16f, 17e and 17f) among the 32 synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole compounds were found to exhibit exceptional inhibitory while the rest of the derivatives showed moderate activities. Additionally, molecular docking analysis of the most active (16f), moderate (15c) and least active (16a) inhibitors reflect excellent binding of 16f with the binding residues of DHFR with higher docking score (-9.13 kcal/mol) than that of 15c and 16a. The docking analysis correlates well with the inhibitory potential of these synthesized molecules. Overall, this study may pave the way to medicinal analogues of 1H-indole-based-meldrum linked 1H-1,2,3-triazoles as potent DHFR inhibition activity.

2024-08-01·ARCHIV DER PHARMAZIE

Synthesis of amide derivatives containing the imidazole moiety and evaluation of their anti‐cardiac fibrosis activity

Article

作者: Yang, Yu‐Xuan ; Wu, Yan‐Ling ; Nan, Ji‐Xing ; Guo, Jia ; Liu, Chuang ; Jin, Cheng‐Hua

Abstract:

Three series of N‐{[4‐([1,2,4]triazolo[1,5‐α]pyridin‐6‐yl)‐5‐(6‐methylpyridin‐2‐yl)‐1H‐imidazol‐2‐yl]methyl}acetamides (14a–d, 15a–n, and 16a–f) were synthesized and evaluated for activin receptor‐like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. The target compounds showed high ALK5 inhibitory activity and selectivity. The half maximal inhibitory concentration (IC50) for phosphorylation of ALK5 of 16f (9.1 nM), the most potent compound, was 2.7 times that of the clinical candidate EW‐7197 (vactosertib) and 14 times that of the clinical candidate LY‐2157299. The selectivity index of 16f against p38α mitogen‐activated protein kinase was >109, which was much higher than that of positive controls (EW‐7197: >41, and LY‐2157299: 4). Furthermore, a molecular docking study provided the interaction modes between the target compounds and ALK5. Compounds 14c, 14d, and 16f effectively inhibited the protein expression of α‐smooth muscle actin (α‐SMA), collagen I, and tissue inhibitor of metalloproteinase 1 (TIMP‐1)/matrix metalloproteinase 13 (MMP‐13) in transforming growth factor‐β‐induced human umbilical vein endothelial cells. Compounds 14c and 16f showed especially high activity at low concentrations, which suggests that these compounds could inhibit myocardial cell fibrosis. Compounds 14c, 14d, and 16f are potential preclinical candidates for the treatment of cardiac fibrosis.

2023-11-01·Bioorganic chemistry

Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77

Article

作者: Li, Kun ; Hu, Hongyu ; Hong, Wenbin ; He, Fengming ; Lin, Gang ; Liu, Jie ; Jia, Rong ; Fang, Meijuan ; Zeng, Jin-Zhang

Hepatic fibrosis remains a great challenge clinically. The orphan nuclear receptor Nur77 is recently suggested as the critical regulator of transforming growth factor-β (TGF-β) signaling, which plays a central role in multi-organic fibrosis. Herein, we optimized our previously reported Nur77-targeted compound 9 h for attempting to develop effective and safe anti-hepatic fibrosis agents. The critical pharmacophore scaffold of pyridine-carbonyl-hydrazine-1-carboxamide was retained, while the naphthalene ring was replaced with an aromatic ring containing pyridyl or indole groups. Four series of derivatives were thus generated, among which the compound 16f had excellent binding activity toward Nur77-LBD (K_D = 470 nM) with the best inhibitory activity against the TGF- β 1 activation of hepatic stellate cells (HSCs) and low cytotoxicity to normal mice liver AML-12 cells (IC₅₀ > 80 μM). In mice, 16f displayed potent activity against CCl₄-induced liver fibrosis with improved liver function. Mechanistically, 16f-mediated inactivation of HSC and suppression of liver fibrosis were associated with its enhancement of autophagic flux in a Nur77-dependent manner. Together, 16f was identified as a potential anti-liver fibrosis agent. Our study suggests that Nur77 may serve as a critical anti-hepatic fibrosis target.

100 项与 16-f 相关的药物交易

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