Search

In the present work, we successfully synthesized Se-alkyl selenopyridines 1 and 3, selenopheno[2,3-b]pyridine 2, and bis-selenopyridine 4 derivatives using an eco-friendly method by utilizing NaHSe instead of toxic hydrogen selenide. The effect of the temperature on the reaction was screening at various temperatures. The regiospecific reaction of selenopyridine 1 with bromine afforded an unexpected product 4,6-diamino-5-bromo-2-[(cyanomethyl)selenyl]-pyridine-3-carbonitrile (5), which was cyclized to selenopheno[2,3-b]pyridine (7) by refluxing in the presence of TEA. While its treatment with thiophenol and/or p-chlorothiophenol gave 8a, b. On the other hand, its reaction with aminothiophenol afforded 2-(benzo[d]-thiazol-2-yl)-5-bromoselenopheno[2,3-b]pyridine-3,4,6-triamine (9). Also, N-(2-cyano-4-methyl-5H-1-seleno-3,5,8-triazaacenaphthylen-7-yl)acetamide (11) and a novel series of selenoazo dyes 12a-d were synthesized by treatment of selenopheno[2,3-b]pyridine 2 with acetic anhydride and/or diazonium chlorides of aromatic amines, respectively. Then, we ascertained the potential activity of synthesized compounds against highly metastatic prostate cancer cells (PC-3) and osteosarcoma cells (MG-63) and found that 12a, 12b, 12c, and 12d were more cytotoxic than doxorubicin in both tested cell lines, showing nearly the same anticancer activity with IC 50 values ranging from 2.59 ± 0.02 µM to 3.93 ± 0.23 µM. Mechanistically, the most potent compounds 12a and 12b proved to be potent EGFR inhibitors with IC 50 values of 0.301 and 0.123 µM, respectively, compared to lapatinib as a positive reference (IC 50  = 0.049 µM). Moreover, the docking results are in good agreement with the anticancer activity as well as the EGFR inhibitory activity, suggesting these two compounds as promising EGFR anticancer candidates., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Uncontrolled inflammation predisposes to pleiotropic effects leading to cancer development thanks to promoting all stages of tumorigenesis. Therefore, cancer-associated inflammation has been delegated as the seventh hallmark of cancer. Thus, raging the war against both inflammation and cancer via the innovation of bioactive agents with dual anti-inflammatory and anticancer activities is a necessity. Herein, a novel series of pyrazole-chalcone analogs of Lonazolac (7a-g and 8a-g) have been synthesized and investigated for their in vitro anticancer activity against four cancer cell lines using the MTT assay method. Among all, hybrid 8g was the most potent against three cancer cell lines, HeLa, HCT-116, and RPMI-822 with IC 50 values of 2.41, 2.41, and 3.34 µM, respectively. In contrast, hybrid 8g showed moderate inhibitory activity against MCF-7 with IC 50 28.93 μM and with a selectivity profile against MCF-10A (non-cancer cells). Mechanistically, hybrid 8g was the most potent inhibitor against tubulin polymerization (IC 50  = 4.77 µM), suggesting tubulin as a molecular target and explaining the observed cytotoxicity of hybrid 8g. This was mirrored by the detected potent pre-G1 apoptosis induction and G2/M cell cycle arrest. Moreover, hybrid8gexhibited selectivity against COX-2 (IC 50  = 5.13 µM) more than COX-1 (IC 50  = 33.46 µM), indicating that 8g may have lower cardiovascular side effects, but is still not potent as celecoxib (COX-2 IC 50  = 0.204 µM, COX-1 = 35.8 µM). Notably, hybrid 8g showed promising inhibitory activity towards 5-LOX (IC 50  = 5.88 µM). Finally, the anti-inflammatory activity of hybrid8 g was confirmed by high iNOS and PGE2 inhibitory activities in LPS-stimulated RAW cells with IC 50 values of4.93 µM and 10.98 µM, respectively, that accompanied by showingthe most potent inhibition of NO release (70.61 % inhibition rate). Molecular docking studies of hybrid 8g confirmed good correlations with the executed biological results. Furthermore, hybrid 8g had good drug-likeness and suitable physicochemical properties. Taken together, the combined results suggested hybrid8gas a promising orally administered candidate in the journey of repurposing NSAIDs for cancer chemopreventionand treatment., 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 © 2022 Elsevier Inc. All rights reserved.)

