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Upstream product

• 19815-16-8 4-chloro-6-nitro-quinazoline 
• 108-42-9 3-chloro-aniline 
• 6943-17-5 6-nitroquinazolin-4-ol 
• 22363-16-2 ethyl N-(2-cyano-4-nitrophenyl)formimidate 
• 39263-34-8 N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformimidamide 
• 17420-30-3 5-nitroanthranilonitrile 
• 220488-24-4 4-chloro-6-nitroquinazoline hydrochloride 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of cinnamamide-quinazoline derivatives as potential EGFR inhibitors to reverse T790M mutation

Gatekeeper T790M mutation in EGFR is the most common factor for acquired resistance. Acrylamide-bearing 4-anilinoquinazoline scaffold are powerful irreversible inhibitors for overcoming resistance. In this work, three series of EGFR inhibitors derived from incorporation of cinnamamide into the quinazoline scaffold were designed and synthesized to reverse resistance resulting from insurgence of T790M mutation. SAR studies revealed that methoxy and acetoxy substitutions on the cinnamic phenyl ring were found to elevate the activity. In particular, compound 7g emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib (0.95 μM) towards H1975 cells with an IC50 value of 1.22 μM. Kinase inhibition studies indicated that 7g showed excellent inhibitory effect on EGFRT790M enzyme, which was 11 times more effective than gefitinib. Besides, selectivity index of 7g toward the EGFRT790M mutant over the EGFRWT is 2.72, hinting its effect of reducing off-target. Mechanism study indicated that 7g induced apoptosis of H1975 cells and arrest the cell cycle at G2/M phase in a dose-dependent manner. Moreover, 7g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 7g inside EGFRWT and EGFRT790M binding sites.

4-amino-quinazoline derivatives and antiviral composition comprising the same

4 -amino - quinazoline (4-amino-quinazoline) derivatives or pharmaceutically acceptable salts thereof, processes for their preparation, and viral therapeutics containing them as active ingredients.

Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl

Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells

Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC50 = 3 and 16 μM, respectively), compared to that of Erlotinib (IC50 = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC50 = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.

First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents

The activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC50 for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.

4-Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected disease leishmaniasis

4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against Leishmania major promastigotes in vitro with IC50 values Combining double low line 1.87-61.48 μM. Among the twenty four synthetic derivatives, 4-[4′-(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2′-methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with IC50 values 1.87 ± 0.31 and 4.37 ± 0.02 μM, respectively, more active than the standard drug, pentamidine (IC50 Combining double low line 5.09 ± 0.09 μM). Compound 16 (IC50 Combining double low line 6.53 ± 0.21 μM) displayed an activity comparable to the standard. Compounds 15 (IC50 Combining double low line 9.04 ± 0.03 μM), 18 (IC50 Combining double low line 12.28 ± 0.18 μM), 14 (IC50 Combining double low line 19.87 ± 0.22 μM), and 5 (IC50 Combining double low line 24.03 ± 2.71 μM) also showed good activities.

Design, synthesis, and biological evaluation of novel quinazoline derivatives as anti-inflammatory agents against lipopolysaccharide-induced acute lung injury in rats

Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide-induced acute lung injury via anti-inflammatory actions. Thirty-three 4-amino quinazolin derivatives were synthesized and screened for anti-inflammatory activities in lipopolysaccharide-induced macrophages. The most potent four compounds, 6h, 6m, 6p, and 6q, were shown dose-dependent inhibition against lipopolysaccharide-induced TNF-α and IL-6 release. Then, the preliminary structure-activity relationship and quantitative structure-activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide-induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q, obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide-induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.

Combination of 4-anilinoquinazoline and rhodanine as novel epidermal growth factor receptor tyrosine kinase inhibitors

Abstract A type of novel rhodanine-based 4-anilinoquinazoline, which designed the combination between quinazoline as the backbone and various substituted biological rhodanine groups as the side chain, have been synthesized, and their antiproliferative act

Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity

Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N6-((5-bromothiophen-2-yl)methyl)-N4-(3- chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50 = 3.11 μM for Hep G2, IC50 = 0.82 μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.

Design, synthesis, and evaluation of substituted 6-amide-4- anilinoquinazoline derivatives as c-Src inhibitors

The 4-anilinoquinazoline scaffold has been historically used for designing EGFR/VEGFR/HER2 inhibitors while it has not been reported widely for developing c-Src inhibitors. Thus, a series of novel 4-anilinoquinazoline derivatives grafting different amide moieties at the 6-position were designed and synthesized as potential inhibitors for c-Src. In this manuscript, all of the designed compounds were screened via molecular docking using Discovery Studio 3.5 software. As expected, the results of the docking study revealed that most of these targeted compounds possessed lower binding energy than the positive control Saracatinib. Subsequently, all of the screened compounds were synthesized and evaluated for their c-Src in vitro inhibitory activities and in vitro antiproliferation assays against four human cancer cells (A549, MCF-7, HepG-2, HeLa). Among these compounds, 24 exhibited the most potent inhibitory activity against c-Src kinase as well as at the cellular level, of which the IC50 value reached up to 2.9 nM, comparable to the positive compound Saracatinib. Kinase selectivity profile also demonstrated that compound 24 showed good selectivity over several close kinase targets. These results, along with relative 3D-QSAR study, could provide an important basis for further development of compound 24 as a potent tyrosine kinase inhibitor.