Promising anticonvulsant and/or analgesic compounds among 5‐chloro‐2‐ or 5‐chloro‐4‐methyl derivatives of xanthone coupled to aminoalkanol moieties—Design, synthesis and pharmacological evaluation

Abstract 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)‐9 H ‐xanthen‐9‐one hydrochloride. Compounds: 1 – 3 , 7 and 10 revealed ED 50 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 ( t max = 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.