621-03-4Relevant articles and documents
(E)-2-Cyano-3-(1H-Indol-3-yl)-N-phenylacrylamide, a hybrid compound derived from indomethacin and paracetamol: Design, synthesis and evaluation of the anti-inflammatory potential
Albino, Sonaly,Espírito-Santo, Renan,Lima, Maria,Moura, Ricardo,Santos, Vanda,Silva, Jamire,Silva, Pablo,Villarreal, Cristiane,de Almeida, Maria
, (2020)
The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p -1) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2-6 h. In addition, there was no significant inhibition of PGE2, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.
Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma
Liang, Xuewu,Sun, Chenxia,Li, Chunpu,Yu, Haolan,Wei, Xiaohui,Liu, Xuyi,Bao, Wei,Shi, Yuqiang,Sun, Xiaochen,Khamrakulov, Mirzadavlat,Yang, Chenghua,Liu, Hong
, p. 9217 - 9237 (2021/07/20)
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
New pyrazolopyrimidine derivatives with anticancer activity: Design, synthesis, PIM-1 inhibition, molecular docking study and molecular dynamics
Hassan, Marwa H. A.,Kamel, Gehan,Khedr, Mohammed A.,Lamie, Phoebe F.,Philoppes, John N.
, (2020/05/25)
In this study, new pyrazolopyrimidine derivatives were designed and evaluated for anticancer activity. PIM-1 inhibitiory activity were measured for the most potent compounds. Molecular docking study and molecular dynamics were also done. Thus, the novel derivatives of pyrazolo[1,5-a]pyrimidine have been synthesized and characterized using different spectroscopic techniques. HMBC and NOESY experiments were used to confirm regiospecific structure of pyrimidine ring. The newly synthesized derivatives were evaluated for their antitumor activities against HCT-116 and MCF-7 cell lines. These derivatives showed clear in vitro antitumor activities. Compound 5h showed the highest bioactivity (IC50 = 1.51 μM) against HCT-116 cell line. While, compound 6c was the most potent derivative, its IC50 was 7.68 μM against MCF-7 cell line. Compounds 5c, 5g, 5h, 6a and 6c showed PIM-1 inhibitory activity with IC50 of 1.26, 0.95, 0.60, 1.82, 0.67, respectively μM that could be correlated with their cytotoxic effect. Molecular docking study was done to predict the mode of binding of the target compounds inside PIM-1 active site. The molecular dynamic simulation was conducted in order to evaluate stability of binding of the tested compounds.
