Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity.

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Design and synthesis of ibuprofen-quinoline conjugates as potential anti-inflammatory and analgesic drug candidates.

A new set of ibuprofen-quinoline conjugates comprising quinolinyl heterocycle and ibuprofen moieties linked by an alkyl chain were synthesized in good yields utilizing an optimized reaction procedure in a molecular hybridization approach to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. The synthesized conjugates were screened for their anti-inflammatory, and ulcerogenic properties. Several conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test without showing any ulcerogenic liability. In addition, most conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate test. The most promising conjugates were the unsubstituted and 6-substituted fluoro- and chloro-derivatives of 2-(trifluoromethyl)quinoline linked to ibuprofen by a propyl chain. Their anti-inflammatory activity was evaluated against LPS-stimulated inflammatory reactions in RAW264.7 mouse macrophages. In this regard, it was found that most of the conjugates were able to significantly reduce the release and production of nitric oxide in the LPS-stimulated macrophages. The secretion and expression of the pro-inflammatory cytokines IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) were also significantly suppressed.

Design, synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors.

Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.

Targeting apoptosis; design, synthesis and biological evaluation of new benzoxazole and thiazole based derivatives.

Several novel approaches to target Bcl-2 proteins and apoptotic pathways have been identified in recent years for the treatment of different types of cancer including colorectal cancer. However, no effective treatments were yet developed for colorectal cancer. Twenty two novel benzoxazole and thiazole-based compounds were designed, synthesized, and evaluated as potential Bcl-2 inhibitors with anti-proliferative activity. Compounds 8g, 12e and 13d showed good to moderate anti-proliferative activity against most of the NCI 60 cell line panel with mean growth inhibition percent of 45.13, 42.29 and 29.25%, respectively. They showed the greatest cell growth inhibition percent to HCT-116 cell line with the values of 68.0, 59.11 and 43.44%, respectively. The aforementioned compounds were furtherly investigated for their effect on HCT-116 cell cycle, and they showed increase in the total apoptosis with 17, 22, and 5%, respectively. Also, the apoptotic effect of compounds 8g, 12e and 13d, were tested by their effect on altering caspase-3 expression level in HCT-116 human cell line. The three compounds showed an increase in the caspase-3 levels by 6, 8 and 3 folds, respectively in comparison with the same untreated ones. Moreover, they were evaluated for their in-vitro Bcl-2 inhibitory activity and they showed percent inhibition of 60.2, 69.2 and 50.0%, respectively. Finally, the most potent compounds 8g and 12e showed 3.864 and 2.834 folds increase in Bax level compared to the control respectively. On the other hand, Bcl-2 was down-regulated to 0.31 and 0.415 folds compared to the control. The induction of apoptosis through increase in caspase 3 expression and down-regulation of Bcl-2 is the suggested mechanism of action.

Serum level of MicroRNA 15a and interleukin 6 as biomarkers for sepsis in critically Ill Patients.

This study intended to evaluate the diagnostic efficacy of serum interleukin-6 (IL-6) and serum expression level of microRNA 15a (miRNA 15a) in sepsis patients admitted to the medical intensive care unit (ICU), and to correlate the results with the outcome of patients. This observational case-control study, was done from January 2022 to June 2022, included 75 adult ICU patients ≥18 years old, divided into 2 groups. Group 1: included 38 adults, critically ill sepsis patients and Group 2 (control group), included 37 adults, non-sepsis patients admitted to the ICU. Venous blood was withdrawn from cases and controls under aseptic conditions for assessment of serum IL-6 level by ELISA and serum expression level of miRNA 15a by quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Patient demographic data in addition to their characteristics including site of infection, blood culture results, length of stay and outcome of patients were included in the study. miRNA 15a was significantly higher in the sepsis group with mean of 3.99±1.61 compared to the controls (1.03±0.03, p < 0.001) while serum IL-6 levels were higher in the sepsis patients compared to the controls, however the difference did not reach statistical significance (p= 0.92). No difference was found in IL-6 and miRNA 15a levels between surviving and non-surviving sepsis patients, shocked and non-shocked sepsis patients. In conclusion, both IL-6 and miRNA 15a were up-regulated in ICU patients with sepsis. Both biomarkers did not show a significant difference regarding the outcome of patients. miRNA 15a could be considered a highly specific and sensitive marker in differentiating sepsis cases from controls, so it could be used as a diagnostic rather than a prognostic biomarker for sepsis.

