Harnessing molecular hybridization approach to discover novel quinoline EGFR-TK inhibitors for cancer treatment.

Aim: Using molecular hybridization approach, novel 18 quinoline derivatives (6a-11) were designed and synthesized as EGFR-TK inhibitors. Materials & methods: The antiproliferative activity was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines. Moreover, the most active quinoline derivatives (6d and 8b) were further investigated for their potential as EGFR-TK inhibitors. In addition, cell cycle analysis and apoptosis induction activity were conducted. Results: A considerable cytotoxic activity was attained with IC50 values spanning from 0.06 to 1.12 µM. Besides, the quinoline derivatives 6d and 8b displayed potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08 µM, respectively. Conclusion: Accordingly, the afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.

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Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kß kinases.

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kß inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kß inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Design, synthesis and antiproliferative screening of newly synthesized coumarin-acrylamide hybrids as potential cytotoxic and apoptosis inducing agents.

On the basis of the observed biological activity of coumarin and acrylamide derivatives, a new set of coumarin-acrylamide-CA-4 hybrids was designed and synthesized. These compounds were investigated for their cytotoxic activity against cancerous human liver cell line HepG2 cells using 5-fluorouracil (5-FU) as a reference drug. Compound 6e had promising antiproliferative activity with an IC50 value of 1.88 µM against HepG2 cells compared to 5-FU (IC50 = 7.18 µM). The results of ß-tubulin polymerization inhibition indicated that coumarin-acrylamide derivative 6e was the most active, with a percentage inhibition value of 84.34% compared to podophyllotoxin (88.19% ß-tubulin inhibition). Moreover, the active coumarin-acrylamide molecule 6e exerted cell cycle cession at the G2/M phase stage of HepG2 cells. In addition, this compound produced a 15.24-fold increase in apoptotic cell induction compared to no-treatment control. These observations were supported by histopathological studies of liver sections. The conducted docking studies illustrated that 6e is perfectly positioned within the tubulin colchicine binding site, indicating a significant interaction that may underlie its potent tubulin inhibitory activity. The main objective of the study was to develop new potent anticancer compounds that might be further optimized to prevent the progression of cancer disease.

Guilingji capsule for Alzheimer's disease: secondary analysis of a randomized non-inferiority controlled trial.

OBJECTIVE: To investigate the effectiveness and safety of Guilingji capsule (, GLJC) in treatment of Alzheimer's disease (AD) patients with kidney-marrow deficiency pattern (KMDP) compared with gingko extract tablets. METHODS: This is a secondary analysis of a large-scale multicenter randomized non-inferiority clinical trial. A total of 120 AD patients with KMDP were enrolled in this study. The participants were randomly categorized into two groups: (a) GLJC group ( = 60) and (b) gingko group ( = 60). The GLJC group was treated with GLJC and gingko extract mimetic tablets, whereas the gingko group received gingko extract tablets and mimetic GLJC. The data on the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Activities of Daily Living (ADL), and Chinese Medicine Symptom Scale (CM-SS) was evaluated at 0, 12, and 24 weeks of treatment. The serum levels of acetylcholine (Ach), acetylcholinesterase (AchE), B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) in the participants were measured before and after 24 weeks of treatment. The safety was based on the incidence of adverse events. RESULTS: Both interventions significantly increased the MMSE scores of the participants and decreased their ADAS-Cog, ADL, and CM-SS scores ( < 0.01). Compared with the gingko group, the GLJC group had a higher effective rate of improvement in the symptoms of "amnesia" and "dull expression and slow thinking" at the 12th week and 24th week ( < 0.05, < 0.01). In the GLJC group, serum Bcl-2 levels were significantly increased at the 24th week ( < 0.05). Serum Bax and AchE levels of the two groups were significantly decreased at the 24th week ( < 0.01). No treatment-related adverse events were reported in the two groups. CONCLUSIONS: GLJC is equivalent to the gingko extract tablets in terms of improving cognitive function and the quality of life in AD patients with KMDP and has good clinical efficacy and safety. When it comes to improving TCM symptoms and anti-aging, GLJC is even more advantageous.

Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors via upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathways and downregulating NF-κB in LPS induced macrophages.

Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 µM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kß, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1ß, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

Three series of curcumin-based analogs, incorporating other heterocycles, were synthesised with the intention of exploring their potential as anti-inflammatory agents.Subsequently, these analogs underwent biological assessment in macrophages induced by LPS to determine their anti-inflammatory efficacy.Among the fourteen coumarin derivatives synthesised, the most potent anti-inflammatory activity was observed in the coumarin compound 14b, which featured a 3,4-dimethoxybenzylidene hydrazinyl moiety, with an EC₅₀ value of 5.32 µM.The anti-inflammatory effects of compound 14b were achieved through the modulation of signalling pathways such as AKT/mTOR and Nrf2/HO-1, as well as the downregulation of NF-kß, resulting in decreased production of pro-inflammatory cytokines including IL-6, IL-1ß, and TNF-α.Molecular modelling studies revealed that both compound 14b and dexamethasone bind to the same binding site on TNF-α, suggesting that 14b has the potential to serve as a therapeutic agent for TNF-α and other pro-inflammatory cytokines that surpasses that of dexamethasone.

