Due to the genetic similarity between SARS-CoV-2 and SARS-CoV, the present work endeavored to derive a balanced Quantitative Structure−Activity Relationship (QSAR) model, molecular docking, and molecular dynamics (MD) simulation studies to identify novel molecules having inhibitory potential against the main protease (Mpro) of SARS-CoV-2. The QSAR analysis developed on multivariate GA–MLR (Genetic Algorithm–Multilinear Regression) model with acceptable statistical performance (R² = 0.898, Q²loo = 0.859, etc.). QSAR analysis attributed the good correlation with different types of atoms like non-ring Carbons and Nitrogens, amide Nitrogen, sp²-hybridized Carbons, etc. Thus, the QSAR model has a good balance of qualitative and quantitative requirements (balanced QSAR model) and satisfies the Organisation for Economic Co-operation and Development (OECD) guidelines. After that, a QSAR-based virtual screening of 26,467 food compounds and 360 heterocyclic variants of molecule 1 (benzotriazole–indole hybrid molecule) helped to identify promising hits. Furthermore, the molecular docking and molecular dynamics (MD) simulations of Mpro with molecule 1 recognized the structural motifs with significant stability. Molecular docking and QSAR provided consensus and complementary results. The validated analyses are capable of optimizing a drug/lead candidate for better inhibitory activity against the main protease of SARS-CoV-2.

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC₅₀ values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC₅₀ values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.

The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff’s bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.

Initiation of colorectal carcinogenesis may be induced by chromosomal instability caused by oxidative stress or indirectly by bacterial infections. Moreover, proliferating tumor cells are characterized by reprogrammed glucose metabolism, which is associated with upregulation of PDK1 and LDHA enzymes. In the present study, some 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in addition to Fe₃O₄ and Fe₃O₄/SiO₂ nanoparticles (NPs) supported with a new Schiff base were synthesized for biological evaluation as PDK1 and LDHA inhibitors as well as antibacterial, antioxidant, and cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer (CRC). The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC₅₀ values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. NPs12a,b and compound 1b exhibited the strongest antioxidant properties with IC₅₀ values (μg/mL) of 80.0, 95.0, and 110.0 μg/mL, respectively, compared to 54.0 μg/mL, which was produced by butylated hydroxy toluene. Moreover, NPs12a and carbamate derivative 3b exhibited significant cytotoxic activities with IC₅₀ values (μg/mL) of 57.15 and 81.50 (LoVo cells) and 60.35 and 71.00 (HCT-116 cells). Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.

Colorectal carcinogenesis is a complex process, which is linked to dysregulation of human secretory phospholipases A2 (hsPLA2-G-IIA, hsPLA2-G-V, and hsPLA2-G-X), proteases (cathepsin-B, collagenase, thrombin, elastase, and trypsin), carbohydrate hydrolyzing enzymes (α-amylase and α-glucosidase), and free radical generating enzyme (xanthine oxidoreductase (XOR)). Therefore, some new quinazolinones were synthesized and evaluated as inhibitors against this array of enzymes as well as cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer. Compounds 3g, 10, 8, 3c, and 1c exhibited promising cytotoxic effects with IC50 values ranging from 206.07 to 459.79 μM. Nine compounds showed promising enzymatic inhibitory effects, 3b, 3d, 3f, 5, 1a, and 12 (α-amylase), 8 (thrombin, elastase and trypsin), 10 (hsPLA2-G-IIA and hsPLA2-G-V), and 3f (α-glucosidase and XOR). Therefore, the most active inhibitors, were subjected to validated molecular docking studies to identify their affinities and binding modes. The expected physicochemical and pharmacokinetic features of the active candidates, 1a, 1c, 3b, 3c, 3d, 3f, 3g, 5, 8, 10, and 12 were predicted using bioavailability radar charts and boiled-egg graphical representations along with the Lipinski rule of five filter. Collectively, these studies showed the significance of derivatives 1c, 3b, 3c, 3d, 8, 10, and 12 as lead scaffolds for further optimization to develop enzymes inhibitors and anti-colorectal agents.

A simple and selective high-performance liquid chromatographic (HPLC) method for the determination of ciprofloxacin in serum has been developed and evaluated. Serum protein was precipitated with acetonitrile. The drug and the internal standard (quinine) were eluated from a 10 μm U-Bondapack C-18 cartridge at ambient temperature with a mobile phase consisting of acetonitrile: 0.1 m sodium dihydrogen phosphate (20:80%, v/v) adjusted to pH 3.9 with phosphoric acid, and at a flow rate of 2.5 ml/min. The effluent was monitored on a fluorescence detector using an excitation and emission wavelength of 280 and 455 nm, respective. Each analysis required no longer than 6 min. Quantification was achieved by the measurement of the peak-height ratio and the limit of quantification for ciprofloxacin in serum is 25 ng/ml. The intraday coefficient of variation (CV) ranged from 0.4 to 5.8%, and interday CV from 4.6 to 8.8% at three different concentrations. Relative recovery ranged from 98 to 100.2% at three different concentrations. Preliminary stability tests show that ciprofloxacin is stable for at least 3 weeks in serum after freezing.