- Design, synthesis, antiproliferative evaluation, and molecular docking study of new quinoxaline derivatives as apoptotic inducers and EGFR inhibitors
-
A new series of quinoxaline derivatives synthesized and pharmacologically evaluated against (HepG-2, HCT-116, and MCF-7) cell lines. Seven compounds were found to possess the highest activities against the examined cell lines with IC50 values ranging from (7.57 to 28.44 μM). To further analyze its apoptotic potential in MCF-7 cells, the most active 3a, 3b, 6, 7b, 7c, 7d, and 7f members have been selected. Interestingly, it found that the Bcl-2 level decreased by 1.95–3.99 folds, and the BAX level increased by 7.2-10.6 folds relative to the control. They also increased the active Caspase-3 level by 5.77-10.69 folds compared to untreated cells. WI38 cells were treated with these compounds to estimate the cytotoxicity level of those compounds in non-tumorigenic cells, and they displayed higher IC50 values (142.21-335.03μM), suggesting may less toxic effect on the normal ones. Further studies on the mechanism of the most promising compounds 3a, 6, 7b and 7d, revealed that it increases apoptotic cells and induced cell cycle arrest at pre-G1 and G2/M phases. Besides, both wild EGFRWT and mutant EGFRL858R-TK inhibitory activity for these derivatives showed that these derivatives had IC50 values ranging from 0.075-1.547 μM versus wild EGFRWT and 63.70-87.34 nM versus the mutant type. Erlotinib was used as a standard reference with IC50 values of 0.0656 μM and 59.56 nM versus both types. Finally, the molecular docking study of most potent quinoxaline derivatives exhibited a good binding inside the active site of EGFR (1M17), with binding energy ranged between (-15.86 to -16.97) compared to Erlotinib (-17.84) kcal/mol. Also, by applying Lipinski's parameters, it was found that these derivatives showed no violations and indicated promiscuity to formulate orally.
- Fayed, Eman A.,Ammar, Yousry A.,Saleh, Marwa A.,Bayoumi, Ashraf H.,Belal, Amany,Mehany, Ahmed B.M.,Ragab, Ahmed
-
-
Read Online
- Synthesis and physicochemical study of a quinoxaline derivative with potencial antineoplasic or anti-HIV activity
-
Kinetics of the synthesis of 3-[3-quinoxaline(1H)-one]propionic acid (I) were performed. This compound was achieved from reaction between o-phenylenediamine and α-ketoglutaric acid under different experimental conditions, and it was sent to the National Cancer Institute (USA) for its pharmacological evaluation.
- Rodrigo, Gabriela A.,Bekerman, Diana G.,Robinsohn, Adriana E.,Fernandez, Beatriz M.
-
-
Read Online
- Design, synthesis and biological evaluation of quinoxaline compounds as anti-HIV agents targeting reverse transcriptase enzyme
-
Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.
- Estrin, Darío,Fabian, Lucas,Gómez, Natalia,Moglioni, Albertina,Salvatori, Melina,Taverna Porro, Marisa,Turk, Gabriela
-
-
- Evaluation of quinoxaline compounds as ligands of a site adjacent to S2 (AS2) of cruzain
-
The binding of ten quinoxaline compounds (1–10) to a site adjacent to S2 (AS2) of cruzain (CRZ) was evaluated by a protocol that include a first analysis through docking experiments followed by a second analysis using the Molecular Mechanics-Poisson-Boltzmann Surface Area method (MM-PBSA). Through them we demonstrated that quinoxaline compounds bearing substituents of different sizes at positions 3 or 4 of the heterocyclic ring might interact with the AS2, particularly interesting site for drug design. These compounds showed docking scores (ΔGdock) which were similar to those estimated for inhibitors that bind to the enzyme through non-covalent interactions. Nevertheless, the free binding energies (ΔG) values estimated by MM-PBSA indicated that the derivatives 8–10, which bear bulky substituents at position 3 of the heterocycle ring, became detached from the binding site under a dynamic study. Surprisingly, the evaluation of the inhibitory activity of cruzipain (CZ) of some derivatives showed that they increase the enzymatic activity. These results lead us to conclude about the relevance of AS2 as a pocket for compounds binding site, but not necessarily for the design of anti-chagasic compounds.
- Fabian,Martini, M. Florencia,Sarduy, Emir Salas,Estrin, Darío A.,Moglioni, Albertina G.
-
p. 2197 - 2202
(2019/07/03)
-
- Quinoxaline derivatives with MMP (matrix metalloproteinase) inhibitory activity as well as preparation method and application thereof
-
The invention discloses quinoxaline derivatives with MMP (matrix metalloproteinase) inhibitory activity as well as a preparation method and application thereof. In the invention, a series of quinoxaline derivatives with specific MMP-9 and/or MMP-13 inhibitory activity are synthesized, and the type of compounds can serve as a specific MMP-9 and/or MMP-13 inhibitor, so that a clinical drug with higher therapeutic index is formed, and the problems in the prior art that drugs for treating osteoarthritis, osteoarthritis, osteoporosis and periodontitis are fewer in type and are not exact in curativeeffect, etc. are solved.
- -
-
Paragraph 0100; 0101; 0102
(2019/01/08)
-
- Synthesis of hydrazones derivatives of quinoxalinone- prospective antimicrobial and antiinflammatory agents
-
A series of quinoxalinone derivatives was synthesized by the condensation of 1,2-diaminobenzene with α-ketoglutaric acid to yield 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propionic acid (2) and then treated with hydrazine hydrate to yield its hydrazones (3). This was further reacted with substituted aromatic aldehydes to produce final compounds (4a-r). These hydrazones derivatives were characterized by FT-IR and 1H-NMR data. All the synthesized compounds were evaluated for their antimicrobial and antiinflammatory activity.
- Khan, Suroor A.,Mullick, Pooja,Pandit, Shabir,Kaushik, Darpan
-
experimental part
p. 169 - 172
(2009/06/24)
-
- Synthesis of potential chemotherapic quinoxalinone derivatives by biocatalysis or microwave-assisted Hinsberg reaction
-
In recent years, great efforts have been dedicated to the design of compounds acting as selective inhibitors of the HIV-1 reverse transcriptase (RT). Due to the promissory results previously attained with some quinoxaline derivatives, we aimed to improve the specific standard Hinsberg synthetic pathway by means of biocatalysis or microwave (MW) irradiation. Both techniques rendered the products in very good yields. However, employing the microwave-assisted organic synthesis (MAOS), in the absence of solvent, the same reactions may be completed in minutes. Some of these quinoxalinone derivatives exhibited good inhibitor activity against some human tumoral cells and the lymphoma related to HIV-1.
- Gris, Javier,Glisoni, Romina,Fabian, Lucas,Fernández, Beatriz,Moglioni, Albertina G.
-
p. 1053 - 1056
(2008/09/18)
-
- Triazolo and derivatives as chemokine inhibitors
-
Novel triazolo derivatives represented by the following formula and pharmaceutically acceptable salts thereof, as well as chemokine inhibitors containing the same as an effective component. These are useful as therapeutic agents for allergic diseases such
- -
-
-