Design and Synthesis of 2-(4-Bromophenyl)Quinoline-4-Carbohydrazide Derivatives via Molecular Hybridization as Novel Microbial DNA-Gyrase Inhibitors.

Microbial DNA gyrase is regarded as an outstanding microbial target. Hence, 15 new quinoline derivatives (5-14) were designed and synthesized. The antimicrobial activity of the afforded compounds was pursued via in vitro approaches. The investigated compounds displayed eligible MIC values, particularly against G-positive Staphylococcus aureus species. Consequently, an S. aureus DNA gyrase supercoiling assay was performed, using ciprofloxacin as a reference control. Obviously, compounds 6b and 10 unveiled IC50 values of 33.64 and 8.45 µM, respectively. Alongside, ciprofloxacin exhibited an IC50 value of 3.80 µM. Furthermore, a significant docking binding score was encountered by compound 6b (-7.73 kcal/mol), surpassing ciprofloxacin (-7.29 kcal/mol). Additionally, both compounds 6b and 10 revealed high GIT absorption without passing the blood brain barrier. Finally, the conducted structure-activity relationship study assured the usefulness of the hydrazine moiety as a molecular hybrid for activity either in cyclic or opened form.

Synthesis and Anticancer Evaluation of Some New 3-Benzyl-4,8-Dimethylbenzopyrone Derivatives.

INTRODUCTION: New benzopyrone derivatives such as Schiff's like compounds, acetohydrazides or substituted with oxadiazole or pyrazole heterocycles were synthesized from parent acid hydrazide compound 3. METHODS AND MATERIALS: Structures of the synthesized compounds were elucidated using IR, NMR and mass spectroscopy. All the synthesized derivatives were selected by National Cancer Institute (NCI), Bethesda, and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay. RESULTS AND CONCLUSION: Schiffs like compounds 4a, b and c were found to have good growth inhibition % against numerous cell lines that belong mainly to leukemia, non-small cell lung, CNS and breast Cancer subpanels.

Management of rainwater harvesting and its impact on the health of people in the Middle East: case study from Yatta town, Palestine.

Water-related diseases are a primary problem in Palestine where many residents revert to harvested rainwater as their primary water source due to water shortages within the area. From an environmental engineering perspective, it is already well known that certain situations (e.g., cross contamination) reduce drinking water quality and ultimately cause diseases in a population. In this study, we investigated the social practices and situations that may lead to lower disease occurrence. Towards this goal, we surveyed 382 residents in Yatta to collect data on the water-related diseases that they experienced and the specific situations that might affect the disease occurrences such as the residents' practices (i) for maintaining a high quality of cistern water, (ii) for maintaining the environment around the cistern, and (iii) for managing the wastewater. In addition, we measured the physicochemical and microbiological parameters in cisterns to support the qualitative survey data. The measured parameters, including turbidity, salinity, free available chlorine, total Coliforms, and fecal Coliforms, were above Palestinian Standard Institution (PSI) and World Health Organization (WHO) guideline levels, suggesting a potential infectious hazard. The poor quality of the water was also observed by residents based on change in taste and by visually noting floating impurities, turbidity, and green coloration. Survey results showed that observations of the poor quality in cisterns and surrounding environment had statistically significant correlation with most of the water-related diseases. Additionally, frequently emptying the septic tank contributes to improving the observed water qualities. Therefore, residents should be encouraged to continue to observe the water quality in the cistern, improve the surrounding environment of cistern, and empty their septic tank frequently, to keep the water diseases away from their households.

Synthesis, docking and in vitro anticancer evaluation of some new benzopyrone derivatives.

The synthesis of some new 3-alkyl-7-hydroxy-4-methyl-8-substituted-1H-benzopyran-2-ones, 6-alkyl-7-methyl-2-substituted amino-5H-pyrano[6,5-e] benzoxazol-5-ones, 7-alkyl-8-methyl-3-substituted-2,6-dihydropyrano[6,5-f]-1,4-benzoxazin-6-ones, 7,8-disubstituted-3-ethyl-4-methyl-1H-benzopyran-2-ones and 3-alkyl-4-methyl-7-substituted-1H-benzopyran-2-ones were described. Fourteen compounds were selected by National Cancer Institute (NCI), Bethesda, and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay by a single dose test. Compounds 4a, 18a, 18b and 23a were found to be broad-spectrum antitumors showing effectiveness toward numerous cell lines that belong to different tumor subpanels. Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the binding site of the casein kinase II (CK2) enzyme which is involved in cell survival and proliferation through a number of downstream effectors.