Search

Hepatocellular carcinoma (HCC) ranks as the third most prevalent reason for cancer-related death on a global scale. Tyrosine kinase inhibitors (TKIs) continue to be the primary treatment option for advanced hepatocellular carcinoma. A series of fluoro-11H-indeno[1,2-b]quinoxaline derivatives as an HCC drug targeting the VEGFR2/AKT axis was designed and synthesized. The novel compounds were investigated against HepG-2 and HuH-7 liver tumor cell lines. Compound 5 was the most active derivative against HepG-2 and HuH-7 cell lines with IC 50  = 0.75 ± 0.04 and 3.43 ± 0.16 μM, respectively, in contrast to Sorafenib which shows IC 50 values of 5.23 ± 0.31 and 4.58 ± 0.21 μM, respectively. IC 50 values on normal liver cells (THLE-2) show that all tests are more selective than Sorafenib, prompting further research. The most promising cytotoxic compound has virtually equal VEGFR2 inhibition efficacy to Sorafenib. The total VEGFR2 and p-VEGFR2 inhibitory effects were subsequently evaluated, showing 38.32 % and 77.64 % attenuation, respectively. Compound 5 also reduced total and phosphorylated AKT concentrations in HepG-2 cells by 55.29 % and 78.01 %, respectively. Furthermore, Compound 5 upregulated BAX and caspase-3 and downregulated Bcl-2 to promote apoptosis. Hybrid 5 stops HepG-2's cell cycle at the S phase 48.02 % higher than untreated. Docking experiments assessed AKT and VEGFR2 binding patterns., 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.)

Multi-drug resistant microbes have become a severe threat to human health and arise a worldwide concern. A total of fifteen spiro-1,3-dithiinoindenoquinoxaline derivatives 2-7 were synthesized and evaluated for their biological activities against five standard and MDRB pathogens. The MIC and MBC/MFC for the most active derivatives were determined in vitro via broth microdilution assay. These derivatives showed significant activity against the tested strains with microbicidal behavior, with compound 4b as the most active compound (MIC range between 0.06 and 0.25 µg/mL for bacteria strains and MIC = 0.25 µg/mL for C. albicans). The most active spiro-1,3-dithiinoindenoquinoxaline derivatives were able to inhibit the activity of SrtA with IC 50 values ranging from 22.15 ± 0.4 µM to 37.12 ± 1.4 µM. In addition, the active spiro-1,3-dithiinoindenoquinoxaline attenuated the in vitro virulence-related phenotype of SrtA by weakening the adherence of S. aureus to fibrinogen and reducing the biofilm formation. Surprisingly, compound 4b revealed potent SrtA inhibitory activity with IC 50  = 22.15 µM, inhibiting the adhesion of S. aureus with 39.22 ± 0.15 % compared with untreated 9.43 ± 1.52 %, and showed a reduction in the biofilm biomass of S. aureus with 32.27 ± 0.52 %. We further investigated the effect of gamma radiation as a sterilization method on the microbial load and found that a dose of 5 kGy was sufficient to eradicate the microbial load. The quantum chemical studies exhibited that the tested derivatives have a small energy band gap (ΔE = -2.95 to -3.61 eV) and therefore exert potent bioactivity by interacting with receptors more stabilizing., 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.)

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.)

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC 50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12-0.25 µM) compared to Vancomycin (1-2 µM), and MBC values ranging from (0.5-1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of quinolines bearing a thiazole moiety were synthesized using thiosemicarbazones 2a-f. Cyclization of 2a-f with ethyl chloroacetate, ethyl 2-chloropropanoate or chloroacetone afforded the corresponding thiazoles 3-5. The antimicrobial activity of the new quinoline derivatives was evaluated. The most of tested compounds revealed potent both of the antibacterial and antifungal activities. Fourfold potency of amphotericin B for the inhibition the growth of the A. fumigatus was displayed by ccompound 5e. The latter compound displayed twofold potency of gentamycin for inhibition the growth of N. gonorrhoeae. Moreover, this compound showed equipotent potency of references drugs for inhibition of the growth of S. flexneri, S. pyogenes, P. vulgaris, A. clavatus, G. candidum and P. marneffei. So, quinolines bearing a thiazole moiety can be suggested as interesting scaffolds for the development both of the novel antibacterial and antifungal agents. Some new derivatives were studied as peptide deformylase enzyme inhibitors. Thiazolidin-4-one derivative 3d and 2,3-dihydrothiazole derivative 5c had shown good PDF inhibition activity, which had been supported by the docking results with highest binding affinity and lowest docking energy score. These results suggested that the most potent compounds might be possible agents as novel bacterial PDF inhibitor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, anti-proliferative effects of twenty-seven indeno[1,2-b]quinoxalin-11-one derivatives were investigated in three human cancer cell lines, namely: the colon cancer cell line HCT-116, the liver cancer cell line HepG-2, and the breast cancer cell line MCF-7. Among them, 5, 6, 13, 14a, b and 15d-f derivatives displayed excellent anti-proliferative activities against the three tested cell lines compared to the reference standard Imatinib. Therefore, they were selected for further studies. First, to ensure the safety of our hits, investigation of the IC 50 values on normal human cells (WI-38) was executed indicating that, they are highly selective (IC 50  > 107 μM) in their cytotoxic effect. Second, the induction of apoptosis by these active compounds was achieved by down-regulation of Bcl-2 and up-regulation of BAX and caspase-3. Further investigations have shown that 14b and 15f, the most potent derivatives, induced cell cycle arrest at G2/M phase. Moreover, in silico evaluation of ADME properties indicated that all the potent compounds are orally bioavailable with no permeation to the blood brain barrier., 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.)

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT)., (Copyright © 2020 Elsevier Inc. All rights reserved.)