Herein, we report design and synthesis of twenty-one dual PIM-1/HDAC inhibitors utilizing 3-cyanopyridines as a novel cap moiety linked with aliphatic /aromatic linker bearing carboxylic acid 3a-g, hydroxamic acid 4a-g or 2-aminoanilide moieties 5a-g as zinc-binding group. Most of the target hybrids revealed promising growth inhibition according to one dose NCI protocol against 60 cancer cell lines. Meanwhile, hydroxamic acids 4b, 4d and 4e displayed strong and broad-spectrum activity against nine tumor subpanels tested (GI 50 0.176-8.87 μM); 4d displayed strong antiproliferative activity with GI 50  ≤ 3 μM against different cancer cell lines (GI 50 range from 0.325 to 2.9 μM). Furthermore, 4a, 4d-4g and 5f manifested a high inhibitory activity against HDACs 1 and 6 isozymes; 4g, displayed potent HDAC 1 and 6 inhibitory activity (45.01 ± 2.1 and 19.78 ± 1.1 nM) more than the reference SAHA (51.54 ± 2.4 and 21.38 ± 1.2 nM, respectively), while 4f was more potent (30.09 ± 1.4 nM) than SAHA against HDAC 1 and less potent (30.29 ± 1.7 nM) than SAHA against HDAC 6. Hybrids 4b, 4d, 4e and 4f exhibited potent PIM-1 inhibitory activity; 4d showed comparable activity to quercetin (IC 50 of 343.87 ± 16.6 and 353.76 ± 17.1 nM, respectively); it exhibited pre G1 apoptosis and arrest cell cycle at G2/M phase. Moreover, it revealed good binding into pocket of HDACs 1,6 and PIM-1 kinase enzymes with good correlation with biological results. Moreover, 4b, 4d and 4e had reasonable drug-likeness properties according to Lipinski's rule. However, multitarget inhibitor of PIM-1/HDAC is a promising strategy in anticancer drug discovery; the most potent hybrids require further in vivo and clinical investigations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Quinolones are well known antibacterial chemotherapeutics. Furthermore, they were reported for other activities such as anticancer and urease inhibitory potential. Modification at C7 of quinolones can direct these compounds preferentially toward target molecules., Methods: Different derivatives of ciprofloxacin by functionalization at the piperazinyl N-4 position with arylidenehydrazinecarbonyl and saturated heterocyclic-carbonyl moieties have been synthesized and characterized using different spectral and analytical techniques. The synthesized compounds were evaluated for anticancer, antibacterial, and urease inhibitory activities., Results: Among the synthesized compounds derivatives 3f and 3g experienced a potent antiproliferative activity against the breast cancer BT-549 cell line, recording growth percentages of 28.68% and 6.18%, respectively. Additionally, compound 3g revealed a remarkable antitumor potential toward the colon cancer HCT-116 cells (growth percentage 14.76%). Activity of compounds 3f and 3g against BT-549 cells was comparable to doxorubicin (IC 50  = 1.84, 9.83, and 1.29 µM, respectively). Test compounds were less active than their parent drug, ciprofloxacin toward Klebsiella pneumoniae and Proteus mirabilis. However, derivative 4a showed activity better than chloramphenicol against Klebsiella pneumoniae (MIC = 100.64 and 217.08 µM, respectively). Meanwhile, many of the synthesized compounds revealed a urease inhibitory activity greater than their parent. Compound 3i was the most potent urease inhibitor with IC 50 of 58.92 µM, greater than ciprofloxacin and standard inhibitor, thiourea (IC 50  = 94.32 and 78.89 µM, respectively)., Conclusion: This study provided promising derivatives as lead compounds for development of anticancer agents against breast and colon cancers, and others for optimization of urease inhibitors.

Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still represents a challenging endeavor. With 15 million death every year in 2030 according to the estimates, cancer has increased rising of an alarm as a real crisis for public health and health systems worldwide. Therefore, scientist began to introduce innovative solutions to control the cancer global health problem. One of the promising strategies in this issue is the multitarget or smart hybrids having two or more pharmacophores targeting cancer. These rationalized hybrid molecules have gained great interests in cancer treatment as they are capable to simultaneously inhibit more than cancer pathway or target without drug-drug interactions and with less side effects. A prime important example of these hybrids, the HDAC hybrid inhibitors or referred as multitargeting HDAC inhibitors. The ability of HDAC inhibitors to synergistically improve the efficacy of other anti-cancer drugs and moreover, the ease of HDAC inhibitors cap group modification prompt many medicinal chemists to innovate and develop new generation of HDAC hybrid inhibitors. Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. This review shed light on the most recent hybrids of HDACIs with one or more other cancer target pharmacophore. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment., 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.)

PDE5 targeting represents a new and promising strategy for apoptosis induction and inhibition of tumor cell growth due to its over-expression in diverse types of human carcinomas. Accordingly, we report the synthesis of series of pyrazolo[3,4-d]pyrimidin-4-one carrying quinoline moiety (11a-r) with potential dual PDE5 inhibition and apoptotic induction for cancer treatment. These hybrids were structurally elucidated and characterized with variant spectroscopic techniques as 1 H NMR, 13 C NMR and elemental analysis. The assessment of their anticancer activities has been declared. All the rationalized compounds 11a-r have been selected for their cytotoxic activity screening by NCI against 60 cell lines. Compounds 11a, 11b, 11j and 11k were the most active hybrids. Among all, compound 11j was further selected for five dose tesing and it displayed outstanding activity with strong antitumor activity against the nine tumor subpanels tested with selectivity ratios ranging from 0.019 to 8.3 at the GI 50 level. Further, the most active targets 11a, b, j and k were screened for their PDE5 inhibitory activity, compound 11j (with IC 50 1.57 nM) exhibited the most potent PDE5 inhibitory activity. Moreover, compound 11j is also showed moderate EGFR inhibition with IC 50 of 5.827 ± 0.46 µM, but significantly inhibited the Wnt/β-catenin pathway with IC 50 1286.96 ± 12.37 ng/mL. In addition, compound 11j induced the intrinsic apoptotic mitochondrial pathway in HepG2 cells as evidenced by the lower expression levels of the anti-apoptotic Bcl-2 protein, and the higher expression of the pro-apoptotic protein Bax, p53, cytochrome c and the up-regulated active caspase-9 and caspase-3 levels. All results confirmed by western blotting assay. Compound 11j exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase. In conclusion, hybridization of quinoline moiety with the privileged pyrazolo[3,4-d]pyrimidinon-4-one structure resulted in highly potent anticancer agent, 11j, which deserves more study, in particular, in vivo and clinical investiagtions, and it is expected that these results would be applied for more drug discovery process., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC 50 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

One of the helpful ways to improve the effectiveness of anticancer agents and weaken drug resistance is to use hybrid molecules. therefore, the current study intended to introduce 20 novel xanthine/chalcone hybrids 9-28 of promising anticancer activity. Compounds 10, 11, 13, 14, 16, 20 and 23 exhibited potent inhibition of cancer cells growth with IC 50 ranging from 1.0 ± 0.1 to 3.5 ± 0.4 μM compared to doxorubicin with IC 50 ranging from 0.90 ± 0.62 to 1.41 ± 0.58 μM and that compounds 11 and 16 were the best. To verify the mechanism of their anticancer activity, compounds 10, 11, 13, 14, 16, 20 and 23 were evaluated for their EGFR inhibitory effect. The study results revealed that compound 11 showed IC 50  = 0.3 µM on the target enzyme which is more potent than staurosporine reference drug (IC 50  = 0.4 µM). Accordingly, the apoptotic effect of the most potent compounds 11 was extensively investigated and showed a marked increase in Bax level up to 29 folds, and down-regulation in Bcl2 to 0.28 fold, in comparison to the control. Furthermore, the effect of compound 11 on Caspases 3 and 8 was evaluated and was found to increase their levels by 8 and 14 folds, respectively. