Exploring new quinazolin-4(3H)-one derivatives as CDK2 inhibitors: Design, synthesis, and anticancer evaluation.

In the present work, five series of new 2,3-disubstituted quinazolin-4(3H)-ones 4a-c, 5a-d, 6a-g, 7a,b, and 9a-c were designed, synthesized, and screened in vitro for their cytotoxic activity against 60 cancer cell lines by the National Cancer Institute, USA. Five candidates 4c, 6a, 6b, 6d, and 6g revealed promising cytotoxicity with significant percentage growth inhibition in the range of 81.98%-96.45% against the central nervous system (CNS) (SNB-19), melanoma (MDA-MB-435), and non-small cell lung cancer (HOP-62) cell lines. The in vitro cytotoxic half maximal inhibitory concentration (IC50 ) values for the most active compounds 4c, 6a, 6b, 6d, and 6g against the most sensitive cell lines were evaluated. Additionally, screening their cyclin-dependent kinase 2 (CDK2) inhibitory activity was performed. Ortho-chloro-benzylideneamino derivative 6b emerged as the most potent compound with IC50 = 0.67 µM compared to Roscovitine (IC50 = 0.64 µM). The most active candidates arrested the cell cycle at G1, S phases, or both, leading to cell death and inducing apoptosis against CNS (SNB-19), melanoma (MDA-MB-435), and non-small cell lung cancer (HOP-62) cell lines. The molecular docking study verified the resulting outcomes for the most active candidates in the CDK2-binding pocket. Finally, physicochemical, and pharmacokinetic properties deduced that compounds 4c, 6a, 6b, 6d, and 6g displayed significant drug-likeness properties. According to the obtained results, the newly targeted compounds are regarded as promising scaffolds for the continued development of novel CDK2 inhibitors.

Design, synthesis, and mechanistic insight of novel imidazolones as potential EGFR inhibitors and apoptosis inducers.

As regards to the structural analysis and optimization of diverse potential EGFR inhibitors, two series of imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates were designed and constructed as potential EGFR suppressors. The cytotoxic effect of the prepared derivatives was assessed toward hepatic, breast, and prostate cancerous cells (Hep-G2, MCF-7, and PC-3). Three derivatives 3d, 3e, and 3f presented potent antiproliferative activity and selectivity against the examined tumor cells showing IC50 values at low micromolar levels. Hence, successive biological assays were applied to determine the probable mechanism of action of the new compounds. They exhibited significant EGFR suppression with an IC50 range of 0.137-0.507 µM. The most effective EGFR inhibitor 3f arrested the MCF-7 cell cycle at the S phase by inducing the apoptotic pathway that was confirmed via increasing the expression of Caspases 8, 9, and Bax, which are associated with Bcl-2 decline. Additionally, molecular docking displayed a distinctive interaction between 3f and EGFR binding pocket. Overall, this work introduces some novel imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates as potential cytotoxic and EGFR inhibitors that deserve further research in tumor therapy.

Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey.

Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value.

Exploring the cytotoxic effect and CDK-9 inhibition potential of novel sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles.

Regarding the structural analysis of variable effective CDK-9 suppressors, we record the design and synthesis of two new sets of sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles with expected anticancer and CDK-9 inhibiting activity. In the designed molecules, the pyrazole ring and sulphaguanidine fragment were linked together for the first time through diazo linkers as they are expected to enhance the anticancer activity and CDK degrading interaction. All derivatives have been estimated regarding their cytotoxic activity toward three tumor cells where CDK overexpression has been reported (HePG2, HCT-116, and MCF-7). Among these, four derivatives VII, VIII, X, and XIII exerted potent cytotoxicity against the chosen tumor cells presenting IC50 range equal to 2.86-25.89 µM. As well cytotoxicity on non-cancer cells and CDK-9 inhibition assay have been also assessed for these candidates to evaluate their selectivity indices and enzyme inhibition. The 3,5-diaminopyrazole-1-carboxamide derivative XIII showed a superior combined profile as cytotoxic with high selectivity toward cancer cells (HePG2: IC50 = 6.57 µM, SI = 13.31; HCT-116: IC50 = 9.54 µM, SI = 9.16; MCF-7: IC50 = 7.97 µM, SI = 10.97). Accordingly, it has been chosen to evaluate its probable mechanistic effect both in vitro (via enzyme assay, apoptosis induction, and cell cycle study) as well as in silico (through molecular docking). Overall, this work introduces the 3,5-diaminopyrazole-1-carboxamide derivative XIII as a potent CDK-9 inhibitor candidate (IC50 = 0.16 µM) that merits further investigations for the management of breast, colorectal, and hepatic malignancies.

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers.

Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 µM) and 4c (IC50 = 3.023 and 3.12 µM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 µM, respectively, while 3b showed IC50 = 0.126 and 6.96 µM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562.

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N-containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚß. Furthermore, in-vivo toxicity study indicated good safety profile for 7f. These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking.

Two series of novel morpholinopyrimidine derivatives were synthesized and screened for their in-vitro cytotoxic activity against 60 tumor cell line by the National Cancer Institute, USA. The in-vitro cytotoxic IC50 values for the most active compounds 6e, 6g, and 6l against the most sensitive cell line leukemia SR were estimated (IC50 = 0.76, 13.59, and 4.37 uM, respectively). To investigate their PI3K enzyme inhibition activity, the assay was done on Class IA (α, ß, & δ) isoforms. The IC50 values were very promising: compound [6e = 11.73 (α), 6.09 (ß), 11.18 (δ)], compound [6g = 8.43 (α), 15.84 (ß), 30.62 (δ)], and compound [6l = 13.98 (α), 7.22 (ß), 10.94 (δ)], compared to the reference compound LY294002 = 6.28 (α), 4.51 (ß), 4.60 (δ) uM, respectively. Moreover, cell cycle analysis and annexin V-FITC staining were done on Leukemia SR, there was arrest at G2/M phase and apoptosis was induced. Finally, docking study was performed to analyze the interactive mode of these derivatives in PI3Kα ATP-binding site. These outcomes proved that compounds 6e, 6g, and 6l are potential leads for further optimization as antileukemic agents.