In this study, we reported the synthesis and biological characterization of a novel series of furan-carboxamide derivatives that were potent inhibitors of the influenza A H5N1 virus. The systematic structure–activity relationship (SAR) studies demonstrated that the 2,5-dimethyl-substituted heterocyclic moiety (furan or thiophene) had significant influence on the anti-influenza activity. In particular, 2,5-dimethyl-N-(2-((4-nitrobenzyl)thio)ethyl)-furan-3-carboxamide 1a showed the best activity against the H5N1 virus with an EC50 value of 1.25 μM. For the first time, the simple scaffold furan-carboxamide derivatives were identified as novel inhibitors of lethal H5N1 influenza A virus.

The tandem enantioselective Michael addition/cyclisation reaction of malononitrile and nitrovinylphenols was catalysed by a recoverable C3-symmetric cinchonine-squaramide organocatalyst 1a to afford the 2-amino-4H-chromene-3-carbonitrile derivatives in excellent yields (up to 95%) and with excellent enantioselectivities (up to 98% ee) under mild reaction conditions. Furthermore, this catalyst can be easily recovered four times without loss in activity or enantioselectivity.

A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In this article, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These OBHS–HDACi conjugates exhibited good ER binding affinity and excellent ERα antagonistic activity, and they also exhibited potent inhibitory activities against HDACs. Compared with the approved drug tamoxifen, these conjugates exhibited higher antitumor potency in ERα-positive breast cancer cells (MCF-7). Moreover, these conjugates not only showed selective anticancer activity that was more potent against MCF-7 cells than DU 145 (prostate cancer), but they had no toxicity toward normal cells.

An efficient organocatalytic asymmetric α-amination of 1,3-dicarbonyl and α-cyanoacetates compounds towards chiral α-amino acid precursors is reported. The enantioselective synthesis of these compounds was achieved with excellent yields and ee values (up to 99% yield and 99% ee) by treatment of 1,3-dicarbonyl compounds or α-cyanoacetates with azodicarboxylates in the presence of multiple hydrogen bond donor BINOL–quinine–squaramide organocatalyst 1a developed in our laboratory. The squaramide catalyst 1a can be recovered and reused for four cycles without loss of activity and enantioselectivity.

A set of BINOL–quinine–squaramides were synthesized, and then used as organocatalysts to promote the catalytic enantioselective Michael addition reaction of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with excellent yields and ees (up to 99% yield and 93% ee) at low catalyst loading (0.5 mol %).

A chiral BINOL–quinine–squaramide has been identified as the best catalyst for the asymmetric Michael addition of nitroalkenes to 1,3-dicarbonyl compounds. A series of chiral nitroalkanes were prepared with approximately >99% ee. Furthermore, the methodology was applied successfully to the synthesis of enantiomerically pure isoxazoles derivatives (>99% ee).Figure optionsDownload full-size imageDownload as PowerPoint slide

The C3-symmetric cinchonine-squaramide catalyzed asymmetric Michael addition of β-ketosulfones to nitroalkenes is presented. Subsequent transformation leads to chiral cyclic nitrones with excellent results (up to 85% yield and >99% ee). The catalyst can be recovered and reused for six cycles without losing activity and selectivity.

A series of chiral bifunctional squaramide multiple H-bond donor organocatalysts have been designed and synthesized by the rational assembly of chiral privileged scaffolds of indanol and cinchona alkaloids. In the presence of 1 mol % 1a, the asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to nitroolefins proceeded to provide the product in high yields (up to 92%) and with good to high ee values (up to 96%). The additional H-bond in this squaramide system plays a crucial role in enhancing the enantioselectivity.

The highly enantioselective Friedel–Crafts reaction of indoles with trifluoropyruvate catalyzed by a C3-symmetric cinchonine-squaramide is reported. A wide variety of trifluoromethylated indole derivatives were obtained in high yields and with excellent enantioselectivities (99% and up to >99% ee). Moreover the C3 catalyst can be easily recovered and was used five times.(S)-3,3,3-Trifluoro-2-hydroxy-2-(3-indolyl)-propionic acid ethyl esterC13H12F3NO3[α]D20=+18.5 (c 1.35, CHCl3), 93% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-fluoro-indol-3-yl)-propionic acid methyl esterC12H9F4NO3[α]D20=+12.1 (c 0.47, CHCl3), 99% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-chloro-indol-3-yl)-propionic acid methyl esterC12H9ClF3NO3[α]D20=+15.5 (c 0.87, CHCl3), 96% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-bromo-indol-3-yl)-propionic acid methyl esterC12H9BrF3NO3[α]D20=+1.8 (c 0.55, CHCl3), 92% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-fluoro-indol-3-yl)-propionic acid ethyl esterC13H11F4NO3[α]D20=+16.5 (c 1.04, CHCl3), 92% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(7-methyl-indol-3-yl)-propionic acid ethyl esterC14H14F3NO3[α]D20=+5.0 (c 0.54, CHCl3), 92% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-bromo-3-indolyl)-propionic acid ethyl esterC13H11BrF3NO3[α]D20=+14.8 (c 1.31, CHCl3), 86% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(3-indolyl)-propionic acid methyl esterC12H10F3NO3[α]D20=+19.5 (c 0.88, CHCl3), 90% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(4-methylformyl-3-indolyl)-propionic acid ethyl esterC15H14F3NO5[α]D20=+15.5 (c 0.87, CHCl3), 86% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-methyl formyl-indol-3-yl)-propionic acid methyl esterC14H12F3NO5[α]D20=+2.1 (c 0.33, CHCl3), 83% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(5-chloro-indol-3-yl)-propionic acid methyl esterC13H11ClF3NO3[α]D20=+12.5 (c 0.97, CHCl3), 80% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-3,3,3-Trifluoro-2-hydroxy-2-(7-methyl-indol-3-yl)-propionic acid methyl esterC13H112F3NO3[α]D20=+17.9 (c 0.53, CHCl3), 80% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)

