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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 [IC50] = 12.50–24.39 µM) and hypoxic conditions (IC50 = 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 (IC50 = 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 r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95. [ABSTRACT FROM AUTHOR]

Abstract\nHIGHLIGHTSTwo new series of quinazolinone derivatives, conjugated with chalcone 4a–k and pyridazine 8a–f moieties, were designed and synthesized as promising anticancer agents and apoptotic inducers. Using MTT assay, they were assessed for their cytotoxicity against HepG-2, HCT-116, and MCF-7 cancer cell lines and normal cell lines, compared to Doxorubicin as a reference drug. Quinazolinone-Pyridazinone hybrid 8a exhibited the highest cytotoxicity against all examined cancer cells and was safe against normal cells. Compounds 4i, 4k, and 8e showed good cytotoxicity against the cancer cell lines. The four most potent compounds were then screened for their effect on cell cycle distribution and apoptosis induction. Compounds 4i and 8a led to a cell cycle arrest at the G1 phase in MCF-7 cancer cells, while compounds 4k and 8e led to cell cycle arrest of HepG-2 cancer cells at the G1 phase and G2/M phase, respectively. The four hybrids induced total apoptosis which was proved via testing their effect on different apoptotic markers. They were further docked into a BCL-2 binding pocket showing good binding interactions. Therefore, the new quinazolinone derivatives might be identified as promising apoptotic inducers and can be used as lead compounds in the future investigations.New quinazolinone chalcone/pyridazine hybrids were designed and synthesized.Using MTT assay, all hybrids were evaluated for their cytotoxic activities.The impact on cell cycle distribution and apoptosis induction was investigated.The effect on caspase 3, caspase 7, cytochrome c, p53, BAX, and BCL-2 markers was examined.Hybrids 4k and 8a were the most apoptotic inducers and the results were matched with docking studies.New quinazolinone chalcone/pyridazine hybrids were designed and synthesized.Using MTT assay, all hybrids were evaluated for their cytotoxic activities.The impact on cell cycle distribution and apoptosis induction was investigated.The effect on caspase 3, caspase 7, cytochrome c, p53, BAX, and BCL-2 markers was examined.Hybrids 4k and 8a were the most apoptotic inducers and the results were matched with docking studies. [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]

The first total synthesis of (±)-eleutherol and eleuthoside A, the natural cytotoxic substances extracted from medicinal Indonesian plant, is described. First, the synthesis of (±)-eleutherol has been accomplished in nine steps starting from bromo methoxy aldehyde with the aid of diazo-transfer chemistry approach. Second, a metalcatalyzed intramolecular cyclization reaction of the corresponding diazonaphthoquinone led to the desired eleuotherol, which served as a precursor to eleuthoside A. Then, several glycosidation routes, using different glucosyl donors, were experimented to reach effective O-glycosidation of eleutherol. The only successful strategy involved Koenigs-- Knorr glycosidation using peracetyl glycosyl bromide in the presence of Ag2O and quinoline. This strategy furnished our desired acetylated glycoside of β-configuration, regioselectively. Finally, deacetylation and successive separation of diastereomers were conducted to give eleuthoside A. [ABSTRACT FROM AUTHOR]

Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve γ-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High γ-selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed s-allyl copper intermediate enhance the rate of the reductive elimination to give γ-products as major isomers. [ABSTRACT FROM AUTHOR]

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.)

In response to the urgent need for new anti-proliferative agents, four novel series of triazolopyrimidine compounds (7a-e, 9a-d, 11a-f, and 13a-e) were synthesized and evaluated for in vitro anticancer efficacy against HCT116, HeLa, and MCF-7 cell lines. Compound 13c emerged as the most potent, with IC 50 values of 6.10, 10.33, and 2.42 μM respectively, while 11e and 7c also showed strong activity. In multi-target suppression tests, 13c exhibited the highest inhibition against EGFR, TOP-II, HER-2, and ARO (IC 50 : 0.087, 31.56, 0.078, and 0.156 μM, respectively). Flow cytometry revealed 13c's ability to suppress the S-phase cell population in MCF-7 cells. In vivo studies of 13c demonstrated significant tumor growth inhibition, comparable to the positive control. Molecular docking studies supported the experimental findings, confirming the binding of the novel motifs to the target enzymes' active sites. This comprehensive evaluation highlights the potential of these triazolopyrimidine compounds, particularly 13c, as promising anticancer agents, warranting further investigation., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds 5c and 5d exhibited the most desirable multiple functions for AD; they were strong h AChE inhibitors with IC 50 values of 0.44 and 0.25 μM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC 50 = 0.08 and 0.14 μM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aβ aggregation and decreasing Aβ-related neurodegeneration, especially compound 5d , which was 8 times more effective than curcumin with IC 50 = 0.74 μM and 76% inhibition at 10 μM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC 50 = 0.38 and 0.44 μM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC 50 = 5.15 and 2.42 μM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe +2 , Zn +2 , and Cu +2 , inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)