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking study was adopted to confirm mechanism of action., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a-g) and their reaction intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS generation during the metabolic phase of phagocytosis in a dose-dependent manner where compounds 5d and 5e were the most potent samples with higher inhibitory activities (IC 50 values 3.3 and 1.4 μM, respectively) than that of the reference acetylsalicylic acid (IC 50  = 9.7 μM). Results for the determination of potential antioxidant properties of the synthesized compounds showed that compounds 5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even comparable to Trolox. Compounds 3d-f and 5d-f with the least IC 50 values in MTT assay were tested against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical study were performed to determine the consequence of exposure to chronic low dose of chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by co-treatment with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies were performed to explore the binding mode of the most active compounds against EGFR and BRAF kinases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Ethyl 4-substituted-3-oxo-quinoxaline-2-carboxylates 3–5 were obtained via alkylation of ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (1). Compound 1 was heterocyclized using hydrazines, ethylenediamine, and ethanolamine to give pyrazoloquinoxalines 6, 7, diazepinoquinoxaline 8, and oxazepinoquinoxaline 10. The quinoxaline-2-carboxamides 9, 11, 12 were prepared via condensation of compound 1 with different amines. Compound 1 was thiated using Lawesson's reagent affording quinoxaline-3-thione 13, in fair yield. In addition, the reaction of 4-methyl-3-oxoquinoxaline 3 with some binucleophiles led to a series of new oxoquinoxaline derivatives 14–18. The molecular structure of compounds 1, 3, and 9 was confirmed by X-ray crystallography. The anti-proliferative activity showed that among all the tested compounds, compounds 3, (IC50 2.51 ± 3.0, 4.22 ± 1.6 and 2.27 ± 1.9 µM), 11 (IC50 1.32 ± 2.61, 1.41 ± 1.23 and 1.18 ± 1.91 µM) and 17 (IC50 1.72 ± 1.32, 1.85 ± 0.94 and 1.92 ± 4.83 µM) showed noteworthy anti-proliferative effects against the three cancer cell lines, HCT116, HePG2 and MCF7, respectively, compared to the reference drugs doxorubicin (IC50 1.41 ± 0.58, 0.90 ± 0.62 and 1.01 ± 3.02 µM) and erlotinib (IC50 1.63 ± 0.81, 1.57 ± 0.62 and 1.49 ± 0.54 µM). Compounds 3 (0.899 nM), 11 (0.508 nM) and 17 (0.807) showed strong EGFR inhibitory activity compared to Erlotinib (0.439 nM) and these results are in agreement with the docking study. These results suggest that compounds could probably be promising anticancer agents with EGFR inhibitory activity. [ABSTRACT FROM AUTHOR]

Since the synthesis of prontosil the first prodrug shares their chemical moiety, sulfonamides exhibit diverse modes of actions to serve as antimicrobials, diuretics, antidiabetics, and other clinical applications. This inspiring chemical nucleus has promoted several research groups to investigate the synthesis of new members exploring new clinical applications. In this study, a novel series of 5(4H)-oxazolone-based-sulfonamides (OBS) 9a–k were synthesized, and their antibacterial and antifungal activities were evaluated against a wide range of Gram-positive and -negative bacteria and fungi. Most of the tested compounds exhibited promising antibacterial activity against both Gram-positive and -negative bacteria particularly OBS 9b and 9f. Meanwhile, compound 9h showed the most potent antifungal activity. Moreover, the OBS 9a, 9b, and 9f that inhibited the bacterial growth at the lowest concentrations were subjected to further evaluation for their anti-virulence activities against Pseudomonas aeruginosa and Staphylococcus aureus. Interestingly, the three tested compounds reduced the biofilm formation and diminished the production of virulence factors in both P. aeruginosa and S. aureus. Bacteria use a signaling system, quorum sensing (QS), to regulate their virulence. In this context, in silico study has been conducted to assess the ability of OBS to compete with the QS receptors. The tested OBS showed marked ability to bind and hinder QS receptors, indicating that anti-virulence activities of OBS could be due to blocking QS, the system that controls the bacterial virulence. Furthermore, anticancer activity has been further performed for such derivatives. The OBS compounds showed variable anti-tumor activities, specifically 9a, 9b, 9f and 9k, against different cancer lines. Conclusively, the OBS compounds can serve as antimicrobials, anti-virulence and anti-tumor agents. [ABSTRACT FROM AUTHOR]