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Novel thienopyrimidinone hybrids 5-25 were developed and synthesized as potential inhibitors of human EGFR and FGFR. The in vitro antiproliferative action of all compounds, towards the human breast tumor cells MDA-MB-231 and MCF-7, was evaluated with doxorubicin serving as a reference (IC 50  = 6.72 µM). Compound 23 demonstrated the highest anti-breast cancer efficacy against both cellular lines having IC 50 ranging from 2.95 to 3.80 µM. The enzyme inhibition of human EGFR and FGFR by the most active candidates 18, 21and 23-25 was further evaluated. Compounds 21 and 25 were the best EGFR inhibitors having IC 50 values of 0.077 and 0.059 µM, respectively, in comparison to Erlotinib (IC 50  = 0.04 µM). In comparison with Staurosporine (IC 50  = 0.024 µM), compounds 24 and 25 were the most active FGFR inhibitors having IC 50 values of 0.055 and 0.029 µM, respectively. The study of molecular docking was carried out among the most active EGFR inhibitors 21 and 25 and the most active FGFR inhibitors 24 and 25 to examine the relation between the binding pattern of these compounds with EGFR and FGFR catalytic active sites and their biological activity, whereas the computational results were aligned with the biological results. Finally, compound 25, which was found to be the best dual inhibitor against EGFR and FGFR, was tested for inducing apoptosis and affecting cellular arrest within G2/M phase as well as it was screened to measure its safety towards normal breast cells MCF10a with IC 50 value of 47.16 µM in contrast to the reference Staurosporine (IC 50  = 18.86 µM). Accordingly, compound 25 could be considered as a potential breast cancer therapy., (© 2025 Wiley Periodicals LLC.)

A series of designed scaffold of dihydropyrimidine was synthesized as dual tyrosine kinase targets inhibitors using a multicomponent Biginelli reaction which provided a high atom economy in a single pot reaction. Several 1,4-DHPM hybrids were obtained via alkylation with different chloroacetylamine derivatives. All the synthesized derivatives were screened for their antiproliferative efficacy towards various cancer cell lines (HCT-116, PC-3, and MCF-7) and normal cell line WI-38 using MTT assay. The results indicated that compounds 8h and 8i have the most significant inhibitory effect on all evaluated cancer cell lines, displaying IC 50 of 3.94-15.78 µM. Also, they demonstrated favorable selectivity towards normal cell lines. Moreover, the most active hybrids 8h and 8i were evaluated for their EGFR and TrkA inhibitory activity. The findings indicated that compound 8h had superior inhibitory activity compared to compound 8i on the targeted kinases, effectively stopping the G1 phase of the MCF-7 cell cycle and encouraging apoptosis. Additionally, the molecular docking studies declared that the most active compounds exhibited a notable binding interaction with the binding site of the target proteins. Furthermore, their physicochemical properties, ADMET profiles, and bioavailability radar plots were predicted and analyzed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure-activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b-23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half-maximal inhibitory concentration [IC 50 ] = 12.50-24.39 µM) and hypoxic conditions (IC 50  = 4.69-11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21-23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ-radiation (IC 50  = 2.23-5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin-dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r 2  = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r 2  = 0.95., (© 2023 Wiley Periodicals LLC.)

A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC 50 values of 0.055 and 0.042 μM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Based on modulation of the monastrol scaffold, two series of pyrimidinone derivatives, 3a-e and 5a-k, were designed, synthesized, and investigated for their in vitro anticancer activity. Compound 5j exhibited the most potent cytotoxic activity against four cancer cell lines, including HCT-116, HeLa, HEPG-2, and MCF-7, with IC 50 values of 3.75-5.13 µM, while proving to be safe in the normal human cell line WI-38, with a selectivity index value of 13.7 on HCT-116 cells. Compounds 3d, 3e, and 5h-j were further assessed for their Eg5 inhibitory activity, where 3d and 5h-j showed high Eg5 inhibition with IC 50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC 50  = 14.89 µM). Cell cycle distribution of HCT-116 cells monitored with compound 5j illustrated that the cell cycle was arrested at the G2/M phase, with considerable apoptotic effect. A molecular docking study was performed to investigate the mode of action of the synthesized anticancer agents as Eg5 inhibitors., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC 50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC 50 = 16.08-23.67 µM), HCT-116 (IC 50 = 8.81-13.85 µM), and MCF-7 (IC 50 = 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 (IC 50 = 0.90 µM). Compounds 2 , 3 , 10 , and 11 displayed significant EGFR TK inhibitory activity with IC 50 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.

Three new series of phenyl dihydropyridazinone derivatives 4b-8i have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Nine compounds showed strong inhibitory activity, among which compound 8b exhibited potent activity against PC-3 cell line with IC 50 value of 7.83 µM in comparison to sorafenib (IC 50 11.53 µM). Compounds 6a, 6c, 7f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7f-h and 8a-d showed high B-Raf inhibition with ranges of IC 50 values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC 50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf inhibitor with IC 50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 8b showed cell cycle arrest at G2-M phase with significant apoptotic effect. Molecular modeling study was performed to understand the binding mode of the most active synthesized compounds with B-Raf enzyme., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

