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[Display omitted] • A novel dual-target agent that binds to both VEGFR-2 and Tubulin was designed and synthesized. • Molecular docking towards VEGFR-2 and Tubulin was performed. • SAR is an indispensable component in the evaluation of new drug candidates. • Compound 19 significantly inhibited tumor growth on MGC-803 xenografts nude mice by intraperitoneal injection. Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC 50 values of 0.76 ± 0.11 μM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC 50 = 0.005 ± 0.001 μM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel inhibitors using fused thienopyrimidine scaffolds were evaluated as anti-proliferative agents against three cancer cell lines. • Two compounds 6 and 17 were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. • Compound 6 inhibited VEGFR-2 and AKT-1 at IC 50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC 50 = 0.164 and 0.452 μM, respectively. • Compound 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. • Compound 17 showed the highest autophagic induction among the evaluated derivatives. • Docking studies were conducted to assess the binding patterns of the active derivatives inside the active sites of both VEGFR-2 and AKT-1 enzymes. Novel thieno[2,3- d ]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC 50 = 4.29 µM HePG-2 , 10.84 µM MCF-7), 6 (IC 50 = 14.86 μM HePG-2 , 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC 50 = 9.98 μM HePG-2 , 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC 50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC 50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC 50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2 , 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands. [ABSTRACT FROM AUTHOR]

