Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

Abstract

There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1 H )-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC 50 range is 2.1 − 9.8 µM), comparing to sorafenib (IC 50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC 50 range is 2.9 − 5.4 µM), comparing to sorafenib (IC 50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10

“…These approaches are essential contributors to the development of new bioactive agents [2][3][4][5][6][7][8]. Computer-assisted drug design has been applied in drug discovery [9][10][11], computational chemistry [12,13], toxicity prediction [14][15][16], ADMET assessment [17][18][19], molecular modeling [20], molecular design [21,22], and rational drug design [23][24][25][26][27]. All these techniques have great popularity and have been used in both academic fields in addition to the pharmaceutical industries [28].…”

Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2

“…The pharmacokinetic characteristics of the prepared compounds were analyzed by applying Discovery Studio 4.0 [45][46][47]. Sorafenib was utilized as a reference.…”

Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

“…Computer-aided (computer-based, computational, or in silico) strategies in drug discovery represent quick and reliable approaches that could predict the bioactivity of any compound reducing the waste of effort, [3,4] time, and money. Computeraided drug discovery approaches include molecular docking [5][6][7], molecular dynamic simulations [8], QSAR [9], pharmacophore modeling [10,11], ADMET [12,13], DFT [14], drug molecular design [15,16], and toxicity prediction [17][18][19]. These approaches target the enhancement of drug activity besides the discovery of new ligands [20].…”