A new series of 1,2,3-triazole-chalcone hybrids has been synthesized and screened in vitro against a panel of 60 human cancer cell lines according to NCI (USA) protocol. Compound 4d having 3, 4-dimethoxyphenyl chalcone moiety, the most potent derivative, inhibited the growth of RPMI-8226 and SR leukemia cell lines by 99.73% and 94.95% at 10 μM, respectively. Also, it inhibited the growth of M14 melanoma, K-562 leukemia, and MCF7 breast cancer cell lines by more than 80% at the same test concentration. 4d showed IC 50 values less than 1 μM on six types of tumor cells and high selectivity index reached to 104 fold on MCF7. Compound 4d showed superior activity than methotrexate and gefitinib against the most sensitive leukemia cell lines in addition to higher or comparable activity against the rest sensitive cell lines. Flow cytometry analysis in RPMI-8226 cells revealed that compound 4d caused cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner. Mechanistic evaluation referred this apoptosis induction to triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A new series of pyrido[2,3-d]pyrimidines 3-18 bearing substitution at C-5 position was synthesized. All compounds were tested for their in vitro antitumor activity against five human cancer cell lines namely; hepatocellular carcinoma (HePG2), breast carcinoma (MCF-7), human prostate carcinoma (PC3), colorectal carcinoma (HCT-116), and cervical carcinoma (Hela) using doxorubicin as a positive control. Compounds 3, 4, 9, 11, 13, 14, 15 and 17 exhibited the highest antitumor activity against the tested cell lines and were selected to screen their enzymatic inhibition against dihydrofolate reductase enzyme (DHFR) compared with the reference drug methotrexate (MTX), to explain the probable mechanism of action of the observed anticancer activity. Compound 11 displayed the highest inhibitory activity (IC 50  = 6.5 µM) among the tested compounds in comparison with MTX (IC 50  = 5.57 µM). Also, compounds 13 and 14 showed high inhibitory activity against DHFR with IC 50 values 7.1 and 8.7 µM, respectively. Comparative molecular modeling study was performed between DHFR inhibitors 11, 13 and 14 of the highest activity and 10 of the lowest activity among the eight inhibitors against MTX. Docking studies into the active site of DHFR domain showed good agreement with the obtained biological results. Finally, compound 11 was found to be best antitumor, DHFR inhibitor, and it induced the process of apoptosis at Pre-G phase and cell cycle arrest at G2/M phase in MCF-7 cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC 50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC 50  = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A series of dihydropyrimidinone derivatives bearing various N-heterocyclic moieties was designed and synthesized. Twelve new compounds were screened for their cytotoxic activity using 60 cancer cell lines according to NCI (USA) protocol. Compound 19 showed a significant activity against NCI-H460, SK-MEL-5, and HL-60 (TB) cell lines with growth inhibition 88%, 86% and 85%, respectively, and was found to be more safe on normal cells when compared to doxorubicin. Enzyme inhibition assay was performed for compound 19 against mTOR (IC 50  = 0.64 μM) and VEGFR-2 (IC 50  = 1.97 μM) to show high potency in comparison to rapamycin (IC 50  = 0.43 μM) and sorafenib (IC 50  = 0.3 μM) as references, respectively. Cell cycle analysis of A549 cells treated with 19 showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining., (Copyright © 2018. Published by Elsevier Masson SAS.)

A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized, and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly derivatives 8a, 8f, and 9 with IC50 values of 0.14 ± 0.003, 0.119 ± 0.003, and 0.115 ± 0.002 μMrespectively showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3, and LS-174T cell lines. Multikinase enzyme inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET, and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK, which also had a resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell-cycle analyses of MCF-7 cells treated with 8a and 9 were measured in addition to other related factors, such as Bax, Bcl-2, caspase-9, and PARP-1. Among the tested compounds, 8a and 8f (with the dithiocarbamate group) and 9 (with the urea group) were the most potent inhibitors against EGFR in comparison with erlotinib as a reference drug. Those three compounds tested against four cell lines MCF-7, H-69, SKOV-3 and LS-174T, where 8a showed the highest cytotoxic activity, among the three tested compounds, 8f exhibits the highest activity against LS-174T, and 9 exhibits the highest activity against the H-69 cell line. Moreover, compound 9 exhibited high multi-inhibitory activities against extra kinases such as VEGFR-2, HER2, c-MET, and c-MER. [ABSTRACT FROM AUTHOR]

In the present study, a set of 2-anilino-4-alkylaminoquinazoline derivatives were synthesized and tested for their antitumor activities in vitro against a panel of four human cancer cell lines and for their DNA-binding affinity. Among the synthesized compounds, 4c and 5b with 4-substitution at the phenyl ring were found to have the highest inhibitory effects against breast adenocarcinoma (MCF-7), colon cancer (HCT-116), hepatocellular carcinoma (HePG-2), and human skin cancer (HFB4). Further investigation revealed that compounds 4a and 5d exhibited better affinity to bind with DNA than other tested compounds. [ABSTRACT FROM AUTHOR]

AbstractWe report the synthesis of new series of 1,3,5-triazines and 2-phenylquinazolines as anti-cancer agents. Compounds 4a-c, 5c, 5g, and 5m showed the highest cytotoxic effect against, most notably, leukemia, non-small cell lung cancer, colon carcinoma, CNS cancer, melanoma and renal cancer. The inhibitory activity against three different kinases; PI3K-α, B-Raf and VEGFR-2, was tested for the most active candidates. The tested compounds exhibited notable activity as PI3K-α inhibitors where compound 5g was found to have the highest inhibitory effect, compounds 4c and 5c showed good activities and compounds 4b and 5m had moderate activities. In B-Raf (V600E) kinase assay, compound 4b was showed the highest inhibitory activity comparable to sorafenib, while compounds 4a and 5g showed weak inhibitory effect. Regarding VEGFR-2 kinase assay, compound 4c had the best inhibitory activity compared to sorafenib, while compound 5g showed weak inhibitory effect. Molecular docking study was performed to understand the mode of binding between compounds 4b,c and 5c,m and PI3K-α, B-Raf and VEGFR-2 as target kinase enzymes. Generally, the synthesized 1,3,5-triazine derivatives were more promising anticancer agents than phenylquinazoline derivatives. The results support the fact that these compounds are worth optimizing for some new drugs in the future. [ABSTRACT FROM AUTHOR]