[Display omitted] • Tumor multidrug resistance is still the main cause of failure in the treatment of cervical cancer. • Overexpression of P-gp is a major factor in the development of multidrug resistance in cervical cancer. • Targeting the VEGF/VEGFR-2 signaling pathway is deemed as a promising therapeutic approach for cervical cancer treatment. • Chalcone matrices may have VEGFR-2 and P-gp inhibitor backbone potential. • Nitrogen-containing heterocycles are key pharmacophore for VEGFR-2 and P-gp inhibitors. Chemotherapy toxicity and tumor multidrug resistance remain the main reasons for clinical treatment failure in cervical cancer. In this study, 79 novel chalcone derivatives were designed and synthesized using the principle of active substructure splicing with the parent nucleus of licorice chalcone as the lead compound and VEGFR-2 and P-gp as the target of action and their potentials for anticervical cancer activity were preliminarily evaluated. The results showed that the IC 50 values of candidate compound B20 against HeLa and HeLa/DDP cells were 3.66 ± 0.10 and 4.35 ± 0.21 μΜ, respectively, with a resistance index (RI) of 1.18, which was significantly higher than that of the positive drug cisplatin (IC 50 :13.60 ± 1.63, 100.03 ± 7.94 μΜ, RI:7.36). In addition, B20 showed significant inhibitory activity against VEGFR-2 kinase and P-gp-mediated rhodamine 123 efflux, as well as the ability to inhibit the phosphorylation of VEGFR-2 and downstream PI3K/AKT signaling pathway proteins, inducing apoptosis, blocking cells in the S-phase, and inhibiting invasive migration and tubule generation by HUVEC cells. Acceptable safety was demonstrated in acute toxicity tests when B20 was at 200 mg/kg. In the nude mouse HeLa/DDP cell xenograft tumor model, the inhibition rate of transplanted tumors was 39.2 % and 79.2 % when B20 was at 10 and 20 mg/kg, respectively. These results suggest that B20 is a potent VEGFR-2 and P-gp inhibitor with active potential for treating cisplatin-resistant cervical cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of thiourea and thiocarbamate derivatives bearing sulfachloropyridazine. • Compounds were screened for cytotoxicity against a panel of 60 cell lines. • VEGFR-2 inhibitory activity was evaluated for promising compounds. • Apoptotic study and cell cycle effect were conducted for the most potent compound. • Radiosensitizer evaluation and docking study for the most potent compounds. In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e , thioureids 4a-h , 5a-e and 4-substituted sulfachloropyridazines 6a, b , 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC 50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c , 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of pyrazole derivatives 16a-l was designed and synthesized. • All the tested compounds 16a-l showed excellent COX-2 selectivity index. • Compounds 16a, 16c, 16d and 16 g were the most potent against NCI cancer cell lines. • Compounds 16a, 16c, 16d and 16 g showed excellent inhibition against VEGFR-2, EGFR. • Compounds 16a, 16c, 16d and 16 g could be promising anti-inflammatory and anti-cancer agents. A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04–47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC 50 = 5.0–7.50, 6.23–8.93 respectively, compared to celecoxib IC 50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63–87.02 %, 98.98–43.10 % and 98.68–23.62 % respectively, and with GI 50 values of 1.76–15.50 µM, 1.60–5.38 µM, 1.68–7.39 µM and 1.81–11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC 50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC 50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC 50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC 50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44–9.40) compared to erlotinib (2.03) and osmertinib (1.89). [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors was synthesized and evaluated for their antiproliferative activities. • The structure-activity relationship study of the target thiophene-3-carboxamide derivatives was summarized. • Compound 14d demonstrated significant inhibition of VEGFR-2 (IC 50 = 191.1 nM), and anti-proliferative activity in A549 cell line (IC 50 = 2.22 ± 0.19 μM). • The compound 14d could inhibit VEGFR-2 protein phosphorylation and could stably bind to the active site of VEGFR-2 in A549 cell line. • The compound 14d exhibited significant inhibitory effects on colony formation, migration, and tube formation in a dose-dependent manner. • The compound 14d could blocked the MEK-ERK signaling pathway in A549 cell lines, and could significantly suppressed the expression of MMP9 to prevent cell migration. VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC 50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two series based 2-oxoindole derivatives. N -aryl acetamides 6a-o having amide linker and its isoster benzyloxy benzylidenes 9a-p were synthesized. • Compounds 6f & 9f were the most promising antiproliferative scaffolds in NCI one dose screening therefore they underwent five-dose testing. • Additionally, 6f & 9f were the most potent agents against pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines with favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). • Moreover, 6f & 9f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRβ, and VEGFR-2 kinases with Nano molar concentrations. • Both 6f & 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. Two new series of N -aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f , which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC 50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC 50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRβ, and VEGFR-2 kinases, with IC 50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC 50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC 50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRβ active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f , possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New thiazolylpyrazolyl coumarin derivatives were designed and synthesized. • Some compounds showed potent cytotoxic effect against MCF-7 and VEGFR-2 inhibition. • Compound 9d induced cell cycle arrest at G2/M phase and activated caspases-7 and 9. • Compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio. • Molecular docking, dynamics simulation, QSAR and ADMET analysis were performed. Abstract New thiazolylpyrazolyl coumarin derivatives were synthesized and tested for their anticancer potential in vitro against five different human cell lines, including breast MCF-7, lung A549, prostate PC3, liver HepG2 and normal melanocyte HFB4. Breast carcinoma revealed higher sensitivity towards compounds 7a, 8c, 9b, 9c and 9d with IC 50 values ranging from 5.41 to 10.75 μM in comparison to the reference drug doxorubicin (IC 50 = 6.73 μM). In addition, no noticeable toxicity was exhibited towards normal cells HFB4. Moreover, in vitro studies of the VEGFR-2 inhibition in human breast cancer MCF-7 cell line for the promising cytotoxic compounds showed that compounds 7a, 8c, 9b, 9c and 9d were potent inhibitors at low micromolar concentrations (IC 50 = 0.034–0.582 μM) compared to the reference drug, sorafenib (IC 50 = 0.019 μM). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis. The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compound 9d due to its remarkable cytotoxic activity against MCF-7 and significant VEGFR-2 inhibition. Flow cytometeric analysis showed that compound 9d induced cell growth cessation at G2/M phase and increased the percentage of cells at pre-G1 phase that stimulates the apoptotic death of MCF-7 cells. Furthermore, real time PCR assay illustrated that compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio which confirmed the mechanistic pathway of compound 9d. Moreover, the apoptotic induction of breast cancer cells MCF-7 was enhanced effectively through activation of caspases-7 and 9 by compound 9d. On the other hand, a set of in silico methods such as molecular docking, molecular dynamics simulation, QSAR analysis as well as ADMET analysis was performed in order to study the protein-ligand interactions and the relationship between the physicochemical properties and the inhibitory activity of the promising compounds 7a , 8c and 9d. Based on the aforementioned findings, compound 9d could be considered as effective apoptosis modulator and promising lead for future development of new anti-breast cancer agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Triazole-quinoxaline hybrids were crafted as dual VEGFR-2 /MAO-B inhibitors for halting CRC. • 11 and 14 surpassed 5-FU against HCT-116 cells regarding potency and selectivity. • 14 recorded one-digit nanomolar IC 50 concentration against VEGFR-2. • 11 was superior to the reference MAOI methylene blue with MAO-B/A selectivity. • 11 and 14 downregulated HIF-1α in HCT-116 cells and inhibited their migration by >75 %. Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H -tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC 50 = 18.04 and 7.850 µM, respectively, against HCT-116 cells within their EC 100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC 50 = 88.79 and 9.910 nM), MAO-A (IC 50 = 0.763 and 629.1 nM) and MAO-B (IC 50 = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116 cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 25 compounds were screened against VEGFR-2 kinase enzyme. • Selected compounds were assessed in vitro against full NCI 60 cell lines. • 10a showed the best in vitro antitumor activity against human breast cancer (T7-47D) and renal cancer (A498) cell lines. • Cell cycle and caspase-3 colorimetric assays were performed. • Molecular Modeling studies have been carried out. Abstract Different series of novel thieno [2,3- d ]pyrimidine derivative (9a-d , 10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d , 15d and 15 g are among the most active inhibitors with IC 50 values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two series of indazole-based derivatives were synthesized. • Compds 11b , 11c , and 11e had VEGFR-2 IC 50 = 5.4 nM, 5.6 nM, and7 nM, respectively. • Compds 11a and 11c showed the most potent anticancer activity. • Molecular dynamics simulation was utilized to study their binding mode. Abstract VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b , 11c and 11e exhibited the most potent action, with IC 50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 μM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI 50) and safety (LC 50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cytotoxicity of seventeen new quinoxaline derivatives was evaluated against MCF-7 and HCT-116 by MTT assay. • VEGFR2 kinase inhibitory activity and anti-angiogenic potential were evaluated for the most active hits. • Apoptosis studies and cell cycle analysis were evaluated for the most active derivative. • Docking of the most active compound in the active site of VEGFR2 kinase enzyme was done. • In silico assessment of all the library was performed. Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC 50 ′s 4.28–9.31 µM) and MCF-7 (IC 50 ′s 3.57–7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69–23.19) and MCF-7 (SI 9.48–27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • VEGFs proof angiogenic and antiapoptotic effects via paracrine and autocrine loops. • Phenylpyridazinone based VEGFR-2 inhibitors were optimized from sorafenib. • Compounds 12c and 13a showed excellent antiproliferative effect against HUVECs. • Compounds 12c and 13a revealed increase in apoptosis and necrosis percentages. • Compounds 12c and 13a distinctly inhibit cells in invasion and migration assays. Appertaining to its paracrine and autocrine signaling loops, VEGFR-2 succeeded in grabbing attention as one of the leading targets in cancer treatment. Based on the foregoing and our comprehensive studies regarding pharmacophoric features and activity of sorafenib, novel phenylpyridazinone based VEGFR-2 inhibitors 4 , 6a-e , 7a,b , 9a,b , 12a-c , 13a,b , 14a,b , 15a,b , and 17a-d were optimized. An assortment of biological assays was conducted to assess the antiangiogenic and apoptotic activities of the synthesized derivatives. In vitro VEGFR-2 kinase assay verified the inhibitory activity of the synthesized derivatives with IC 50 values from 49.1 to 418.0 nM relative to the reference drug sorafenib (IC 50 = 81.8 nM). Antiproliferative activity against HUVECs revealed that compounds 2-{2-[2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetyl]hydrazineyl}- N -(p-tolyl)acetamide (12c) and 2-[(5-mercapto-4-methyl- 4H -1,2,4-triazol-3-yl)methyl]-6-phenylpyridazin-3(2H)-one (13a) possessed superior activity (IC 50 values = 11.5 and 12.3 nM, respectively) in comparison to sorafenib (IC 50 = 23.2 nM). For the purpose of appraising their antiproliferative effect, derivatives 12c and 13a were exposed to cell cycle analysis, apoptotic, cell invasion and migration assays in addition to determination of VEGFR-2 in protein level. Moreover, cytotoxicity as well as selectivity index against WI-38 cell line was measured to examine safety of derivatives 12c and 13a. After that, molecular docking study was executed on the top five compounds in the in vitro VEGFR-2 kinase assay 6d , 12c , 13a , 14a and 17c to get a deep perception on binding mode of the synthesized compounds and correlate the design strategy with biological results. Finally, physicochemical, pharmacokinetic properties, and drug-likeness studies were performed on the top five derivative in in vitro VEGFR-2 kinase assay. [ABSTRACT FROM AUTHOR]

