New Imadazopyrazines with CDK9 Inhibitory Activity as Anticancer and Antiviral: Synthesis, In Silico, and In Vitro Evaluation Approaches.

This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound 1d exhibited the highest CDK9 inhibition with an IC50 of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC50 values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound 4a showed the highest antiviral potency with an IC50 of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that 4a displayed a good affinity to proteases. The result of the docking studies of 4a with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.

Synthesis and Biological Evaluation of Imadazo[1,2-a]pyrazines as Anticancer and Antiviral Agents through Inhibition of CDK9 and Human Coronavirus.

In this work, novel imadazo[1,2-a]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-a]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC50 of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC50s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-a]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC50 of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.

The integrative bioinformatics approaches to predict the xanthohumol as anti-breast cancer molecule: Targeting cancer cells signaling PI3K and AKT kinase pathway.

Background: Breast cancer is the most common type of cancer in women, and vast research is being conducted throughout the world for the treatment of this malignancy by natural products using various computational approaches. Xanthohumol, a prenylated flavonoid, is known for its anticancer activity; however, the mechanism behind its action is still in the preliminary stage. Methods: The current study aimed to analyze the efficacy of xanthohumol compared to the currently available anticancer drugs targeting phosphoinositide-3-kinase (PI3K), serine/threonine kinase (AKT) receptors, and human epidermal growth factor receptor 2 (HER2) for breast cancer treatment through in silico analysis. Results: The result revealed that the target compound showed significant binding affinity to targets within the PI3K, AKT, and HER2 signaling pathways with a binding energy of -7.5, -7.9, and -7.9 kcal/mol, respectively. Further prediction studies were then made concerning this compound's absorption, distribution, metabolism, and excretion (ADME) as well as drug-likeness properties, resulting in its oral bioavailability with only a single violation of Lipinski's rule of five. Conclusions: The finding revealed the ability of xanthohumol to bind with multiple cancer cell signaling molecules including PI3K, AKT kinase, and HER2. The current novel study opened the door to advancing research into the management and treatment of breast cancer.

Evaluation of the Potential of National Sharing of a Unified Progress Test Among Colleges of Pharmacy in the Kingdom of Saudi Arabia.

BACKGROUND: With the expansion in pharmacy education in Saudi Arabia, there is a pressing need to maintain quality assurance in pharmacy programs using several tools. The progress test is a formative assessment tool that can serve to provide information to all stakeholders. This study evaluated the results of a unified progress test that was shared among 15 colleges of pharmacy. METHODS: The progress test was composed of 100 MCQs where 30% of which cover basic pharmaceutical sciences and 70% cover pharmacy practice. The questions were collected from all the 15 colleges of pharmacy participated in the test. The test was administered online to all undergraduate students in the professional programs of these colleges. RESULTS: The overall attendance rate was 80% from the total number of students enrolled in the participating colleges. Mean scores of students in basic pharmaceutical sciences were relatively higher than in pharmacy practice. The assessment results of the students in the unified program learning outcomes among colleges were higher in the domains of knowledge and skills compared to competence domain. There was a significant increment in the mean scores of the students as they progress through the years of the professional program. No correlation was found between the mean scores in the test and the cumulative grade point average (cGPA) of all students regardless of their level. CONCLUSION: The results indicated growth and maintenance of the gained knowledge and skills by the students as they progress through the years of the professional program with consistency in the results among the participating colleges. Sharing a unified test was effective as a valuable tool for the colleges of pharmacy for the purposes of benchmarking and improving the curricula. In addition, it could serve to evaluate learning of students and harmonize knowledge and skills gained by students at different institutions.