Antiproliferative Activity, Multikinase Inhibition, Apoptosis- Inducing Effects and Molecular Docking of Novel Isatin-Purine Hybrids.

The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.

Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy.

Background: Morus alba Linn, referred to as white mulberry, is a potential traditional medicine for diabetes and neuroprotection. Aim: Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy. Material and methods: The stem Bark of M. alba was peeled and subjected to extraction. A phytoconstituent was then isolated by column chromatography and characterized using Mass spectroscopy, FTIR, and NMR. The isolated phytoconstituent was used to formulate a nanoemulsion. Nanoemulsion was also characterized for viscosity, surface tension, refractive index, pH, and particle size. Selected nanoemulsion formulations were then tested for acute oral toxicity and diabetic neuropathy, including behavioral, hematological, histopathological, and biomarker examinations. Results: The spectral analysis affirmed that the isolated compound was found to be chrysin. A nanoemulsion formulation was made using the chrysin and was characterized and found to be stable during the stability testing and fulfilled all other testing parameters. Then acute oral toxicity study of the formulations was found to be safe. Formulations were found to possess significant results against diabetic neuropathy in rats. Biomarkers were analyzed for their mechanistic involvement in reducing neuropathy in rats, and it was found that the oxidative pathway was considerably restored, suggesting that chrysin causes these effects via this pathway. Conclusions: Results suggests that isolated phytoconstituent (chrysin) from the bark of Morus alba derived nanoemulsion has protective and beneficial effects by diminishing the oxidative damage against alloxan-induced diabetic neuropathy in rats.

Design, synthesis, antitumor evaluation, and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors.

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis.

Gastroprotective evaluation of Medicago sativa L. (Fabaceae) on diabetic rats.

Traditional uses for the plant Medicago sativa (M. sativa) (Alfalfa) (Family: Fabaceae) include liver protection, antioxidant activity, and the treatment of bleeding and digestive issues. This study aims to assess the effect of ethanol extract of M. sativa (EEMS) on experimental-induced ulcers in diabetic rats. By pylorus ligation and ethanol administration, gastric ulcers were induced in diabetic rats. Five groups each consisting of six rats in each model were used. All other groups except Group I were made diabetic by giving rats alloxan (140 mg/kg i.p.). Vehicles were given to Group I (normal control) and Group II (diabetes control) rats. Group III (positive control) received ranitidine 50 mg/kg, and Group IV and V received EEMS at doses of 100 and 400 mg/kg, respectively. In the pylorus ligation and ethanol-induced stomach ulcer model of rats, the findings demonstrated that EEMS (100 mg/kg) showed a decreased ulcer index of 2.01 ± 0.41 and was found statistically significant against the diabetes control group (p < 0.001) as well as, an ulcer index of 0.68 ± 0.22 by EEMS (400 mg/kg) with a significant reduction in the ulcer index (p < 0.001). EEMS (100 and 400 mg/kg) reduce free acidity by 13.16 ± 0.65 mEq/L and 9.83 ± 0.30 mEq/L, respectively. EEMS also showed a protective impact on the liver and kidneys of diabetic rats. Antihyperglycemic action was also discovered in diabetic animals. The findings of the current investigation demonstrated that ethanolic extract of M. sativa possesses anti-ulcer activity in diabetic rats. Ethanolic extract of M. sativa may be a treatment option for stomach ulcers that also have diabetes.

Design, synthesis, antitumor, and VEGFR-2 inhibition activities of novel 4-anilino-2-vinyl-quinazolines: Molecular modeling studies.