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h , 12b and 12d . Based on the further enzyme assay in vitro , compound 12d was considered as the most promising one, the IC 50 values of which were 0.11 μM and 0.19 μM for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study. [ABSTRACT FROM AUTHOR]

[Display omitted] • VEGFR-2 is aberrantly expressed in many malignant tumors. • Developments or discoveries of VEGFR-2-based inhibitors with multi-targeting capabilities were summarized. • The rational design and SARs of multi-targeting agents were discussed. • The therapeutic effects might be improved by simultaneously inhibiting VEGFR-2 and other targets. Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents. [ABSTRACT FROM AUTHOR]

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, 1 H NMR, 13 C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10 μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N -(4,6-dimethylthieno[2,3- b ]pyridine)-7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC 50 value 2.6 μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators. [ABSTRACT FROM AUTHOR]

[Display omitted] • The synthesis of new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines. • Seventeen of the target compounds were evaluated as dual EGFR/HER2 inhibitors compared to lapatinib and fourteen compounds were tested as VEGFR-2 inhibitors. • The most active compounds were screened for their cytotoxicity. • Compounds 9d , 11c and 14c were subjected to cell cycle analysis and apoptotic assay. • A molecular modeling study was achieved. The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l , 11a-e , 13a-c , 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b , 9d , 9f , 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC 50 = 1.54 µM) relative to Lapatinib (IC 50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC 50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC 50 = 9.29 µM). Moreover, compounds 13a-c , 13a-c , 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a , 14c and 14e exhibited remarkable inhibition (IC 50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC 50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC 50 = 17.51 and 5.56 µM, respectively) and 14c (IC 50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC 50 = 19.33 and 6.82 µM, respectively). Compounds 9d , 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • New thiophene, thienopyridine, and thiazoline-based derivatives 5a-c , 7, 9, 12a,b, and 14a,b were designed and synthesized. • The cytotoxic activity of the new compounds was evaluated in vitro against the liver (HepG-2), breast (MCF-7), colon (HCT-116), and WI-38 cell lines. • The most promising cytotoxic agents 5a-c were examined as multitargeting inhibitors against Pim, VEGFR, and EGFRWT. • The impact of compound 5c was evaluated on the cell cycle, apoptosis, and the proapoptotic parameters Bax/Bcl-2 ratio, p53, and caspase-3. • Antimicrobial assay of all compounds was carried against different types of pathogenic gram-positive, gram-negative bacteria and fungi. • Molecular docking results of compounds 5a proved its promising binding interactions with Pim, VEGFR, and EGFRWT. In silico ADMET studies were carried out to explore the drug-likeness properties of the new compounds. Multitargeting kinase inhibitors recently proved to be a profitable approach for conquering cancer proliferation. The current study represents the design and synthesis of new thiophene, thienopyridine, and thiazoline-based derivatives 4-14a,b. All the target compounds were examined in vitro against three cancer cell lines; the liver (HepG-2), breast (MCF-7), and colon (HCT-116) where the thiophene-based compounds 5a-c , demonstrated the most potent activity. Furthermore, the latter derivatives revealed a safety profile against WI-38 normal cell line of selectivity indices ranging from 4.43 to 17.44. In vitro enzyme assay of 5a-c revealed that the carbohydrazide analog 5c has the most promising multitargeting inhibiting activity against Pim-1, VEGFR-2, and EGFRWT enzymes of IC 50 values; 0.037 ± 0.02, 0.95 ± 0.24, and 0.16 ± 0.05 µM, respectively. As it was the most potent analog, 5c was further subjected to cell cycle and apoptosis analysis. The results indicated that it induced preG1 arrest and an apoptotic effect in the early and late stages. Moreover, further apoptosis studies were carried out for 5c to evaluate its proapoptotic potential. Interestingly, 5c enhanced the levels of Bax/Bcl-2 ratio, p53, and active caspase 3 by 18, 6.4, and 24 folds, respectively compared to the untreated cells. The antimicrobial evaluation showed that only compounds 3 and 5a produced broad-spectrum potency, while 5b and 5c exhibited outstanding antifungal effects. Finally, a molecular docking study was carried out to discover the probable interactions of compound 5c with the active sites of Pim-1, VEGFR-2, and EGFRWT kinases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Twelve 1,2,3-triazoles bearing semicarbazone and thiosemicarbazone fragments were designed and synthesized. • Their cytotoxicity was evaluated against sixty human cancer cell lines. • Myeloid leukemia cancer cells were the most sensitive toward their effect. • Compounds 21, 26, and 30 exerted the most potent cytotoxic activity. • Compound 30 further evaluated for its apoptosis induction and VEGFR-2 inhibition potential. Vascular Endothelial Growth Factor II (VEGFR-2) has been proved as a rational target in cancer therapy. Although currently prescribed VEGFR-2 inhibitors are showing potent antitumor activity, they are often causing serious unwanted effects, restricting their extensive use as chemotherapeutics. Herein, after analyzing the structures of the effective VEGFR-2 inhibitor molecules, we report the synthesis of a new set of semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles with expected potency of inhibiting the VEGFR-2 signaling. The design of new compounds considered maintaining the essential pharmacophoric features of sorafenib for effective binding with the receptor target. All compounds have been evaluated for their growth inhibition effect against a panel of sixty cancer cells at the National Cancer Institute. Leukemia cancer cells, especially HL-60 and SR, were shown to be the most sensitive to the cytotoxic effect of new compounds. Thiosemicarbazones 21 , 26 , and 30 exhibited the best activity against almost all tested cancer cells. Therefore, a set of subsequent in vitro biological evaluations has been performed to understand the mechanistic effect of these compounds further. They inhibited the VEGFR-2 with IC 50 values of 0.128, 0.413, and 0.067 µM respectively compared with 0.048 µM of Sorafenib. The probable mechanistic effect of 30 has been further evaluated on a number of apoptotic and antiapoptotic markers including BAX, BCL2, caspase-3, and caspase-9. Results revealed the potential of the thiosemicarbazone-linked triazole 30 to induce both the early and the late apoptosis, elevate BAX/BCL2 ratio, induce caspase-3 & caspase-9, and arrest the HL-60 cell cycle at the G2/M and G0-G1 phases. Molecular docking of new semicarbazones and thiosemicarbazones into the proposed biological target receptor has also been performed. Results of docking studies proved the potential of new semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles to effectively bind with crucial residues of the VEGFR-2 binding pocket. [ABSTRACT FROM AUTHOR]

