A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a-k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b-c, and 7e-g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a-c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.

https://www.mdpi.com/1420-3049/23/1/48/pdf

Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects

Natural products are a source of many novel compounds with biological activity for the discovery of new pesticides and pharmaceuticals. Quinoxaline is a fused N-heterocycle in many natural products and synthetic compounds, and seven novel quinoxaline derivatives were designed and synthesized via three steps. Pesticidal activities of title quinoxaline derivatives were bioassayed. Most of these compounds had herbicidal, fungicidal, and insecticidal activities. The compounds 2-(6-methoxy-2-oxo-3-phenylquinoxalin-1(2H)-yl)acetonitrile (3f) and 1-allyl-6-methoxy-3-phenylquinoxalin-2(1H)-one (3g) were the most active herbicides and fungicides. Mode-of-action studies indicated that 3f is a protoprophyrinogen oxidase-inhibiting herbicide. Compound 3f also possessed broad-spectrum fungicidal activity against the plant pathogen Colletotrichum species. Some of these compounds also had insecticidal activity. Molecular docking and DFT analysis can potentially be used to design more active compounds.

Synthesis and Pesticidal Activities of New Quinoxalines

Epigenetic dysfunction has been widely implicated in several diseases especially cancers thus highlights the therapeutic potential for chemical interventions in this field. With rapid development of computational methodologies and high-performance computational resources, computer-aided drug design has emerged as a promising strategy to speed up epigenetic drug discovery. Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes. Finally, we discuss about major limitations of current virtual drug design strategies in epigenetics drug discovery and future directions in this field.

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Computer-Aided Drug Design in Epigenetics

Introduction: The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, functions as an 'epigenetic reader' that binds to acetylated lysine (KAc) residues on histone tails sophisticatedly regulating chromatin structure and gene expression. Recently, emerging evidence demonstrates that BRD4 plays a significant role in the occurrence and progression of several malignant human diseases especially cancers, making it a hot target in cancer therapy.Areas covered: This review mainly summarizes the patents of BRD4 inhibitors that have been authorized from 2013 to 2019. The patents are mostly described in terms of chemical structures, molecular mechanisms of action, pharmacological activities and potential clinical applications, including combination therapies. The development of BRD4 inhibitors in the clinical phase has been highlighted. Prospects for further development of more selective BRD4 inhibitors are provided.Expert opinion: In 2013-2019, several previously known chemical scaffolds have been further developed and disclosed. Although many small molecule BRD4 inhibitors with high potency and diverse scaffolds have been developed, the selectivity of most BRD4 inhibitors still needs to be improved. Therefore, the development of more selective small molecule inhibitors or combined use of drugs such as immunotherapy may provide new ideas for drug development.

A patent review of BRD4 inhibitors (2013-2019).

Urea transporter A (UT-A) isoforms encoded by the Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-A1 inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4-triazolo[4,3-a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-A1 urea transport by a noncompetitive mechanism with IC50 ≈ 150 nM; the IC50 was ∼2 μM for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-A1 cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substant...

/pdf/nanomolar-potency-1-2-4-triazoloquinoxaline-inhibitors-of-xbfg35biq8.pdf

Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1.

Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.

Identification of TRD-35 as Potent and Selective DRAK2 Inhibitor

Provided are a novel [1,2,4]triazolo[4,3-a]quinoxaline derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating bromodomain extra-terminal (BET) protein-related diseases including cancer and autoimmune diseases, containing the same as an active ingredient.

Novel [1,2,4]Triazolo[4,3-a]Quinoxaline Derivative, Method For Preparing Same, And Pharmaceutical Composition For Preventing Or Treating BET Protein-Related Diseases, Containing Same As Active Ingredient

Provided are: novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives; a preparation method thereof; and a pharmaceutical composition for preventing or treating Bromodomain extra-terminal (BET) protein-related diseases, including cancer and autoimmune diseases, containing the derivatives as active ingredients.

[124][43-a] BET Novel [124]Triazolo[43-a]quinoxaline derivatives preparation method therof and pharmaceutical composition for use in preventing or treating BET protein related diseases containing the same as an active ingredient

Imran Ali

Papers

Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.

Identification of TRD-35 as Potent and Selective DRAK2 Inhibitor

Novel [1,2,4]Triazolo[4,3-a]Quinoxaline Derivative, Method For Preparing Same, And Pharmaceutical Composition For Preventing Or Treating BET Protein-Related Diseases, Containing Same As Active Ingredient

[124][43-a] BET Novel [124]Triazolo[43-a]quinoxaline derivatives preparation method therof and pharmaceutical composition for use in preventing or treating BET protein related diseases containing the same as an active ingredient