The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)­ethyl)-4-phenyl-1H-imidazol-5-yl)­phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure–activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)­pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.

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Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the ( Z )-2-benzylidene-6-hydroxybenzofuran-3(2 H )-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were ( Z )-2-((2-((1-ethyl-5-methoxy-1 H -indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile ( 5a ) and ( Z )-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2 H )-one ( 5b ) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC 50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.

New substituted 4-chloromethylcoumarins that were used as alkylating agents to modify cytisine were synthesized by Pechmann condensation.A series of 4-(12-cytisylmethyl)coumarins containing pharmacophores of the natural heterocycles coumarin and cytisine in a single molecule was prepared. The alkylation gave the best results if diisopropylethylamine was used as the base.In continuation of research on the modification of natural compounds, we decided to investigate the alkaloid (-)-cytisine from seeds of Cytisus laburnum L. and Thermopsis lanceolata R.Br. Cytisine is of great interest to many researchers because of its effect on the ganglionic nervous system and its use in medicine as a respiratory analeptic [1]. A variety of N-alkyl derivatives of cytisine has been synthesized [2-4], among which are compounds with analgesic, antihypertensive, and inotropic activities [3]. According to the patent literature [5], N-methyl derivatives also possess anti-inflammatory and hypoglycemic activities.Therefore, the search for methods of modifying cytisine is very timely. The combination into one molecule of two natural heterocyclic compounds can lead to the production of compounds with new types of physiological activity. Considering this, we selected substituted 4-chloromethylcoumarins, which are used to synthesize compounds with antimicrobial [6] and antiinflammatory [7] properties, as alkylating agents for modifying cytisine. 1, 12: R 1 = R 2 = R 4 = H, R 3 = CH 3 ; 2, 13: R 1 = R 3 = R 4 = H, R 2 = CH 3 ; 3, 14: R 1 = R 2 = H, R 3 = OH, R 4 = CH 3 4, 15: R 1 = R 2 = H, R 3 = R 4 = CH 3 ; 5, 16: R 1 = R 4 = H, R 2 = Cl, R 3 = CH 3 ; 6, 17: R 1 = R 4 = H, R 2 = OH, R 3 = CH 3 7, 18: R 1 = R 3 = CH 3 , R 2 = R 4 = H; 8,19: R 1 = R 3 = H, R 2 = R 4 = CH 3 ; 9, 20: R 1 = R 3 = R 4 = H, R 3 = CH 2 CH 3 10, 21: R 1 = R 4 = H, R 2 R 3 = CH 2 CH 2 CH 2 ; 11, 22: R 1 = R 4 = H, R 2 = R 3 = CH 3 Several synthetic methods for 4-chloromethylcoumarins are known. These include the reaction of phenols with 4-chloroacetoacetic ester in H 2 SO 4 (Pechmann condensation) [8-10], chlorination of coumarin-4-acetic acid in AcOH [11], and reaction of 4-hydroxymethylcoumarins with PCl 5 in benzene [8,12]. Based on the literature, we selected the Pechmann condensation for preparing 4-chloromethylcoumarins 1-11.