Ten new xanthone derivatives have been designed and synthesized for their potential antibacterial activity. All compounds have been screened against Staphylococcus epidermidis strains ATCC 12228 and clinical K/12/8915. The highest antibacterial activity was observed for compound 3: 5-chloro-2-((4-(2-hydroxyethyl)piperazin-1-yl) methyl)-9H-xanthen-9-one dihydrochloride, exhibiting MIC of 0.8 µg/ml against ATCC 12228 strain, compared to linezolid (0.8 µg/ml), ciprofloxacin (0.2 µg/ml) or trimethoprim and sulfamethoxazole (0.8 µg/ml). For the most active compound 3, genotoxicity assay with use of Salmonella enterica serovar Typhimurium revealed safety in terms of genotoxicity at concentration 75 µg/ml and antibacterial activity against Salmonella at all higher concentrations. A final in silico prediction of skin metabolism of compound 3 seems promising, indicating stability of the xanthone moiety in the metabolism process.
Forty new aminoalkanol derivatives with potential anticonvulsant activity were designed and synthesized. In vivo studies (mice, intraperitoneal administration) showed anticonvulsant activity (maximal electroshock seizure test, MES test) of nineteen compounds, (ED50 values and protective indices PI ranging 22.62–78.30 mg/kg b.w. and 1.78–4.25, respectively). Compounds 30 (R,S‐1‐((2‐(2‐(2‐chloro‐5‐methylphenoxy)ethoxy)ethyl)amino)propan‐2‐ol), 31 (R,S‐2‐((2‐(2‐(2‐chloro‐5‐methylphenoxy)ethoxy)ethyl)amino)propan‐1‐ol) and 33 (S enantiomer of 31) showed relatively low ED50 values (26.45–34.26 mg/kg b.w.) accompanied by PI indexes above 3. Compounds 30 and 31 were investigated in terms of mechanism of action (5‐HT1A receptors binding assay and in silico database screening) and safety against gastrointestinal flora (both compounds proved safe). An integral part of the study was also a comprehensive structure‐activity relationship, including current and previously obtained results for aminoalkanol derivatives.
A series of 10 aminoalkanol derivatives of 5‐chloro‐2‐ or 5‐chloro‐4‐methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5‐chloro‐2‐([4‐hydroxypiperidin‐1‐yl]methyl)‐9H‐xanthen‐9‐one hydrochloride. Compounds: 1–3, 7 and 10 revealed ED50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma‐1 (σ1) and sigma‐2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU‐Chromotest) compounds 1, 7 and 10 proved safe at dose 150–300 μg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (tmax = 5–30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood–brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration.
Xanthone derivatives constitute an interesting and widely studied group of compounds, both in terms of the activity of naturally occurring plant ingredients and as a scaffold with high biological activity potential for medicinal chemists. This group of compounds has already been the subject of reviews. However, our purpose was to prepare a publication for medicinal chemists to have a clear overview of anticancer activity, particularly in central nervous system cancer glioblastoma, and to be able to compare their new achievements to the anticancer activity that has already been found in this group. An integral part of the work is a tabular summary of the literature results of antineoplastic activity (e.g., IC50 values) for xanthone derivatives in various types of in vitro viability assays.
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