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3-oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea ( VIIa ) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel thieno[2,3- d ]pyrimidine derivatives 3, 4a-d, 5a-c, 7a,b and 9a,b were designed as anticancer agents. • The anticancer activity of compounds was determined by the NCI (USA) as one dose and five doses on 60 cell lines. • IC 50 values of compounds 4a and 4b were determined against VEGFR-2 and BRAFV600E and BRAFWT protein kinases. • 4a and 4b treated breast MCF7 cell line showed down-regulation of total VEGFR-2 and phosphorylated VEGFR-2. • 4a and 4b induced apoptosis in MCF7 cell line and increased the level of caspase-9 apoptotic marker. A series of novel thieno[2,3- d ]pyrimidine derivatives was designed and synthesized based on multitarget directed drug design strategy. All the newly synthesized compounds were evaluated for their antiproliferative activity in the National Cancer Institute (NCI) against a panel of 60 tumor cell lines. Compounds 4a and 4b showed a significant antiproliferative activity at 10 µM dose, and were accordingly evaluated at five dose concentrations. They showed potent and broad-spectrum antiproliferative activity, with GI 50 values in the micromolar range of 1.44–6.93 µM and 1.66–5.82 µM, respectively. They also showed TGI values in the cytostatic range of 3.49–97.3 µM and 3.33–77.3 µM respectively. These two compounds potently inhibited VEGFR-2 with IC 50 = 0.111 ± 0.006 and 0.049 ± 0.003 µM, BRAFV600E with IC 50 = 0.089 ± 0.005 and 0.063 ± 0.003 µM and BRAFWT IC 50 = 0.071 ± 0.004 and 0.05 ± 0.003 µM, respectively in comparison to sorafenib IC 50 values of 0.031 ± 0.002, 0.035 ± 0.002 and 0.021 ± 0.001 µM against VEGFR-2, BRAFV600E and BRAFWT, respectively. Compounds 4a and 4b showed also potent down-regulation of total VEGFR-2 and phosphorylated VEGFR-2. In addition, the HUVECs migratory potential was greatly reduced resulting in significantly disrupted wound healing patterns after treatment with compounds 4a and 4b for 72 h. Furthermore, Compounds 4a and 4b induced apoptosis by 22.82- and 25.81-fold increase in the total apoptosis percentage in breast cancer MCF7 cell line. This apoptotic activity was supported by an increase in the level of apoptotic caspase-9 by 6.17- and 9.07-fold, respectively. Moreover, the cell cycle analysis showed that compounds 4a and 4b arrested the cell cycle mainly in the G1 and G1/S phases, respectively. The molecular modeling studies were performed to assess the binding pattern and affinity of derivatives 4a and 4b toward the VEGFR-2 and BRAF active sites. [ABSTRACT FROM AUTHOR]