Design, synthesis, and biological evaluation with molecular dynamics study of novel pyrazolo[3,4-d]pyrimidine derivatives as anti-cancer agents.

In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-d]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as FLT3 inhibitors. All of the newly synthesized compounds were evaluated for their cytotoxicity on 60-NCI cell lines. Compounds with the piperazine acetamide linkage XIIa-f & XVI exhibited a remarkable anticancer activity among all of the tested compounds, especially against non-small cell lung cancer, melanoma, leukemia and renal cancer models. Furthermore, compound XVI (NSC no - 833644) was further screened with a 5-dose assay on nine subpanels and exhibited a GI50 between 1.17 and 18.40 µM. On the other hand, molecular docking and dynamics studies were performed to predict the binding mode of the newly synthesized compounds in the FLT3 binding domain. Finally, through a predictive kinetic study, several ADME descriptors were calculated.

A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells.

Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against 18F-labeled d-fructose-based probe 6-[18F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.

Design, Synthesis, and Biological Evaluation of Novel 7H-[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine Inhibitors as Antitumor Agents.

A series of novel anticancer hydrazinotriazolothiadiazine-based derivatives were designed based on the structure-activity relationship of the previously reported anticancer triazolothiadiazines. These derivatives were synthesized and biologically screened against full NCI-60 cancer cell lines revealing compound 5l with a potential antiproliferative effect. 5l was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 ß (GSK-3ß) with IC50 equal to 0.883 µM and 14-fold selectivity over CDK2. Also, 5l increased active caspase-3 levels, induced cell cycle arrest at the G2-M phase, and increased the percentage of Annexin V-fluorescein isothiocyanate-positive apoptotic cells in PC-3 prostate cancer-treated cells. Molecular docking and dynamics were performed to predict the binding mode of 5l in the GSK-3ß ATP binding site. 5l can be utilized as a starting scaffold for developing potential GSK-3ß inhibitors.

Synthesis of some tropane-based compounds targeting colon cancer.

Background: In continuation of a previous work concerned with the anticancer activity of some 8-alkyl-2,4-bisarylidene-8-nortropan-3-ones, this work focuses on further modification to the tropane/pyran fused skeleton aiming to obtain improved anticancer activity. Methodology: Reaction of 8-alkyl-2,4-bisarylidene-8-nortropan-3-ones 1-21 with malononitrile under basic conditions afforded tropane/pyran hybrids 22-40 and tropane/pyridine hybrids 41, 42. X-ray crystallography for compounds 22 and 41 as representative examples confirmed their structures. They were tested for their anticancer activity in the HCT116 cell line. Results: Compounds 26 and 33 were the most active compounds with IC50 values of 3.39 and 0.01 µM against HCT116. Moreover, they revealed cyclin-dependent kinase-2 (CDK2) inhibition with IC50 = 104.91 and 49.13 nM, respectively. Furthermore, molecular docking of compounds 26 and 33 in the active site of CDK2 confirmed the obtained results. Conclusion: Tropane/pyran scaffold can be considered as a promising core for anticancer agents acting as CDK2 inhibitors.

Synthesis, antiproliferative activity and 2D-QSAR study of some 8-alkyl-2,4-bisbenzylidene-3-nortropinones.

AIM: Colon cancer is the third leading cause of death worldwide; therefore, there is a need for an effective therapy with lower side effects. METHODS: A series of 8-alkyl-2,4-bisbenzylidene-3-nortropinones 3 & 14-39 was prepared via Claisen-Schmidt condensation of 8-alkyl-3-nortropinones 11-13 with different aromatic aldehydes. The target compounds were screened for their antiproliferative activity. RESULTS: Most of the prepared compounds showed promising antiproliferative activity against many of 60 National Cancer Institute cell lines at 10 µM. Furthermore, 8-ethyl-2,4-bis(3,4-dimethoxybenzylidene)-8-nortropin-3-one 29 and its 3,4,5-trimethoxy analog 30 were the most active compounds against HCT116 cell line with IC50 values 0.01 and 0.46 µM, respectively. Using CODESSA-Pro software, a significant 2D-quantitative structure-activity relationship (QSAR) model was obtained. CONCLUSION: The 8-Alkyl-2,4-bisbenzylidene-8-azabicyclo[3.2.1]octan-3-one represents an interesting core for further structural optimization to obtain more promising hits.

Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules.

Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 µM) than that of the reference drug (doxorubicin, IC50 = 9.8 µM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 µM and 6.7 µM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.