A new series of pyrimidine-5-carbonitrile derivatives has been designed as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). These compounds were synthesized and evaluated for their in vitro cytotoxic activities against a panel of four human tumor cell lines, namely colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), breast cancer (MCF-7), and non-small cell lung cancer cells (A549). Five of the synthesized compounds, 11_a, 11_b, 12_b, 15_b and 16_a, were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib. In particular, compound 11_b showed 4.5- to 8.4-fold erlotinib activity against HCT-116, HepG-2, MCF-7, and A549 cells with IC₅₀ values of 3.37, 3.04, 4.14, and 2.4 μM respectively. Moreover, the most cytotoxic compounds that showed promising IC₅₀ values against the four cancer cell lines were subjected to further investigation for their kinase inhibitory activities against EGFR^WT and EGFR^T790M using homogeneous time resolved fluorescence (HTRF) assay. Compound 11_b was also found to be the most active compound against both EGFR^WT and mutant EGFR^T790M, exhibiting IC₅₀ values of 0.09 and 4.03 μM, respectively. The cell cycle and apoptosis analyses revealed that compound 11_b can arrest the cell cycle at the G2/M phase and induce significant apoptotic effects in HCT-116, HepG-2, and MCF-7 cells. Additionally, compound 11_b upregulated the level of caspase-3 by 6.5 fold in HepG-2 when compared with the control. Finally, molecular docking studies were carried out to examine the binding mode of the synthesized compounds against the proposed targets; EGFR^WT and EGFR^T790M. Additional in silico ADMET studies were performed to explore drug-likeness properties.

Zygophyllum coccineum, an edible halophytic plant, is part of the traditional medicine chest in the Mediterranean region for symptomatic relief of diabetes, hypertension, wound healing, burns, infections, and rheumatoid arthritis pain. The current study aimed to characterize Z. coccineum phytoconstituents, and the evaluations of the anti-microbial-biofilm, and anti-cancers bioactivities of the plant’s mother liquor, i.e., aqueous-ethanolic extract, and its subsequent fractions. The in silico receptors interaction feasibility of Z. coccineum major constituents with Staph GyraseB, and human topoisomerase-IIβ (h-TOP-IIβ) were conducted to confirm the plant’s anti-microbial and anti-cancer biological activities. Thirty-eight secondary metabolites of flavonoids, stilbene, phenolic acids, alkaloids, and coumarin classes identified by LC-ESI-TOF-MS spectrometric analysis, and tiliroside (kaempferol-3-O-(6′′′′-p-coumaroyl)-glucoside, 19.8%), zygophyloside-F (12.78%), zygophyloside-G (9.67%), and isorhamnetin-3-O-glucoside (4.75%) were identified as the major constituents. A superior biofilm obliteration activity established the minimum biofilm eradication concentration (MBEC) for the chloroform fraction at 3.9–15.63 µg/mL, as compared to the positive controls (15.63–31.25 µg/mL) against all the microbial strains that produced the biofilm under study, except the Aspergillus fumigatus. The aqueous-ethanolic extract showed cytotoxic effects with IC₅₀ values at 3.47, 3.19, and 2.27 µg/mL against MCF-7, HCT-116, and HepG2 cell-lines, respectively, together with the inhibition of h-TOP-IIβ with IC₅₀ value at 45.05 ng/mL in comparison to its standard referral inhibitor (staurosporine, IC₅₀, 135.33 ng/mL). This conclusively established the anti-cancer activity of the aqueous-ethanolic extract that also validated by in silico receptor-binding predicted energy levels and receptor-site docking feasibility of the major constituents of the plant’s extract. The study helped to authenticate some of the traditional phytomedicinal properties of the anti-infectious nature of the plant.