[Display omitted] • Simultaneous inhibition of MMP-2, CA II and VEGFR-2 via triazoles bearing sulfonamide appendages. • 8d and 8e were nanomolar MMP-2/VEGFR-2 inhibitors and sub-micromolar inhibitors of CA II. • They upregulated p53 up to 3 folds, induced HepG-2 cells apoptosis and were superior to doxorubicin. • Docking studies predicted the structural determinants of activity. • They displayed drug-like in silico ADMET properties and ligand efficiency metrics. Recently, the interest in targeting metalloenzymes is obviously growing for halting various tumor progression events and surmounting the resistance due to routine chemotherapy regimen. In this regard, attention to MMP-2 and CA II has been drawn as validated druggable anticancer targets that share vital signaling pathways. The vast majority of MMP and CA inhibitors are designed to function as directed single-target agents. In spite of their transient efficacy, they are often susceptible to tumor resistance. Hence, several dual inhibitors of correlated MMPs and CAs were introduced. This set the stage to simultaneously target the common vital signaling nodes as well. VEGFR-2 is considered central to various tumorigenesis processes involving both MMP-2 and CA II. Herein, we report concomitant inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed 1,2,3- and 1,2,4-triazole hybrids bearing various sulfonamide appendages following pharmacophore hybridization strategy. The designed adducts were efficiently elaborated in an almost quantitative yield utilizing microwave-assisted click 1,3-dipolar cycloaddition reaction between various alkynes-based 1,2,4-triazole and 4-azido benzensulfonamides. All derivatives were evaluated for their anticancer potential against three human cancer cell lines (Caco-2, MDA-MB-231, and HepG-2) after safety assessment on normal human cells (Wi-38). Amongst those click adducts, 8d and 8e were the most potent and safest anticancer agents exhibiting low range nanomolar IC 50 (7.37–11.96 nM) and high selectivity (SI = 3.01–4.46), against the studied cancer cell lines, hence superior to doxorubicin concerning potency (IC 50 = 10.63–48.25 nM) and selectivity (SI = 0.43–1.93). They significantly elevated the expression level of the tumor suppressor p53 in the three tested cancer cell lines up to 3 folds and induced apoptosis in HepG-2 cells with higher potential to 8d over 8e. Enzymatic evaluation showed that both derivatives were potent dual MMP-2/VEGFR-2 inhibitors, particularly 8d (MMP-2; IC 50 = 5.66 nM and VEGFR-2; IC 50 = 6.65 nM), relative to the reference MMP-2 inhibitor NNGH (IC 50 = 299.50 nM) and VEGFR-2 inhibitor sorafenib (IC 50 = 4.92 nM). Both 8d and 8e exhibited relatively moderate activity against the human CA II isoform (IC 50 = 116.9 and 187.5 nM, respectively) relative to the reference (IC 50 = 27.3 nM). Docking studies clearly explained the superior in vitro enzymatic inhibition profiles of 8d over 8e and predicted the structural determinants of activity. Nevertheless, 8d displayed promising in silico ADMET properties and ligand efficiency metrics. These findings evidently demonstrated the sulfatriazole 8d as an auspicious multi-target-directed ligand that deserves further optimization for developing novel antitumor agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Benzimidazole substituted oxindolinone hybrids as VEGFR-2 and EGFR inhibitors. • The IC 50 value of 5b was found 6.81 and 13 nM against VEGFR-2 and EGFR, respectively. • The cytotoxicity was found as GI 50 at 0.9 µM against epidermoid carcinoma cells. • Mechanistically 5b governs through VEGF/EGF, p53, bcl/bax and MMP9 signalling proteins. • Comparatively 5b was found more potent and safer than other dual inhibitors. • The dual inhibition was facilitated due to conformational switch in designed molecules. Dual TK inhibitors have shown significant clinical effects against many tumors, but with unmanageable side effects. Design approach and selectivity of these inhibitors plays substantial role in their potency and side-effects. Understanding the homology of binding sites in targeted receptors, and involvement of signaling proteins after the inhibition might help in producing less toxic but effective inhibitors. Herein, we designed benzylideneindolon-2-one derivatives based on homology modeling in binding sites of VEGFR-2 and EGFR receptors as dual- inhibitor potent anticancer compounds with high selectivity. The benzylideneindolon-2-one derivatives were found to possess conformational switch in form of oxindole, substituted at 2-benzimidazole. Within synthesized compounds, 5b was found most active in in-vitro enzyme inhibition assay against VEGFR-2 and EGFR with highest IC 50 value of 6.81 ± 2.55 and 13.04 ± 4.07 nM, respectively. Interestingly, cytotoxicity studies revealed selective toxicity of compound 5b against proliferation of A-431 cell lines (over expressed VEGFR-2 and EGFR) with GI 50 value of 0.9 ± 0.66 µM. However, the compounds showed mild to moderate activity in all other cancer cell line in the range of 0.2–100 μM. Further mode of action studies by flow cytometry and western blot on A-431 indicated that they work via apoptosis at S- phase following Bcl/Bax pathway, and cell migration via MMP9. 5b not only suppressed tumor growth but also improved vandetanib associated with weight loss toxicity. Moreover, 5b was found safer than sunitinib and erlotinib with LD 50 of 500 mg/kg body weight. These results propose 5b as potential anti-tumor drug with safer profile of conventional inhibitors of VEGFR-2 and EGFR for solid tumors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and synthesis of diaryl pyrazoline TZD derivatives as dual inhibitors of HDAC and VEGFR-2. • Lead compound 14b inhibited HUVECs proliferation, migration, and tube formation. • CAM assay revealed in-vivo anti-angiogenic potential of 14b. • 14b displayed cytotoxicity to different cancer cell lines and. • 14b modulated the expression of proteins, VEGFR-2 and Caspase 3 in western blotting. • 14b displayed the tumor regression capacity in HT29 mice xenografts. In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot. [ABSTRACT FROM AUTHOR]

[Display omitted] • New furan, furopyrimidine and furotriazolopyrimidine derivatives were synthesized as potential VEGFR-2 inhibitors. • Furopyrimidine 8b and furotriazolopyrimidine 10c exhibited the highest inhibitory activity and were equipotent to sorafenib. • 8a-c and 10c showed good in vitro antiproliferative activity against HUVECs. • 8a-c and 10c had good inhibitory activity against HUVECs invasion and migration. • Molecular docking study was conducted to gain insight about the potential binding mode. Novel furan 6a-c , furo[2,3- d ]pyrimidine 7a-f , 9 , 10a-f , 12a,b , 14a-d and furo[3,2- e ][1,2,4]triazolo[1,5- c ]pyrimidine 8a-f derivatives were designed based on their structural similarity to a previously described oxazole VEGFR-2 back pocket binding fragment. The designed compounds were synthesized and screened for their in vitro VEGFR-2 inhibitory activity where they exhibited good to moderate nanomolar inhibition with improved ligand efficiencies. 8b and 10c (IC 50 = 38.72 ± 1.7 and 41.40 ± 1.8 nM, respectively) were equipotent to sorafenib and 6a, 6c , 7f, 8a, 8c, 10b, 10f, 12b , 14c and 14d showed good activity (IC 50 = 43.31–98.31 nM). The furotriazolopyrimidines 8a-c and furopyrimidine derivative 10c were further evaluated for their in vitro antiproliferative activity against human umbilical vein endothelial cells (HUVECs) where 8b showed higher potency than sorafenib and resulted in cell cycle arrest at G2/M phase whereas 8c revealed good antiproliferative activity with cell cycle arrest at G1 phase. Moreover, 8a-c and 10c showed significant inhibitory effects on the invasion and migration of HUVECs. Molecular docking study was conducted to gain insight about the potential binding mode. The furo[3,2- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives 8b and 8c represent interesting starting point for antiangiogenic compounds based on their activity and favorable drug likeness profiles. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of thienopyrimidine-aminothiazole hybrids 7a-j were designed as anticancer agents. • The anticancer activity of compounds was determined by the NCI (USA) as one dose on 60 cell lines. • IC 50 values of compounds 7c and 7d and were determined against SF-295, SNB-75 and CAKI-1 cell lines. • 7c treated SNB-75 cell lines showed down-regulation of total VEGFR-2 and phosphorylated VEGFR-2. • 7c induced apoptosis in SNB-75 cells and increased the level of caspase-3 apoptotic marker. A series of novel hybrid compounds of hexahydrobenzo[4,5]thieno[2,3- d ]pyrimidine with aminothiazole scaffolds were synthesized. The synthesized compounds were evaluated for their cytotoxic activity against the NCI-60 human tumor cell line panel. Compounds 7c , 7d and 7e exhibited significant antiproliferative activities at 10−5 M dose. Compound 7c exhibited excellent cytotoxic activity against CNS cancer cell lines including SNB-75 and SF-295 as well as renal cancer cell line CAKI-1 when compared with sorafenib as standard anticancer drug. In addition, compound 7d showed almost comparable anticancer activity to sorafenib against SNB-75 cell line and displayed moderate activity against SF-295 and CAKI-1 cell lines in comparison to sorafenib. Compound 7c inhibited the vascular endothelial growth factor receptor 2 (VEGFR-2) with IC 50 of 62.48 ± 3.7 nM and decreased both total VEGFR-2 and phosphorylated VEGFR-2 in treated SNB-75 cells suggesting its ability to down regulate cell proliferation, growth, and survival.. The flow cytometric analysis showed that 7c displayed its cytotoxic activity through the reduction of the cellular proliferation and induction of cell cycle arrest at the G2/M phase. Compound 7c clearly boosted the level of the apoptotic caspase-3. All the synthesized compounds were also screened for their antibacterial and antifungal activity against four pathogenic strains of both Gram-positive and Gram-negative as well as Candida albicans. Only compound 7d exhibited antifungal activity against Candida albicans compared to nystatin as the standard antifungal compound. [ABSTRACT FROM AUTHOR]

