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EGFR inhibitors are a class of targeted therapies utilized in the management of certain tumor kinds such as NSCLC and breast cancer. Series of 1,2,3-triazole-Schiff's base hybrids were designed, synthesized, and estimated for their antitumor effect toward breast cancer cells, MCF-7 and MDA-MB-231. The safety and selectivity of the new compounds were tested using normal cell (WI-38). Analogs 4a, 4b, and 5f demonstrated significant antitumor effects toward both MCF-7 and MDA-MB-231 with IC 50 range of 5.61-18.01 µM in comparison to Doxorubicin (6.72 µM). Moreover, they proved considerable selectivity toward the tested cancer cells (SI values of 4.36-5.33). The superior compounds were investigated for EGFR inhibition where compounds 4b and 5f showed the highest EGFR inhibition effect with IC 50 equal 0.16 and 0.15 µM, respectively utilizing Gefitinib as reference (IC 50  = 0.081 µM). Further mechanistic studies for hybrid 5f in MDA-MB-231 cells, exhibited cell cycle arrest at G2/M phase by 29.85 % that was accompanied by the elevation of apoptosis percent by 48-fold more than the control. The apoptosis studies indicated that hybrid 5f was able to upregulate Bax (9.43 folds) while downregulate Bcl-2 (0.27) with substantial remarkable elevation of Bax/Bcl-2 ratio (35:1). Furthermore, it upregulated both caspases 8 and 9 by 2.93 and 6.54-fold, respectively. Molecular modeling studies showed the good binding affinity of compounds 4b and 5f with EGFR kinase active site explaining their potent biological effects. Drug likeness and ADMET features of compounds 4b and 5f demonstrated that they represent promising drug like candidates against breast cancer., 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.)

Applying various drug design strategies including ring variation, substituents variation, and ring fusion, two series of 2-(alkylthio)-5-(arylidene/heteroarylidene)imidazolones and imidazo[1,2-a]thieno[2,3-d]pyrimidines were designed and prepared as dual potential Chk1 and Chk2 inhibitors. The newly synthesized hybrids were screened in NCI 60 cell line panel where the most active derivatives 4b, d-f, and 6a were further estimated for their five dose antiproliferative activity against the most sensitive tumor cells including breast MCF-7 and MDA-MB-468 and non-small cell lung cancer EKVX as well as normal WI-38 cell. Noticeably, increasing the carbon chain attached to thiol moiety at C-2 of imidazolone scaffold elevated the cytotoxic activity. Hence, compounds 4e and 4f, containing S-butyl fragment, exhibited the most antiproliferative activity against the tested cells where 4f showed extremely potent selectivity toward them. As well, compound 6a, containing imidazothienopyrimidine core, exerted significant cytotoxic activity and selectivity toward the examined cells. The mechanistic investigation of the most active cytotoxic analogs was achieved through the evaluation of their inhibitory activity against Chk1 and Chk2. Results revealed that 4f displayed potent dual inhibition of both Chk1 and Chk2 with IC 50 equal 0.137 and 0.25 μM, respectively. It also promoted its antiproliferative and Chk suppression activity via EKVX cell cycle arrest at S phase through stimulating the apoptotic approach. The apoptosis induction was also emphasized by elevating the expression of Caspase-3 and Bax, that are accompanied by Bcl-2 diminution. The in silico molecular docking and ADMET profiles of the most active analogs have been carried out to evaluate their potential as significant anticancer drug candidates., 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.)

As regards to the structural analysis and optimization of diverse potential EGFR inhibitors, two series of imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates were designed and constructed as potential EGFR suppressors. The cytotoxic effect of the prepared derivatives was assessed toward hepatic, breast, and prostate cancerous cells (Hep-G2, MCF-7, and PC-3). Three derivatives 3d, 3e, and 3f presented potent antiproliferative activity and selectivity against the examined tumor cells showing IC 50 values at low micromolar levels. Hence, successive biological assays were applied to determine the probable mechanism of action of the new compounds. They exhibited significant EGFR suppression with an IC 50 range of 0.137-0.507 µM. The most effective EGFR inhibitor 3f arrested the MCF-7 cell cycle at the S phase by inducing the apoptotic pathway that was confirmed via increasing the expression of Caspases 8, 9, and Bax, which are associated with Bcl-2 decline. Additionally, molecular docking displayed a distinctive interaction between 3f and EGFR binding pocket. Overall, this work introduces some novel imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates as potential cytotoxic and EGFR inhibitors that deserve further research in tumor therapy., 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.)

Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized. This was accomplished through the heteroannelation of purines, for the first time, with thiazepine. The obtained thiazepinopurines derivatives were assessed for their cytotoxicity toward tumor cells of three different types, HepG2, MCF-7, and PC-3 as well as one normal cell (WI38). Among the studied compounds, 3b and 3c exhibited significant antiproliferative activity against tumor cells presenting IC 50 range of 5.52-17.09 µM in comparison with Roscovitine (9.32-13.82 µM). Additionally, both compounds displayed superior selectivity indices (SI = 3.00-7.15) toward tested cancer cells. The 4-chlorophenyl analog 3b has shown the best selectivity index, and hence it has been subjected to additional investigations to determine its proper mechanistic effect. Accordingly, the CDK2 inhibition potential, apoptosis induction, and cell cycle analysis of MCF-7 were evaluated. Results revealed that this analog displayed a potent CDK2 inhibition potential with an IC 50 value of 0.219 µM. Findings also showed that 3b was thought to arrest MCF-7 cell cycle at S phase together with apoptosis induction by the increased expression of Bax, Caspase-8, and -9 markers with a concomitant decrease in Bcl-2 expression. Besides, the probable interaction of 3b with CDK2 binding pocket was investigated by molecular docking., 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 © 2023 Elsevier Inc. All rights reserved.)

Regarding the structural analysis of variable effective CDK-9 suppressors, we record the design and synthesis of two new sets of sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles with expected anticancer and CDK-9 inhibiting activity. In the designed molecules, the pyrazole ring and sulphaguanidine fragment were linked together for the first time through diazo linkers as they are expected to enhance the anticancer activity and CDK degrading interaction. All derivatives have been estimated regarding their cytotoxic activity toward three tumor cells where CDK overexpression has been reported (HePG2, HCT-116, and MCF-7). Among these, four derivatives VII, VIII, X, and XIII exerted potent cytotoxicity against the chosen tumor cells presenting IC 50 range equal to 2.86-25.89 µM. As well cytotoxicity on non-cancer cells and CDK-9 inhibition assay have been also assessed for these candidates to evaluate their selectivity indices and enzyme inhibition. The 3,5-diaminopyrazole-1-carboxamide derivative XIII showed a superior combined profile as cytotoxic with high selectivity toward cancer cells (HePG2: IC 50  = 6.57 µM, SI = 13.31; HCT-116: IC 50  = 9.54 µM, SI = 9.16; MCF-7: IC 50  = 7.97 µM, SI = 10.97). Accordingly, it has been chosen to evaluate its probable mechanistic effect both in vitro (via enzyme assay, apoptosis induction, and cell cycle study) as well as in silico (through molecular docking). Overall, this work introduces the 3,5-diaminopyrazole-1-carboxamide derivative XIII as a potent CDK-9 inhibitor candidate (IC 50  = 0.16 µM) that merits further investigations for the management of breast, colorectal, and hepatic malignancies., 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 © 2023 Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Leukemia is a life-threatening nonepithelial malignant disorder that is characterized by uncontrolled growth of the hematopoietic cells. To date, there are still unmet needs for effective and less toxic medication for the management of this malignant tumor. Here, we report the synthesis of a new set of suggested anticancer molecules by joining the 1,2,3-triazole and chalcone privileged fragments in one scaffold to develop novel candidates in leukemia therapy. All the synthesized compounds have been screened for their cytotoxicity effect against a panel of 60 cancer cell lines at the National Cancer Institute. The leukemia cancer cells were found to be the most sensitive toward the effect of new molecules. A subsequent set of in vitro biological evaluation studies has been conducted on the most promising derivatives to identify their effect on such a cancer type. Four derivatives (11b, 11e, 11h, and 11j) showed excellent anticancer activity in the RPMI-8226 cells with IC 50 values at low micromolar concentrations. Among these compounds, 11e was the most effective with an IC 50 value of 3.17 µM (32-folds stronger than Staurosporine). The potential mechanistic effect of the latter has been further studied through the investigation of its potential effect on the cell cycle, PARP-1, and certain apoptotic and anti-apoptotic markers in the RPMI-8226 cells. Results of those studies revealed the potential of 11e to induce apoptosis through the upregulation of BAX, caspase-3, and caspase-9, and to arrest the cell cycle at the S phase., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A novel series of pyrazoles and pyrazolo[1,5-a]pyrimidines bearing benzothiazole moiety were designed and synthesized. Chemical structures were confirmed by spectral data and elemental analyses. Nine compounds were selected and screened for their cytotoxic activity at the National Cancer Institute (NCI), USA against 60 cancer cell lines in a single dose assay. Compounds 4 and 5 exerted the most potent growth inhibitory activity against most cancer cell lines with growth inhibition (GI%) ranges from 44.86% to 84.59% and 31.20% to 52.36%, respectively. Consequently, they were further investigated through IC 50 determination using five dose MTT colorimetric assay against three sensitive cell lines, leukemia CCRF-CEM, non-small cell lung cancer HOP-92 and liver cancer Hep-G2. Compound 4 exhibited potent cytotoxic activity against the three tested cell lines with IC 50 16.34, 3.45 and 7.79 μM, respectively representing half potency, 3.5 folds potency and nearly equipotent to roscovitine. To investigate its mechanism of action, cell cycle analysis of compound 4 was conducted and showed that it induced cell cycle arrest at G2/M phase and apoptosis in HOP-92 cells. In correlation with the previous results, caspase-3 activation was tested and illustrated elevation in its concentration by nearly 14 folds than control. Besides, enzyme inhibition assay of compound 4 was evaluated towards two common antitumor targets namely KDM1 and CDK1 showing significant inhibitory activity with IC 50 0.096 and 0.078 μM, respectively., 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 Inc. All rights reserved.)