Asphodelus tenuifolius Cav. (A. tenuifolius) is a medicinal plant with a long history of traditional use to treat ailments. In this study, total phenolic and flavonoid content evaluation using LC-ESI/MS analysis and various biological activities (antioxidant, antibacterial, antifungal, antiviral and cytotoxicity) of organic extracts from the aerial parts of A. tenuifolius were analyzed. ADME tools were used to predict the potential of the identified compounds from the most potent extract as specific drugs. As shown, LC-ESI/MS results of chloroformic extract allowed the tentative identification of 12 compounds. Chloroformic extract was rich in polyphenols and flavonoids and exhibited the highest antioxidant activity given by DPPH (IC₅₀ = 25 µg/mL) as compared to the BHT standard (11.5 µg/mL) and β-carotene bleaching assays (IC₅₀ = 95.692 µg/mL). Antibacterial activity results showed that chloroformic extract has a highest activity against Gram-positive and -negative bacteria, especially against Salmonella Typhimurium DT104 (IZ = 19.3 mm, MIC = 18.75 mg/mL, MBC = 37.5 mg/mL). The MBC/MIC ratio was evaluated to interpret the activity that was bacteriostatic rather than bactericidal. Conversely, weaker antifungal activity was registered, and no antiviral activity was observed for all extracts against Herpes Simplex Virus type 2 and Coxsakievirus B-3 viruses. Cytotoxic activity on VERO cell line results revealed that butanol extract was not toxic, with CC₅₀ value of 1430 µg/mL, while chloroformic extract showed moderate cytotoxicity. Additionally, in silico studies performed proved promising pharmacokinetic and drug-likeness properties of the main compounds from the chloroformic extract. Taken together, this work highlights the potent bioactivity and acceptable drug-likeness of this plant, which supports its further preclinical development.

In recent decades, molecular hybridization has proven to be an efficient tool for obtaining new synthetic molecules to treat different diseases. Based on the core idea of covalently combining at least two pharmacophore fragments present in different drugs and/or bioactive molecules, the new hybrids have shown advantages when compared with the compounds of origin. Hybridization could be successfully applied to anticancer drug discovery, where efforts are underway to develop novel therapeutics which are safer and more effective than those currently in use. Molecules presenting naphthoquinone moieties are involved in redox processes and in other molecular mechanisms affecting cancer cells. Naphthoquinones have been shown to inhibit cancer cell growth and are considered privileged structures and useful templates in the design of hybrids. The present work aims at summarizing the current knowledge on antitumor hybrids built using 1,4- and 1,2-naphthoquinone (present in natural compounds as lawsone, napabucasin, plumbagin, lapachol, α-lapachone, and β -lapachone), and the related quinolone- and isoquinolinedione scaffolds reported in the literature up to 2021. In detail, the design and synthetic approaches adopted to produce the reported compounds are highlighted, the structural fragments considered in hybridization and their biological activities are described, and the structure–activity relationships and the computational analyses applied are underlined.

Polyketide 13 [=2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2- propylchroman-4-one] and three related known compounds 7, 9 and 11 were obtained and structurally characterized from Streptomyces sundarbansensis strain, an endophytic actinomycete isolated from the Algerian marine brown algae Fucus sp. Compound 13 was obtained as the major metabolite from optimized culture conditions, by using Agar state fermentation. Due to tautomeric equilibrium, 13 in CD₃OD solution was able to incorporate five deuterium atoms, as deduced by NMR and ESI-MS/MS analysis. The 2-hydroxy-γ-pyrone form was established for these metabolites based on the comparison of their experimental IR spectra with the DFT calculated ones, for both the corresponding 4-hydroxy-α-pyrone and 2-hydroxy-γ-pyrone forms. During antibacterial evaluation, compound 13 stood out as the most active of the series, showing a selective activity against the gram positive pathogenic methicillin-resistant S. aureus (MRSA, MIC = 6 μΜ), with a bacteriostatic effect.

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI₅₀ than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI₅₀ < 10 nM).

The increasing number of Alzheimer’s disease (AD) cases requires the development of new improved drug candidates, possessing the ability of more efficient treatment as well as less unwanted side effects. Cholinesterase enzymes are highly associated with the development of AD and thus represent important druggable targets. Therefore, we have synthesized eight organoruthenium(II) chlorido complexes 1a–h with pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione, a), bearing either pyrithione a, its methyl (b-e) or bicyclic aromatic analogues (f–h) and tested them for their inhibition towards electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE). The experimental results have shown that the novel complex 1g with the ligand 1-hydroxyquinoline-2-(1H)-thione (g) improves the inhibition towards eeAChE (IC₅₀ = 4.9 μM) and even more potently towards hsBuChE (IC₅₀ = 0.2 μM) in comparison with the referenced 1a. Moreover, computational studies on Torpedo californica AChE have supported the experimental outcomes for 1g, possessing the lowest energy value among all tested complexes and have also predicted several interactions of 1g with the target protein. Consequently, we have shown that the aromatic ring extension of the ligand a, though only at the appropriate position, is a viable strategy to enhance the activity against cholinesterases.

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1–3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1–3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.