Sets of 3-alkenyl-2-oxindoles were synthesized of potential antiproliferative (against PaCa-2 and MCF7cancer cell lines) and promising properties against SARS-CoV-2. [Display omitted] • 3-Alkenyl-2-oxindoles were prepared in a facile synthetic pathway. • The synthesized agents show potent properties against PaCa2 cell line. • CAM assay reveals the anti-angiogenic properties of the targeted agents. • The agents synthesized show multi-targeted inhibitory properties against VEGFR-2 and c-kit. • Antiviral properties against SARS-CoV-2 and high SI were revealed by the synthesized agents. Sets of 3-alkenyl-2-oxindoles (6 , 10 , 13) were synthesized in a facile synthetic pathway through acid dehydration (EtOH/HCl) of the corresponding 3-hydroxy-2-oxoindolines (5 , 9 , 12). Single crystal (10a , c) and powder (12a , 26f) X-ray studies supported the structures. Compounds 6c and 10b are the most effective agents synthesized (about 3.4, 3.3 folds, respectively) against PaCa2 (pancreatic) cancer cell line relative to the standard reference used (Sunitinib). Additionally, compound 10b reveals antiproliferative properties against MCF7 (breast) cancer cell with IC 50 close to that of Sunitinib. CAM testing reveals that compounds 6 and 10 demonstrated qualitative and quantitative decreases in blood vessel count and diameter with efficacy comparable to that of Sunitinib, supporting their anti-angiogenic properties. Kinase inhibitory properties support their multi-targeted inhibitory activities against VEGFR-2 and c-kit in similar behavior to that of Sunitinib. Cell cycle analysis studies utilizing MCF7 exhibit that compound 6b arrests the cell cycle at G1/S phase while, 10b reveals accumulation of the tested cell at S phase. Compounds 6a and 10b reveal potent antiviral properties against SARS-CoV-2 with high selectivity index relative to the standards (hydroxychloroquine, chloroquine). Safe profile of the potent synthesized agents, against normal cells (VERO-E6, RPE1), support the possible development of better hits based on the attained observations. [ABSTRACT FROM AUTHOR]

[Display omitted] • New quinoxaline-2(1 H)-one-based derivatives incorporating amide linker moieties were designed and synthesized. • Cytotoxic activities were evaluated against HepG-2, MCF-7 and HCT-116 cell lines. • In vitro antiVEGFR-2 activities were evaluated. • ADMET profile and molecular docking studies were carried out. VEGF/VEGFR2 pathway is the crucial therapeutic target in the treatment of cancer. So that, a new series of quinoxaline-2(1 H)-one derivatives were designed and synthesized. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) aiming to evaluate its anti-proliferative activities. Doxorubicin as a universal anticancer drug and sorafenib as a potent VEGFR-2 inhibitor were used as positive controls. The data obtained from biological activity were found highly correlated with that obtained from molecular modeling studies. The most sensitive cell line to the influence of our new derivatives was HCT-116. Compounds 13 b , 15, 16 e and 17 b exert the highest cytotoxic activities against the tested cell lines. Overall, compound 15 was the most active member with IC 50 values of 5.30, 2.20, 5.50 µM against HepG-2, MCF-7 and HCT-116, respectively. Compounds 15 and 17 b showed better anti-proliferative activities than doxorubicin and sorafenib against the three cancer cell lines. Additionally, compound 16 e showed better anti-proliferative activities than doxorubicin and sorafenib against HepG-2 and HCT-116 but exhibited lower activity against MCF-7 cell line. In addition, the most promising members were further evaluated for their inhibitory activities against VEGFR-2. Compounds 15 and 17 b potently inhibited VEGFR-2 at lower IC 50 values of 1.09 and 1.19 µM, respectively, compared to sorafenib (IC 50 = 1.27 µM). Moreover , docking studies were conducted to investigate the binding pattern of the synthesized compounds against the prospective molecular target VEGFR-2. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eighteen compounds of thieno[2,3- d pyrimidine derivatives were designed and synthesized. • Anticancer activity was tested against three cancer cell lines. • In vitro anti VEGFR-2 activity was evaluated. • Molecular docking studies were performed against VEGFR-2. • Full ADMET and toxicity studies were determined for the tested compounds. Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3- d pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i , and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC 50 values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC 50 value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC 50 = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b. [ABSTRACT FROM AUTHOR]

