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.

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, 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.

Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules.

A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of ß-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit ß-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.