186544-90-1

Upstream product

• 347-88-6 4-fluoro-N-(4-nitrophenyl)benzamide 
• 100-01-6 4-nitro-aniline 
• 403-43-0 4-fluorobenzoyl chloride 
• 106-50-3 1,4-phenylenediamine 
• 456-22-4 4-Fluorobenzoic acid 
• 71026-66-9 N-(tert-butoxycarbonyl)-1,4-phenylenediamine 

Relevant academic research and scientific papers

Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazoline and diarylamide fragments

VEGF/VEGFR-2 signaling plays a critical part in tumor angiogenesis. Inhibition of this pathway has been considered as a promising approach for cancer treatment. In this work, a series of 6,7-dimethoxy-4-anilinoquinazoline derivatives bearing diarylamide moiety were designed, synthesized and evaluated as potent inhibitors of VEGFR-2 kinase. Their in vitro antiproliferation activities against two human cancer cell lines Hep-G2 and MCF-7 have also been determined. Among them, compound 14b exhibited the most potent inhibitory activity against VEGFR-2 with IC50 value of 0.016 ± 0.002 μM and it showed the most potent antiproliferative effect against Hep-G2 and MCF-7 with IC50 values at low-micromolar range. Molecular docking studies revealed that these compounds represented by the most potent compound 14b could bind well to the ATP-binding site of VEGFR-2, which suggested that compound 14b could be a potential anticancer agent targeting VEGFR-2.

Synthesis of ring-opened derivatives of triazole-containing quinolinones and their antidepressant and anticonvulsant activities

Based on the potent antidepressant and anticonvulsant activities of the triazole-containing quinolinones reported in our previous work, a series of ring-opened derivatives of them were designed, synthesized in this work. Their antidepressant and anticonvulsant activities were screened using the forced swimming test (FST) and the maximal electroshock seizure test (MES), respectively. The results showed that compounds 4a, 5a, 6c-6e, 6g-6i, and 7 led to significant reductions in the accumulated immobility time in the FST at a dose of 50 mg/kg. Especially compound 7 exhibited higher levels of efficacy than the reference standard fluoxetine in the FST and the tail suspension test. The results of an open field test excluded the possibility of central nervous stimulation of 7, which further confirmed its antidepressant effect. Meanwhile, compounds 6a-6i and 7 showed different degrees of anticonvulsant activity in mice at the doses range from 300 to 30 mg/kg in the MES. Among them, compounds 6e and 7 displayed the ED50 of 38.5 and 32.7 mg/kg in the MES, and TD50 of 254.6 and 245.5 mg/kg, respectively. No one showed neurotoxicity at the dose of 100 mg/kg. The preliminary investigation forward to their mechanism indicated that regulation of GABAergic system might contribute to their anticonvulsive and anti-depressive action.

Amide derivatives of Gallic acid: Design, synthesis and evaluation of inhibitory activities against in vitro α-synuclein aggregation

Gallic acid (GA), a natural phenolic acid, has received numerous attention because of its anti-oxidative, anti-inflammatory, and anti-cancer activity. More importantly, GA can act as an efficient inhibitor of α-Synuclein (α-Syn) aggregation at early stages. Nevertheless, some evidences suggest that GA is unlikely to cross the blood–brain barrier because of its high hydrophilicity. Hence, GA may not be considered as a promising candidate or entering brain and directly affecting the central nervous system. Accordingly, we have designed and synthesized a series of amide derivatives of GA, some of which possess appropriate lipophilicity and hydrophilicity with LogP (2.09–2.79). Meanwhile, these sheet-like conjugated compounds have good π-electron delocalization and high ability of hydrogen-bond formation. Some compounds have shown better in vitro anti-aggregation activities than GA towards α-Syn, with IC50 down to 0.98 μM. The valid modification strategy of GA is considered an efficient way to discover novel inhibitors of α-Syn aggregation.

Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking

Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 μM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.

AMIDO-SUBSTITUTED AZOLE COMPOUNDS

The present invention relates to amido-substituted azole compounds of general formula (I), in which X1, X2, R1, R2, R4, R5, R7 and R8 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

AMIDO-SUBSTITUTED AZOLE COMPOUNDS

The present invention relates to amido-substituted azole compounds of general formula (I), in which X1, X2, R1, R2, R4, R5, R7 and R8 are as defined in the claims which are inhibitors of TNKS1 and/or TNKS2, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU)

Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine- 1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.

SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors

Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8] naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.

N-[3-(2-dimethylaminoethyl).2-methyl-1H-indol-5-yl]-4-fluorobenzamide: A potent, selective, and orally active 5-HT1F receptor agonist potentially useful for migraine therapy

Recent studies have demonstrated that selective 5-HT1F receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)-ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT1F receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.

METHODS OF TREATING OR AMELIORATING THE SYMPTOMS OF COMMON COLD OR ALLERGIC RHINITIS WITH SEROTONIN 5-HT1F

This invention provides methods for the treatment or amelioration of the symptoms of the common cold or allergic rhinitis which comprises administering to a mammal in need thereof a serotonin 5-HT 1F agonist.