- Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents
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The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.
- Thamban Chandrika, Nishad,Shrestha, Sanjib K.,Ngo, Huy X.,Tsodikov, Oleg V.,Howard, Kaitlind C.,Garneau-Tsodikova, Sylvie
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p. 158 - 173
(2018/02/10)
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- Rhodium-Catalyzed Bis-Hydroaminomethylation of Linear Aliphatic Alkenes with Piperazine
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An efficient protocol was developed to prepare a series of dialkylpiperazines via Rh-catalyzed bis-hydroaminomethylation of linear aliphatic alkenes with piperazine. The well-known Rh/Biphephos catalytic system was applied, yielding the desired dialkylpiperazines within six tandem catalytic steps, already at low catalyst loadings of 0.1 mol%. For the model alkene 1-octene, good yields and linearities of 80% and 77:23, respectively, were achieved under optimized conditions. Influences on the catalytic system regarding n/iso ratio, possible side reactions and the reaction path are discussed on the basis of yield vs. time plots and parameter optimization. With the developed general protocol, other linear, functionalized and branched substrates were effectively transformed to the corresponding linear N,N-disubstituted piperazines.
- Seidensticker, Thomas,Vosberg, Jonas M.,Ostrowski, Karoline A.,Vorholt, Andreas J.
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p. 610 - 621
(2016/02/27)
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- ALKYL-SUBSTITUTED COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
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Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, optionally substituted, unsaturated 5-or 6-membered, homo-or heterocyclic rings; X 1 is selected from CH 2, O, NH, S, C. dbd.O, CH--OH, CH--N(C 1-4 alkyl) 2, C=CHCl, C=CHCN, N--C 1-4 alkyl, N-acetyl, SO 2 and SO;X 2---is selected from N=, CH 2--, CH= and C(O);Y is selected from N and CH;R. sub.1 represents C 1-4 alkyl;n is 0, 1 or 2;q is 1 or 2; andZ is C 5-10 alkyl optionally substituted with OH, halo, C 1-4 alkyl or C 1-4 alkoxy and optionally incorporating a heteroatom selected from O, N and S;and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which D4 receptor stimulation is implicated, such as schizophrenia, is also described.
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- ALKYL-SUBSTITUTED COMPOUNDS HAVING DOPAMINE RECEPTOR AFFINITY
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Described herein are D4 receptor-selective compounds of the general formula: STR1 wherein: A and B are independently selected, optionally substituted, saturated or unsaturated 5-or 6-membered, homo-or heterocyclic rings;X 1 is selected from CH 2, O, NH, S, C=O, CH--OH, CH--N(C 1-4 alkyl) 2, C=CHCl, C= CHCN, N--C 1-4 alkyl, N-acetyl, SO 2 and SO;X. sub.2 . . . is selected from N=, CH 2--, CH=, C(O)--, O--, and S--;Y is selected from N and CH; R. sub.1 represents C 1-4 alkyl;n is 0, 1 or 2;q is 1 or 2; andZ is C 5-10 alkyl optionally substituted with OH, halo, C 1-4 alkyl or C 1-4 alkoxy and optionally incorporating a heteroatom selected from O, N and S; and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described.
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- Trifluorothymidine derivatives, process for producing the same and anti-cancer agent containing the same
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Novel trifluorothymidine derivatives having anti-cancer activities are disclosed. The trifluorothymidine derivatives of the present invention are represented by the formula [I]: (wherein R1 represents hydrogen atom or C1 - C4 alkyl group; R2 represents hydrogen atom, C1 - C30 saturated or unsaturated alkyl-substituted carbonyl group, alkyl-substituted benzoyl group, C1 - C4 alkyloxycarbonyl group; dimethylaminoethyloxycarbonyl group, C1 - C4 alkyloxymethyl group, butoxyethoxyacetyl group, benzyl group, C1 - C20 alkyl-substituted silyl group, silyl group substituted with C1 - C10 alkyl group and/or phenyl group, C1 - C30 cyclic or chain alkyl-substituted carbamoyl group, diethylaminopropylcarbamoyl group, N-alkylpiperazinylacetyl group, N-alkylprolyl group, valyl group, trityl group, alkyl-substituted phosphoryl group or propargyl group; R3 represents hydrogen atom, C1 - C4alkyl group, benzyl group, benzoyl group, C1 - C4 alkyloxy-substituted benzoyl group, furoyl group, C1 - C4 alkyloxymethyl group or C1 - C4 alkyl-substituted carbonyl group).
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