Design, synthesis and activity against Staphylococcus epidermidis of 5‐chloro‐2‐ or 5‐chloro‐4‐methyl‐9H‐xanthen‐9‐one and some of its derivatives

Abstract

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.

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

“…The first reaction was the Ullmann's condensation of 2,3‐dichlorobenzoic acid with p ‐cresol for compounds 1–6 and o ‐cresol for compounds 7–10 , respectively. In the second step, obtained products of condensation underwent the reaction of cyclization, performed in 98% H 2 SO 4 in 100°C for 3 h, in order to obtain 5‐chloro‐2‐methyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) (for 1 – 6 ) or 5‐chloro‐4‐methyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) (for 7 – 10 ). In the next step, obtained intermediate products underwent the reaction of free‐radical bromination of the methyl group with N ‐bromosuccinimide (NBS), performed in CCl 4 as a solvent, in the presence of benzoyl peroxide as a catalyst and under light, resulting in 5‐chloro‐2‐bromomethyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) or 5‐chloro‐4‐bromomethyl‐9 H ‐xanthen‐9‐one,(Mazur et al, 2020) respectively.…”

“…In the second step, obtained products of condensation underwent the reaction of cyclization, performed in 98% H 2 SO 4 in 100°C for 3 h, in order to obtain 5‐chloro‐2‐methyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) (for 1 – 6 ) or 5‐chloro‐4‐methyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) (for 7 – 10 ). In the next step, obtained intermediate products underwent the reaction of free‐radical bromination of the methyl group with N ‐bromosuccinimide (NBS), performed in CCl 4 as a solvent, in the presence of benzoyl peroxide as a catalyst and under light, resulting in 5‐chloro‐2‐bromomethyl‐9 H ‐xanthen‐9‐one (Mazur et al, 2020) or 5‐chloro‐4‐bromomethyl‐9 H ‐xanthen‐9‐one,(Mazur et al, 2020) respectively. The final step was aminolysis of the appropriate bromo‐substituted derivative by means of commercially available aminoalkanols: 2‐(methylamino)ethan‐1‐ol for 1 and 7 , D,L ‐ trans ‐piperidin‐3‐ol for 2 , piperidin‐4‐ol for 3 and 10 , D,L ‐ trans ‐2‐aminocyclohexan‐1‐ol for 4 , trans ‐4‐aminocyclohexan‐1‐ol for 5 , R,S ‐azepan‐4‐ol for 6 , R,S ‐2‐aminopropan‐1‐ol for 8 and R,S ‐2‐aminobutan‐1‐ol for 9 .…”

“…All semi‐products are known compounds characterized in the literature (5‐chloro‐2‐methyl‐9 H ‐xanthen‐9‐one,(Eckstein & Marona, 1980) 2‐(bromomethyl)‐5‐chloro‐9 H ‐xanthen‐9‐one,(Eckstein & Marona, 1980) 5‐chloro‐4‐methyl‐9 H ‐xanthen‐9‐one,(Rewcastle et al, 1989) 4‐(bromomethyl)‐5‐chloro‐9 H ‐xanthen‐9‐one (Rewcastle et al, 1989)) and were synthesized via previously published procedures (Mazur et al, 2020). The amines were produced by heating the appropriate bromide and aminoalkanol in toluene (reflux) in the presence of K 2 CO 3(anh) .…”

“…The aim of the current research was to investigate the potential anticonvulsant activity of the 5‐substituted derivatives. Our former research on structure‐anticonvulsant activity in a group of phenoxyalkylaminoalkanol derivatives showed advantages of incorporation of aminoalkanol moieties with two or at most four carbons between hydroxyl and amino groups as well as cyclic aminoalkanols (either piperidinol or cyclohexanolamine) (Klesiewicz et al, 2018; Kubacka et al, 2020; Mazur et al, 2020; Pańczyk et al, 2020; Pytka, Zmudzka, et al, 2016). Therefore, we decided to include the aminoalkanols which had been used so far in the most potent compounds, such as in reference structures I – III (Figure 1).…”

“…Research conducted by our group focuses mainly on neurological activity of aminoalkanol and piperazine derivatives coupled to aryl moieties, with potential anticonvulsant, antidepressant, (Pytka et al, 2015;Pytka, Kazek, et al, 2016) anxiolytic, (Pytka, Zmudzka, et al, 2016) analgesic, (Pańczyk et al, 2020) antibacterial (Mazur et al, 2020) and antifungal (Klesiewicz et al, 2018) activities. Among research conducted within aminoalkanol derivatives, the main area of our interest is their potential anticonvulsant activity.…”