The antitumor activity of newly synthesized 4-anilino-2-vinylquinazolines 8a-r was measured comparable to sorafenib as a standard drug. The 2-vinylquinazolines 8a-r were evaluated for their in vitro antitumor activity. The most active antitumor agents were subjected to in vitro VEGFR-2 inhibition and apoptotic inducing assay. Compounds 8 h, 8 l, and 8r showed potential antitumor activities with IC50 values of 4.92-14.37 µM relative to the reference drug, sorafenib (IC50 values of 5.47-9.18 µM). Compound 8 h possessed potential VEGFR-2 inhibitory activity (IC50 = 60.27 nM) compared to standard drug sorafenib (IC50 = 55.43 nM), whereas compound 8 l showed moderate inhibitory activity (IC50 = 93.50 nM). The most active compound, 8 h, exhibited total apoptosis with 36.24% on MCF-7 cells, more than the apoptotic effect provoked by sorafenib (32.46%) and the cell cycle arrested at a G1/S phase. Compound 8 h, a potent VEGFR-2 inhibitor, was docked into the VEGFR-2 binding pocket, where this compound showed binding interaction similar to co-crystallized inhibitor sorafenib.

Design, synthesis and molecular docking of new [1,2,4] triazolo[4,3-a]quinoxaline derivatives as anticancer agents targeting VEGFR-2 kinase.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC50 values of 6.2 and 4.9 µM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC50 = 3.53 and 2.18 µM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC50 value of 3.9 nM, which is very close to that of sorafenib (IC50 = 3.13 nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC50 values ranging from 11.7 to 15.3 µM. Also, these compounds showed promising VEGFR-2 inhibition with IC50 values of 4.2, 5.7, and 4.7 nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness.

Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies.

Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.

Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations.

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⋯ S and C-H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 µM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.

A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches.

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy.

Interaction Characterization of a Tyrosine Kinase Inhibitor Erlotinib with a Model Transport Protein in the Presence of Quercetin: A Drug-Protein and Drug-Drug Interaction Investigation Using Multi-Spectroscopic and Computational Approaches.

The interaction between erlotinib (ERL) and bovine serum albumin (BSA) was studied in the presence of quercetin (QUR), a flavonoid with antioxidant properties. Ligands bind to the transport protein BSA resulting in competition between different ligands and displacing a bound ligand, resulting in higher plasma concentrations. Therefore, various spectroscopic experiments were conducted in addition to in silico studies to evaluate the interaction behavior of the BSA-ERL system in the presence and absence of QUR. The quenching curve and binding constants values suggest competition between QUR and ERL to bind to BSA. The binding constant for the BSA-ERL system decreased from 2.07 × 104 to 0.02 × 102 in the presence of QUR. The interaction of ERL with BSA at Site II is ruled out based on the site marker studies. The suggested Site on BSA for interaction with ERL is Site I. Stability of the BSA-ERL system was established with molecular dynamic simulation studies for both Site I and Site III interaction. In addition, the analysis can significantly help evaluate the effect of various quercetin-containing foods and supplements during the ERL-treatment regimen. In vitro binding evaluation provides a cheaper alternative approach to investigate ligand-protein interaction before clinical studies.

Carbonic Anhydrase Inhibition Activities of Schiff's Bases Based on Quinazoline-Linked Benzenesulfonamide.

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4-27. The hCA I isoform was efficiently inhibited by Schiff's bases 4-6, 10-19, 22-27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2-27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15-19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7-14, 19-23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).

Identification of new [1,2,4]triazolo[4,3-a]quinoxalines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, anticancer evaluation, and in silico studies.

Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC50 = 8.2 and 5.4 µM, respectively), compared to sorafenib (IC50 = 3.51 and 2.17 µM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC50 = 3.4 nM) exhibited good activity compared to sorafenib (IC50 = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro-apoptotic marker (Bax) expression by 2.33-fold and decreased anti-apoptotic (Bcl-2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4).

New bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation.

A new series of bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and20mshowed promising VEGFR-2 inhibitory activities with IC50values of 5.7, 6.7, 3.2, and 3.1 µM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC50values ranging from 3.3 to 14.2 µM, comparing to sorafenib (IC50 = 2.17 and 3.43 µM against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib.

Design and discovery of new antiproliferative 1,2,4-triazin-3(2H)-ones as tubulin polymerization inhibitors targeting colchicine binding site.

