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In order to exploit the 430-cavity in the active sitesof neuraminidases,22 zanamivir analogs with C-1 and C-4 modification were synthesized,and their inhibitory activities against both group-1 (H5N1, H1N1)and group-2 neuraminidases (H3N2) were determined. Compound 9fexerts the most potency, with IC50value of0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, whichis similar to that of zanamivir (H3N2 IC50= 0.0014 μM,H5N1 IC50= 0.012 μM, H1N1 IC50= 0.001μM). Pharmacokinetic studies of compound 9finrats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose).Molecular modeling provided information about the binding model betweenthe new inhibitors and neuraminidase, with the elongated groups atthe C-1-position being projected toward the 430-loop region. Thisstudy may represent a novel starting point for the future developmentof improved antiflu agents. [ABSTRACT FROM AUTHOR]

RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ∼200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1–3). Compound 1was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a–v, 13a–h, and 14a–j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC50values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14gand 14 h)demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents. [ABSTRACT FROM AUTHOR]

An efficient, economical, and convenient method was developed for the preparation of 2-substituted (N, O, C) benzothiazoles from N'-substituted-N-(2-halophenyl)thioureas, O'-substituted-N-(2-halophenyl) carbamothioates, or N-(2-halophenyl) thioamides via a base-promoted cyclization in dioxane without any transition metal. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated. High yields were obtained, and a variety of functional groups were tolerated under these conditions. Transition-metal-free, mild reactive conditions, wide application scope, and shorter reaction times make this method superior to the reported methods for the synthesis of 2-substituted benzothiazoles and suitable for combinatorial format.

A regioselective hydroamidation of 2-(1-alkynyl)phenylacetamides with Au(PPh(3))Cl/AgSbF(6) as the catalyst proceeded by a 7-endo-dig pathway to afford 3-benzazepinones. This method accommodates a broad range of alkyl and aryl alkynyl substitutes in moderate to high yields (63-91%). Moreover, unexpectedly, we also discovered a gold-mediated transformation from 2-(1-alkynyl)phenylacetamides to 5-bromo-3-benzazepinones, and AuBr(3) was found to not only play an activation role but also act as a reactant in the reaction for the first time.

A novel and efficient process for the synthesis of alpha-sialyl spirohydantoin analogues via one-pot sequential reaction involving various carbodiimides and peracetylated Neu5Ac is reported. BF(3) x Et(2)O mediating intramolecular N-sialylation with excellent alpha-selectivity is first demonstrated.

We have developed a simple method for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido[2,1-a]quinazolinones from 2-amino benzoic acids and 2-amino benzamides via a gold(I)-catalyzed tandem coupling/cyclization process. The tricyclic or polycyclic molecular architectures were constructed in one pot with the formation of three new bonds.

An efficient protocol was developed for the synthesis of fused heterocyclic multiring compounds pyrrolo[1,2-a]quinolin-1(2H)-ones via a AuBr(3)/AgSbF(6)-catalyzed cascade transformation. Significantly, the strategy affords a straightforward and efficient approach to construction of tricyclic lactam molecular architectures in which two new C-C bonds and one new C-N bond are formed in a one-pot synthetic operation from simple starting materials. Moreover, a broad spectrum of substrates can participate in the process effectively to produce the desired products in good yields and with excellent regio- and chemoselectivities.

We developed an efficient and convenient method for preparing N-substituted 2H-1,4-benzoxazin-3-(4H)-ones from 2-halophenols via a nucleophilic substitution with 2-chloroacetamides followed by a CuI-catalyzed coupling cyclization. A broad spectrum of substrates can be effectively employed to afford the desired products in good yields. Since this method involves simple reaction conditions, a short reaction time, and a broad substrate scope, it is particularly attractive for the efficient preparation of biologically and medicinally interesting molecules.

An efficient approach to the dehydrative sialylation of various substrates with C-4-aminated sialyl-hemiketal donors by using the reagent combination of diphenyl sulfoxide and triflic anhydride is reported. By using a C-4-hindered non-nucleophilic amine auxiliary, excellent yields and high alpha-stereoselectivities were obtained for coupling with a wide range of primary and secondary acceptors.