• 26 new quinazolin based antiproliferative and antiangiogenic agents are synthesized. • The proliferation rate of PC3 cells was reduced by 9f (IC 50 = 17.7 μ M) vs sorafenib (17.3 μ M). • CAM assay revealed that the growth of blood vessels was inhibited by 9f moderately. • Western blot analysis of 9f revealed the inhibition of VEGFR-2 phosphorylation. A series of quinazolin-4(3 H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC 50 = 17.7 μ M) which was comparable with sorafenib (IC 50 = 17.3 μ M). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC 50 = 6.1 μ M). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f , they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y. [ABSTRACT FROM AUTHOR]

A novel series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized in an endeavor of developing potent VEGFR2 inhibitors. Compound 3e was very promising as it showed dual antiangiogenic and antineoplastic activities. • Biphenylurea/thiourea derivatives (3a-l) were designed, synthesized & characterized. • Angiogenesis inhibition was evident by antiproliferative activity against HUVECs. • VEGFR2 inhibition was proved by Western Blotting. • Most of the compounds showed antiangiogenic activity superior to sorafenib. Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as a vital tool for cancer treatment. In this study, a new series of biphenylurea/thiourea derivatives tagged with heteroarylsulfonamide motifs (3a-l) was designed and synthesized as novel VEGFR2 inhibitors. The biochemical profiles of the target compounds were investigated using viability of human umbilical vascular endothelial cells (HUVECs), migration assay and Western blot using sorafenib as reference antiangiogenic drug. Most of the tested compounds exhibited significant antiproliferative activity against HUVECs, where compounds 3a , 3e , 3g , 3h and 3l exhibited better antiproliferative activity than sorafenib. All compounds significantly inhibited VEGF stimulated migration of HUVECs at 10 µM dose with (3a, 3e, 3g, 3h and 3l) showing better or comparable inhibitory activities to that of sorafenib. Moreover, Western blotting analysis confirmed antiangiogenic effect of those compounds with significant reduction in the level of VEGFR-2 compared to sorafenib. Finally, cytotoxicity screening of these derivatives against four cancer cells and RPE1 as normal cell line was performed. The mechanistic effectiveness in cell cycle progression and apoptotic induction were evaluated for the promising compound 3e due to its remarkable cytotoxic activity against tested cancer cell lines and significant VEGFR-2 inhibition. Flow cytometric analysis showed that compound 3e induced cell growth arrest at G2/M phase and stimulated the apoptotic death of HepG2 cells. [ABSTRACT FROM AUTHOR]

• Sixteen compounds of new quinazolin-4(3 H)-one derivatives were designed and synthesized. • Cytotoxic activities were evaluated against HepG-2, MCF-7 and HCT-116 cell lines. • In vitro anti VEGFR-2 activities were evaluated. • Molecular docking studies were carried out. Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18 d was observed to have promising cytotoxic activity (IC 50 = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 µM) in comparison to the reference drug doxorubicin (IC 50 = 8.28, 9.63 and 7.67 µM) and sorafenib (IC 50 = 7.31, 9.40 and 7.21 µM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18 d showed VEGFR-2 inhibitory activity (IC 50 = 0.340 ± 0.04 µM) superior to that of the reference drug, sorafenib (IC 50 = 0.588 ± 0.06 µM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents. [ABSTRACT FROM AUTHOR]

• Novel indolyl-1,2,4-triazole hybrids were designed and synthesized. • All target compounds inhibited VEGFR-2 kinase at submicromolar level. • Analogs 5c,d and 9b were superior to sunitinib against VEGFR-2. • In vitro anticancer screening was carried out. • Compounds 5b,d, 11c and 12c were more potent than sunitinib against tested cancer cell lines. Targeting VEGFR-2 signaling pathway is well-established as an important approach for the treatment of solid tumors, particularly renal cancer. Herein, novel indolyl-1,2,4-triazole hybrids were designed and synthesized as VEGFR-2 kinase inhibitors with potential anti-renal cancer activity. The structures of the newly synthesized compounds were confirmed based on their spectral and elemental analyses. The results of in vitro kinase assay indicated that all target compounds revealed submicromolar inhibition of VEGFR-2 kinase enzyme. Analogs 5c, 5d and 9b emerged as the most active compounds (IC 50 = 0.034–0.064 µM), showing VEGFR-2 inhibitory activity much superior to that of sunitinib reference drug (IC 50 = 0.075 µM). Moreover, compounds 5a, 8c, 9d, 12c were equipotent to sunitinib against VEGFR-2 kinase. Additionally, the most potent compounds were further examined for their anticancer activity against two human renal cancer cell lines. All screened compounds effectively inhibited the growth of the two tested cell lines with IC 50 values spanning from sub-micromolar to low micromolar levels. Compounds 5b, 5d, 11c and 12c were three to five-fold more potent than sunitinib against CAKI-1 cell line. Analogue 8c was superior/comparable to sunitinib against CAKI-1/A498 cell lines. Moreover, compound 9d showed double potency of sunitinib against A498 cell line. Besides, compounds 8c and 12c demonstrated a safety profile much better than that of sunitinib against non-cancer human renal cells. As well, the docked models of title compounds revealed strong interactions with key residues within the active site of VEGFR-2 kinase. [ABSTRACT FROM AUTHOR]

• A series of novel 1,6-dihydropyrimidin-2-thio was designed and synthesized. • Compounds 3a , 3b , 3e and 4b were selected for in vitro anticancer activity by National Cancer Institute. • Compound 3e exhibited a remarkable anticancer activity against most of the cell lines. • In vitro five dose assay results showed that 3e have GI 50 ranging from 19 to 100 μM with selectivity ratios from 0.75 to 1.71. • Compounds 3a and 3e showed a good fitting to the active site of VEGFR-2. A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a , 3b , 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI 50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI 50 level. VEGFR-2-kinase was tested against 3a , 3b , 3e , 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC 50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC 50 = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of −9.80 to −11.25 kcal/mol compared to −12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e. [ABSTRACT FROM AUTHOR]

