The therapeutic efficacy of cytarabine (Ara-C) in anaplastic large cell lymphoma (ALCL) is frequently compromised by dose-limiting myelosuppression and drug resistance. To address this, we developed a series of novel 1,2,3-triazole-dithiocarbamate hybrids designed to target Aurora A kinase and enhance chemosensitivity to Ara-C. Compound 22h emerged as the lead candidate, exhibiting potent Aurora A inhibition (IC₅₀ = 0.296 μM) with threefold preferential inhibition over Aurora B (IC₅₀ = 0.887 μM) and sub-micromolar activity against ALK (IC₅₀ = 0.332 μM). Molecular docking and 100-ns molecular dynamics simulations suggest that 22h engages a putative allosteric pocket in Aurora A, centered on Cys290 (S-score -13.67 kcal/mol), conferring superior stability over ATP-site binding, while simultaneously forming stable interactions within the ALK hinge region. In ALK+ ALCL SR cells, 22h demonstrated significant cytotoxicity (IC₅₀ = 5.10 μM) and high tumor selectivity (SI = 7.0) relative to normal peripheral blood mononuclear cells. Mechanistically, 22h induced potent G₂/M arrest (3.2-fold increase), supporting Aurora A as the primary functional target, alongside cellular ALK depletion as a complementary mechanism. Furthermore, it triggered mitochondrial apoptosis (17.8% total apoptotic fraction) and dismantled chemoresistance pathways by elevating intracellular ROS (3.5-fold) and inhibiting ALDH1 activity (IC₅₀ = 2.8 μg/mL). Crucially, co-treatment with 22h synergistically potentiated Ara-C efficacy (Combination Index = 0.78), reducing the Ara-C IC₅₀ by 12.8-fold (from 27.65 μM to 2.15 μM) and dramatically widening the therapeutic window by 14-fold (SI = 29.6). These findings identify 22h as a novel multi-target scaffold with potent Aurora A/ALK inhibitory activity that restores Ara-C sensitivity in ALCL, supporting its further development as a precision chemosensitizer.

We 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.

Two 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.

ABSTRACT 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 , 21 and 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.

A series of tacrine-based 4-H-pyran derivatives were synthesized and biologically estimated as multifactorial ligands against Alzheimer's disease. Pyranotacrines were characterized by having the main core tacrine (ChE inhibition) and tetrahydro-4H-pyran (calcium channel blockers and β-amyloid activity). Among the series, compound 6c displayed a well-balanced multi-targeted activity against Alzheimer's disease and it was a potent AChE inhibitor with IC50 = 0.06 ± 0.005 μM, approximately 3-folds more active than tacrine as a reference drug. Kinetic analysis and molecular docking displayed that 6c targeted both key binding regions of AChE. Moreover, its inhibitory activity against BuChE was 8-folds more active than rivastigmine with IC50 = 0.09 ± 0.016 μM. Compound 6c showed blockade power of 46 % as a Ca2+ blockade agent and strong inhibition activity against β-amyloid with IC50 = 1.09 ± 0.05 μM (71 % aggregation inhibition). Additionally, it showed higher anti-oxidative activity with 10.36 TE and chelating anchors activity for metal ions. The safety of 6c towards SH-SY5Y normal cells and HepG2 cancer cells was interesting with safety index ratio (Si = 2273), in addition to its BBB permeability and pharmacokinetic profile.

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 IC50 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.

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 IC50 values of 6.10, 10.33, and 2.42 mu M 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 (IC50: 0.087, 31.56, 0.078, and 0.156 mu M, 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.

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.

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 IC50 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.

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 hAChE inhibitors with IC50 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 IC50 = 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 IC50 = 0.74 μM and 76% inhibition at 10 μM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC50 = 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 IC50 = 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.

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.

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.

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 IC50 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 IC50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC50  = 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.

In the present investigation, we focused on the development of dual drugs able to inhibit carbonic anhydrase enzyme (CA) by harboring sulfonamide group and to increase the sensitivity of hypoxic tumors to radio and chemotherapies by incorporating 5-nitroimidazole scaffold. The synthesized compounds were evaluated as cytotoxic agents under oxic and hypoxic conditions against three cell lines including human colorectal carcinoma (HCT116), epithelioid carcinoma (Hela), and mammary gland carcinoma (MCF-7) cells. Compounds 13a and 15a,b exhibited the highest cytotoxic activity against the three cell lines under both oxic (IC50 = 6.18 -23.06 }IM) and hypoxic (IC50 = 5.63 -19.78 }IM) conditions. The capability of compounds 13a and 15b to augment the lethal effect of gamma-irradiation was evaluated. Both compounds increased the sensitivity of cancerous HCT116 cells to the cell-killing effect of ionizing radiation (IC50 = 4.18 and 2.53 }IM, respectively). Sulfonamide derivatives 13a,b, 15a,b, and 17a,b were evaluated for their inhibitory effect against the tumor-associated hCA IX and XII isoforms in comparison to acetazolamide. Molecular docking and molecular dynamics simulation were performed for some sulfonamides on isoforms hCA IX and XII to understand the elements governing the inhibitory effect and the stability of interaction under dynamic conditions. (C) 2022 Elsevier B.V. All rights reserved.

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

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 IC50 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.

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 IC50 value of 7.83 mu M in comparison to sorafenib (IC50 11.53 mu M). Compounds 6a, 6c, 7 f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7 f-h and 8a-d showed high B-Raf inhibition with ranges of IC50, values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf inhibitor with IC50 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.

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.

The asymmetric access to unreported trans 4-quinolinoxy oxaproline precursors is investigated here in a comparative way by 1,3-dipolar cycloaddition of vinyloxy quinolines with chiral α-alkoxycarbonyl aldonitrones and chiral cyclic surrogates.

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.