Ali Altharawi

The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, 5d, showed broad-spectrum anti-cancer activities against all tested cell lines (IC50 = 1.94–7.1 µM) in comparison to doxorubicin (IC50 = 3.18–5.57 µM). Interestingly, compound 5d exhibited lower toxicity in the normal WI-38 cells (IC50 = 40.85 µM) than doxorubicin (IC50 = 6.72 µM), indicating a good safety profile. Additionally, the potential of compound 5d as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound 5d exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound 5d was the least active against CDK2 (2.097 ± 0.126 µM) when compared to the positive control roscovitine (0.32 ± 0.019 µM). The apoptotic activity investigation in HepG2 cells demonstrated that compound 5d arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound 5d showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors.

Since active pharmaceutical ingredients (APIs) are directly related to human health, monitoring and quantifying them in the environment is a crucial and challenging issue. Using capillary-zone electrophoresis (CZE), four frequently used fluoroquinolones (FQs), ciprofloxacin, sparfloxacin, moxifloxacin, and gatifloxacin, were efficiently isolated and measured in pharmaceutical industrial wastewater. Solid-phase extraction (SPE) was developed and used as an efficient sample pretreatment procedure. The capillary electrophoretic procedure’s various parameters were tuned to produce the optimal separation pattern for the drugs under consideration. All of the drugs under study were quantified in a concentration range of 0.5 to 50 µg/mL. After full assay validation in compliance with ICH-Q2B criteria, real wastewater samples were subjected to effective SPE, and the proposed assay was successfully used to determine the examined FQs in real wastewater samples.

Diabetic polyneuropathy is characterized by structural abnormalities, oxidative stress, and neuroinflammation. The current study aimed to determine the antinociceptive effects of isoeugenol and eugenol and their combinations in neuropathic pain resulting from streptozotocin (STZ)-induced diabetes and neuroinflammation. Female SD rats were categorized into normal control, diabetic control, and treatment groups. On the 28th day and 45th day, behavioral studies (allodynia and hyperalgesia) were performed to analyze the development and protection of diabetic polyneuropathy. The levels of inflammatory and oxidative mediators, such as superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), catalase, reduced glutathione, and thiobarbituric acid reactive substances (TBARS), were estimated. In addition, the level of nerve growth factor (NGF) was estimated at the end of the study in different groups. The anti-NGF treatment decreased its upregulation in the dorsal root ganglion significantly. The results showed that isoeugenol, eugenol, and their combination have therapeutic potential against neuronal and oxidative damage induced by diabetes. In particular, both compounds significantly affected behavioral function in treated rats and showed neuroprotection against diabetic neuropathy, and their combination had synergistic effects.