Scaffold hopping was applied to design quinazoline-based derivatives featuring ester (4a-j) , (6a-e), (7a,b) and amide (5a-j) moieties linked to biarylurea motif (DFG anchoring motif) as potent VEGFR-2 inhibitors. Compounds (5d, 5e, 5h, 5i, 7a and 7b) exhibited nanomolar VEGFR-2 inhibition. • Twenty seven novel quinazoline derivatives were designed, synthesized and biologically evaluated. • Inhibitory activities of all derivatives were evaluated toward VEGFR-2 kinase at 10 μM concentration. • Calculate the IC 50 values for the promising candidates, which exhibited VEGFR-2 inhibition percent above 90%. • In-vitro antiproliferative activity assay against NCI 60-cell line panel. • Docking study and Field alignment technique were performed to interpret and understand the biological evaluation results. In our attempt to discover effective anticancer agents, three series of novel quinazoline-based compounds have been designed, synthesized and tested as VEGFR-2 inhibitors. Five quinazoline −2-carboxamide derivatives (5d, 5e, 5 h, 5i, 5j) revealed potent nanomolar VEGFR-2 inhibition with IC 50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of the reference drug sorafenib (IC 50 78.9 nM). Additionally, the quinazoline 2-carboxylate derivative bearing a fluorine substituent in middle ring (7a) showed IC 50 values of 14.8 nM. Most of the new synthesized compounds are examined on NCI sixty cell lines of human cancer cells. Furthermore, molecular modeling study was administered to realize any clarification of the binding mode in the inactive VEGFR-2 conformation that demonstrates compatible binding modes similar to those of sorafenib and regorafenib. Finally, several ADME descriptors were calculated through a predictive kinetic study. [ABSTRACT FROM AUTHOR]

• New pyrazole derivatives were designed and synthesized. • Some compounds showed potent cytotoxic effect against MCF-7 and VEGFR-2 inhibition. • Compound 12c induced cell cycle arrest at G2/M phase and activated caspase-3. • Molecular docking study of the promising derivatives was performed. Based on the previous studies that revealed the valuable role of pyrazole scaffold in cancer management and VEGFR-2 inhibition, a new set of pyrazole conjugated with pyrazoline, triazolopyrimidine and pyrazolone moieties were synthesized and investigated for their anticancer efficiency against human breast cancer MCF-7. The anticancer screening revealed the significant sensitivity of breast carcinoma towards compounds 4b , 5c , 6c , 7b , 7c and 12c with IC 50 values ranging from 16.50 − 26.73 µM in comparison with tamoxifen (IC 50 = 23.31 µM). Moreover, the new analogues were further examined for their VEGFR-2 inhibitory activity, among the tested derivatives 5c , 6c , 7b , 7c and 12c displayed prominent inhibitory efficiency versus VEGFR-2 kinase with % inhibition ranging from 70 to 79%. Compounds 6c , 7c and 12c revealed inhibitory efficiency in nanomolar level with IC 50 (913.51, 225.17 and 828.23 nM, respectively) comparing to sorafenib (IC 50 = 186.54 nM). Flow cytometric analysis revealed that the promising compound 12c prompted pre-G1 apoptosis and cell growth cessation at G2/M phase and stimulated apoptosis via activation of caspase-3. Moreover, molecular docking study of the promising derivatives was performed to highlight their binding modes and interactions with the amino acid residues of VEGFR-2 enzyme. [ABSTRACT FROM AUTHOR]

• Twenty-four compounds of novel quinazolin-4(3 H)-one derivatives were designed and synthesized. • Cytotoxic activities were evaluated against HepG-2, MCF-7 and HCT-116 cell lines. • In vitro anti VEGFR-2 and in vivo antitumor activities were evaluated. • Molecular docking studies were carried out. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26 b , 29 a , 29 b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC 50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC 50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities. [ABSTRACT FROM AUTHOR]

• New substituted pyridines and thieno[2,3- b ]pyridines were synthesized. • They were evaluated for their cytotoxic activities against four cancer cell lines. • Compounds 3a, 9e, 10b and 10c exhibited the highest anticancer potential. • They activated caspase 3/7 and induced apoptosis more than Dox. • They exhibited higher therapeutic potential to alter the expression of VEGF than Dox. • Compound 10b , exhibited the highest dual VEGFR-2/PIM-1 kinase inhibition. Angiogenesis is a hallmark in cancer. Most antiangiogenic agents block the action of vascular endothelial growth factor (VEGF). In clinic, patients develop hypoxia-mediated resistance consistent with vascular responses to these agents. Recent studies underlying such resistance revealed hypoxia-inducible PIM-1 kinase upregulation which promotes cancer progression. PIM-1 kinase expression is thus viewed as a new resistance mechanism to antiangiogenic agents. Hence, combining PIM kinase inhibitors with anti-VEGF therapies provides synergistic antitumor response. Inspired by these facts, the current study aims at designing novel dual VEGFR-2/PIM-1 kinase inhibitors via molecular hybridization and repositioning of their pharmacophoric features. Moreover, enhancing the cytotoxic potential of the designed compounds was considered via incorporating moieties mimicking caspase 3/7 activators. Accordingly, series of novel pyridine and thieno[2,3- b ]pyridine derivatives were synthesized and screened via MTT assay for cytotoxic activities against normal fibroblasts and four cancer cell lines (HepG-2, Caco-2, MCF-7 and PC-3). Compounds 3a, 9e , 10b and 10c exhibited anticancer activities at nanomolar IC 50 with promising safety, activated caspase 3/7 and induced apoptosis as well as DNA fragmentation more than doxorubicin in the four cancer cell lines. Furthermore, they exerted promising dual VEGFR-2/PIM-1 kinase inhibition and significantly exhibited higher therapeutic potential to alter the expression levels of VEGF, p53 and cyclin D than doxorubicin. Interestingly, the most active anticancer compound 10b conferred the highest dual VEGFR-2/PIM-1 kinase inhibition. Finally, their in silico ligand efficiency metrics were acceptable. [ABSTRACT FROM AUTHOR]

• New c-Met and VEGFR-2 dual inhibitors were designed and synthesized. • Enzymatic activities against c-Met and VEGFR-2 were evaluated. • Cellular inhibitory activities against MHCC97H, HUVEC, HEK293 and LO2 cell lines were conducted. • Anti-tumor activity was observed in MHCC97H cells xenograft model in vivo assay. Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3- f ]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC 50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro , compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy. [ABSTRACT FROM AUTHOR]