A novel C3-symmetric prolinol-squaramide has been developed for the asymmetric reduction of ketones by borane. By using only 5 mol % catalyst 1a for the reaction, high yields and excellent enantioselectivities (up to 95% yield, 93% ee) were obtained. Moreover, 1a can be easily recovered by simple precipitation and re-used for four cycles without losing the selectivity.(S)-2-Bromo-1-(4-bromophenyl)-ethanolC8H8Br2O[α]D20=+27.6 (c 0.41, CHCl3), 88% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-2-Bromo-1-(4-methylphenyl)-ethanolC9H11BrO[α]D20=+34.7 (c 0.63, CHCl3), 85% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-2-Bromo-1-(4-nitro-phenyl)-ethanolC8H8BrNO3[α]D20=+34.5 (c 0.27, CHCl3), 50% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-1-Phenyl-propanolC9H12O[α]D20=+37.1 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-1-Phenyl-butanolC10H14O[α]D20=+30.5 (c 0.2, CHCl3), 70% ee.Source of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-2-Chloro-1-(4-fluoro-phenyl)-ethanolC8H8FClO[α]D20=+47.0 (c 0.21, CHCl3), 90% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-1,2,3,4-Tetrahydronaphthalen-1-olC12H12O[α]D20=-20.8 (c 0.25, CHCl3), 70% ee.Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-1-Phenyl-ethanolC8H10O[α]D20=+27.5 (c 0.2, CHCl3), 68% eeSource of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-2-Bromo-1-(4-fluoro-phenyl)-ethanolC8H8BrClO[α]D20=+27.5 (c 0.2, CHCl3), 84% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)2-Bromo-1-(3-bromophenyl)-ethanolC8H8Br2O[α]D20=+22.3 (c 0.95, CHCl3), 90% eeSource of chirality: asymmetric synthesis2-Bromo-1-(4-fluorophenyl)-ethanolC8H8BrFO[α]D20=+30.6 (c 0.64, CHCl3), 90% ee.Source of chirality: asymmetric synthesisTris(3-ethylamino-4-[2(S)-(hydroxyl-diphenyl-methyl)-pyrrolidin-1-yl]-cyclobut-3-ene-1,2-dione)amineC69H69N7O9[α]D23=+33.6 (c 3, DMSO)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-Bromo-1-phenyl-ethanolC8H9BrO[α]D23=+48.3 (c 1, CHCl3), 93% eeSource of chirality: asymmetric synthesisAbsolute configuration: (S)1,3,5-Tris(3-[2-(S)-(hydroxyl-diphenyl-methyl)-pyrrolidin-1-yl]-4-methylamino-cyclobut-3-ene-1,2-dione)benzeneC72H66N6O9[α]D23=+78.6 (c 3, DMSO)Source of chirality: l-prolineAbsolute configuration: (S)1,3,5-Tris(3-[2-(S)-(hydroxyl-diphenyl-methyl)-pyrrolidin-1-yl]-4-methylamino-cyclobut-3-ene-1,2-dione)-2,4,6-trismethylbenzeneC75H72N6O9[α]D23=+82.7 (c 3, DMSO)Source of chirality: l-prolineAbsolute configuration: (S)1,3,5-Tris(3-(1R,2S)-(2-hydroxy-indan-1-ylamino)-4-methylamino-cyclobut-3-ene-1,2-dione)benzeneC48H42N6O9[α]D23=+14.1 (c 1.7, DMSO)Source of chirality: (1R,2S)-indanolAbsolute configuration: (1R,2S)1,3,5-Tris(3-(1R,2S)-(2-hydroxy-1,2-diphenyl-ethylamino)-4-methylamino-cyclobut-3-ene-1,2-dione)benzeneC63H54N6O9[α]D23=-25.3 (c 3, DMSO)Source of chirality: (1R,2S)-2-hydroxy-1,2-diphenylethylamineAbsolute configuration: (1R,2S)

A strategy involving palladium-catalyzed cyclization of halo-phenyl hydrazones and aryl isocyanates provides a convenient approach to the synthesis of 1,3,4-benzotriazepines (4) or 1-arylamide-1H-indazoles (5) in good isolated yields. Microwave irradiation was found to afford high reaction efficiency, while the choice of halophenyl hydrazone had an effect on the pathway of the reaction.

A strategy involving palladium-catalyzed cyclization of halo-phenyl hydrazones and aryl isocyanates provides a convenient approach to the synthesis of 1,3,4-benzotriazepines (4) or 1-arylamide-1H-indazoles (5) in good isolated yields. Microwave irradiation was found to afford high reaction efficiency, while the choice of halophenyl hydrazone had an effect on the pathway of the reaction.