Thirty-five new colchicine binding site inhibitors have been designed and synthesized based on the 1,2,4-triazin-3(2H)-one nucleus. Such molecules were synthesized through a cascade reaction between readily accessible α-amino ketones and phenyl carbazate as a masked N-isocyanate precursor. The synthesized derivatives are cisoid restricted combretastatin A4 analogues containing 1,2,4-triazin-3(2H)-one in place of the olefinic bond, and they have the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesized compounds were evaluated in vitro for their antiproliferative activities against a panel of three human cancer cell lines (MCF-7, HepG-2, and HCT-116), using colchicine as a positive control. Among them, two compounds 5i and 6i demonstrated a significant antiproliferative effect against all cell lines with IC50 ranging from 8.2 - 18.2 µM. Further investigation was carried out for the most active cytotoxic agents as tubulin polymerization inhibitors. Compounds 5i and 6i effectively inhibited microtubule assembly with IC50 values ranging from 3.9 to 7.8 µM. Tubulin polymerization assay results were found to be comparable with the cytotoxicity results. The cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 5i in HepG-2 cells. The most active compounds 4i, 4j, 5 g, 5i and 6i did not induce significant cell death in normal human lung cells Wl-38, suggesting their selectivity against cancer cells. Also, These compounds upregulated the level of active caspase-3 and boosted the levels of the pro-apoptotic protein Bax by five to seven folds in comparison to the control. Moreover, apoptosis analyses were conducted for compound 5i to evaluate its apoptotic potential. Finally, in silico studies were conducted to reveal the probable interaction with the colchicine binding site. ADME prediction study of the designed compounds showed that they are not only with promising tubulin polymerization inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties.

New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis.

New series of [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized, and biologically assessed for their anti-proliferative activities against two selected tumor cell lines MCF-7 and HepG2. Comparing to sorafenib (IC50 = 2.17 ± 0.13 and 3.51 ± 0.21 µM against MCF-7 and HepG2, respectively), compound 25d, 25e, 25i, and 27e exhibited the highest activities against the examined cell lines with IC50 values extending from 4.1 ± 0.4 to 11.7 ± 1.1 µM. Furthermore, VEGFR-2 inhibitory activities were assessed for all the synthesized compounds as potential mechanisms for their anti-proliferative activities. Compounds 25d, 25e, 25i, and 27e displayed prominent inhibitory efficiency versus VEGFR-2 kinase with IC50 value ranging from 3.4 ± 0.3 to 6.8 ± 0.5 nM. Fascinatingly, the results of VEGFR-2 inhibitory assays were matched with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited promising VEGFR-2 inhibitory activities. Further studies displayed the ability of compound 25d to induce apoptosis in HepG2 cells and can arrest the growth of such cells at the G2/M phase. Also, compound 25d produced a significant increase in the level of BAX/Bcl-2 ratio (3.8-fold), caspase- 3 (1.8-fold), and caspase-9 (1.9-fold) compared to the control cells. Molecular docking studies were carried out to investigate the possible binding interaction inside the active site of the VEGFR-2.

Synthesis, potential antitumor activity, cell cycle analysis, and multitarget mechanisms of novel hydrazones incorporating a 4-methylsulfonylbenzene scaffold: a molecular docking study.

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 µM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 µM, respectively) and HER2 (IC50 = 0.13 and 0.07 µM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

Design, synthesis, and analysis of antiproliferative and apoptosis-inducing activities of nitrile derivatives containing a benzofuran scaffold: EGFR inhibition assay and molecular modelling study.

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC50 = 16.08-23.67 µM), HCT-116 (IC50 = 8.81-13.85 µM), and MCF-7 (IC50 = 8.36-17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC50 = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers.

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC50 of 3.2 nM very close to positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC50 of 7.7 and 4.5 µM in comparison to sorafenib (IC50 = 3.51 and 2.17 µM). In addition, compounds 28, 30f, 30i, and 31b exhibited excellent VEGFR-2 inhibition activities (IC50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a. Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles.

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

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(1H)-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 (IC50 range is 2.1 - 9.8 µM), comparing to sorafenib (IC50 = 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 (IC50 range is 2.9 - 5.4 µM), comparing to sorafenib (IC50 = 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).