Synthesis of Functionalized 3-pyrrolo-[1,2,3-] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes.

A gold-catalyzed protocol to obtain functionalized 3-pyrrolo [1,2,3-] quinoxalines from suitable substituted indoles has been proposed. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism.

Synthesis of 3-substituted 2,3-dihydropyrazino[1,2-]indol-4(1)-ones by sequential reactions of 2-indolylmethyl acetates with α-amino acids.

The synthesis of 2,3-dihydropyrazino[1,2-]indol-4(1)-ones from the sequential reaction of amino acid methyl esters with readily available indole-2-ylmethyl acetates is described. The reaction proceeds under basic conditions of highly unstable and reactive 2-alkylideneindolenines followed by Michael-type addition of α-amino acid methyl esters/intramolecular cyclization.

Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.

Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound , a highly potent SHP2 allosteric inhibitor.

Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones.

The gold-catalyzed cyclization of 2,2-bis(3-arylprop-2-yn1-yl)malonic acid has been proposed as an efficient approach to substituted 3,8-dibenzyl-2,7-dioxaspiro[4.4]nonane-1,6-diones. The reaction proceeds smoothly in mild reaction conditions to give the desired products in quantitative yields in the presence of variously substituted starting materials.

Gametocyte-specific and all-blood-stage transmission-blocking chemotypes discovered from high throughput screening on Plasmodium falciparum gametocytes.

Blocking Plasmodium falciparum human-to-mosquito transmission is essential for malaria elimination, nonetheless drugs killing the pathogenic asexual stages are generally inactive on the parasite transmissible stages, the gametocytes. Due to technical and biological limitations in high throughput screening of non-proliferative stages, the search for gametocyte-killing molecules so far tested one tenth the number of compounds screened on asexual stages. Here we overcome these limitations and rapidly screened around 120,000 compounds, using not purified, bioluminescent mature gametocytes.

Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins.

Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P.

Amphiphile Meets Amphiphile: Beyond the Polar-Apolar Dualism in Ionic Liquid/Alcohol Mixtures.

The mesoscopic morphology of binary mixtures of ethylammonium nitrate (EAN), the protic ionic liquid par excellence, and methanol is explored using neutron/X-ray diffraction and computational techniques. Both compounds are amphiphilic and characterized by an extended hydrogen bonding network: surprisingly, though macroscopically homogeneous, these mixtures turn out to be mesoscopically highly heterogeneous. Our study reveals that even in methanol-rich mixtures, a wide distribution of clusters exists where EAN preserves its bulk, sponge-like morphology.

Regio- and diastereoselective synthesis and X-ray structure determination of (+)-2-deoxyoryzalexin S from (+)-podocarpic acid. Structural nonidentity with its nominal natural isolated enantiomer.

(+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures.

Heck reaction of arenediazonium salts with N,N-diprotected allylamines. Synthesis of cinnamylamines and indoles.

Novel palladium-catalyzed reactions of arenediazonium tetrafluoroborates with N,N-diprotected allylamines are presented. The reaction of arenediazonium tetrafluoroborates with N,N-(Boc)(2) allylamine allows for an easy approach to cinnamylamines whereas using 2-alkynyl-N-(allyl)trifluoroacetanilides and 2-iodo-N-(allyl)trifluoroacetanilide the reaction provides a useful tool for appending indole rings to aniline fragments.

2,3-Disubstituted indoles via palladium-catalyzed reaction of 2-alkynyltrifluoroacetanilides with arenediazonium tetrafluoroborates.

A novel palladium-catalyzed synthesis of free N-H 2,3-disubstituted indoles from arenediazonium tetrafluoroborates and 2-alkynyltrifluoroacetanilides is presented. The reaction tolerates a variety of useful substituents both in the starting alkyne and the arenediazonium salt, including bromo and chloro substituents, nitro, cyano, keto, ester, and ether groups, as well as ortho substituents such as methoxy and methyl groups.

pH variation as the switch for chiral recognition in a biomembrane model.

Chiral recognition was observed in a biomembrane model. Micellar aggregates formed by N-dodecyl-l-proline were, in fact, able to convert the racemic mixture of a biphenyl derivative into an enantiomerically enriched mixture. The extent of deracemization was established by HPLC on a chiral stationary phase and, in some conditions, resulted in the highest ever observed in these systems.