Synthesis of 1,2,3-triazole-substituted coumarins and also 1,2,3-triazolyl or 1,2,3-triazolylalk-1-inyl-linked coumarin-2,3-furocoumarin hybrids was performed by employing the cross-coupling and copper catalyzed azide-alkyne cycloaddition reaction approaches. The synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Bacillius subtilis, Actinomyces viscosus and Escherichia coli bacterial strains. Coumarin-benzoic acid hybrids 4с, 42с and 3-((4-acetylamino-3-(methoxycarbonyl)phenyl)ethynyl)coumarin (29) showed promising activity against S. aureus strains, and the 1,2,3-triazolyloct-1-inyl linked coumarin-2,3-furocoumarin hybrid 37c was endowed with high selectivity against B. subtilis and E. coli species. The in vitro antibacterial activity of 4с, 29, 37c and 42с can potentially be compared with that of a number of modern antibiotic drugs used in the clinic, suggesting promising prospects for further research. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations and the obtained results are quite promising.
The moderate toxicity of compounds 20 and 22 (LD50 valuewas more than 3000 mg/kg) encouraged the further design of therapeutically relevant analogues based on these novel type of coumarin hybrids.
A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6-8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9-11. The methoxy-, hydroxyl-and formyl-substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD 50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937.
Palladium-catalyzed Heck reaction of oreoselone trifluoromethanesulfonate with various terminal alkenes (methyl acrylate, styrene, vinylpyridines, N-vinylpyrrole, and N-vinyl-1,2,4-triazole) led to the formation of the corresponding (E)-3-vinyl-7H-furo[3,2-g]chromen-7-ones. The yield was found to depend on the catalytic system and initial olefin structure. * For communication V, see [1].Interest in linearly fused furocoumarins is determined by important role of these compounds in vital activity of plants and animals, as well as by their strong and diverse biological activity. Such furocoumarins as psoralens exert various biological effects on eukaryotic cells (inhibit cell division in the G-2 and S-phases and induce apoptosis) and are used in therapy of skin diseases (PUVA therapy) [2, 3]. Studies on structure-activity relationships showed that introduction of additional substituents into the 3-position of the furocoumarin system reduces phototoxic effect (skin phototoxicity) of fused psoralens [3]. 3-Aryl-substituted furocoumarins were found to possess cardiotropic activity [4]. A number of metabolites of the dihydrofurocoumarin series containing a substituent on C 3 were isolated and found to exhibit vasodilator activity [5].The goal of the present work was to synthesize new furocoumarin derivatives having various substituents on C 3 from an accessible plant coumarin, peucedanin (I) [6]. Treatment of peucedanin (I) with hydrochloric acid in methanol quantitatively afforded oreoselone (II) which reacted with trifluoromethanesulfonic anhydride in the presence of a base to give 2-isopropyl-7-oxo-7H-furo[3,2-g]chromen-3-yl trifluoromethanesulfonate (III) in up to 72% yield (Scheme 1). The structure of oreoselone trifluoromethanesulfonate III was proved by X-ray analysis.Furocoumarins having functionalized olefinic fragments in the furan ring were synthesized by the Heck reaction [7] of trifluoromethanesulfonate III with various terminal alkenes. Initially, the reaction of III with methyl acrylate (IV) was carried out using Pd(OAc) 2 /(o-Tol) 3 P (2/8 mol %) as catalytic system, which was shown to be effective in the cross coupling of functionally substituted bromides with acrylates; triethylamine was used as base, and dimethylformamide, as solvent [8]; however, 3-(3-methoxy-3-oxoprop-1-en-1-yl) derivative V was obtained in a poor yield. It was more effective to use as ligand tris(tert-butyl)phos-
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