An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors.

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acidchlorides (5a-d) using HSnBu(3).

Microwave assisted synthesis of novel functionalized hydantoin derivatives and their conversion to 5-(Z) arylidene-4H-imidazoles.

2-(Alkyl-1-yl)-1H-imidazol-5(4H)-ones 5a-n were synthesized via nucleophilic substitution of the methylsulfanyl group of the corresponding 2-(methylthio)-1H-imidazol-5(4H)-ones 3a-c with suitably substituted secondary amines. The starting 2-thioxo- imidazolidin-4-ones 2a,2b were prepared by condensation of thiohydantoin and benzo[b]-thiophene-3-carbaldehyde or benzofuran-3-carbaldehyde under microwave irracdiation (MW) conditions. 2-Methylthio derivatives 3a-c were prepared by treatment of 2a-b with methyl iodide in the presence of aqueous sodium hydroxide.

Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease and conditions such as ischemic stroke affect millions of individuals annually and exert an enormous financial burden on society. A hallmark of these conditions is the abnormal loss of neurons. Currently, there are no effective strategies to prevent neuronal death in these pathologies. We report that several 2-arylidine and 2-hetarylidin derivatives of the 1,4-benzoxazines class of compounds are highly protective in tissue culture models of neurodegeneration. Results obtained using pharmcalogical inhibitors indicate that neuroprotection by these compounds does not involve the Raf-MEK-ERK or PI-3 kinase-Akt signaling pathways nor other survival-promoting molecules such as protein kinase A (PKA), calcium calmodulin kinase A (CaMK), and histone deacetylases (HDACs). We tested one of these compounds, (Z)-6-amino-2-(3',5'-dibromo-4'-hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one, designated as HSB-13, in the 3-nitropropionic acid (3-NP)-induced mouse model of Huntington's disease. HSB-13 reduced striatal degeneration and improved behavioral performance in mice administered with 3-NP. Furthermore, HSB-13 was protective in a Drosophila model of amyloid precursor protein (APP) toxicity. To understand how HSB-13 and other 1,4-benzoxazines protect neurons, we performed kinase profiling analyses. These analyses showed that HSB-13 inhibits GSK3, p38 MAPK, and cyclin-dependent kinases (CDKs). In comparison, another compound, called ASK-2a, that protects cerebellar granule neurons against low-potassium-induced death inhibits GSK3 and p38 MAPK but not CDKs. Despite its structural similarity to HSB-13, however, ASK-2a is incapable of protecting cortical neurons and HT22 cells against homocysteic acid (HCA)-induced or Abeta toxicity, suggesting that protection against HCA and Abeta depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.

Asymmetric synthesis of both antipodes of beta-hydroxy nitriles and beta-hydroxy carboxylic acids via enzymatic reduction or sequential reduction/hydrolysis.

Use of isolated carbonyl reductases in the reduction of aromatic beta-ketonitriles have completely eliminated the competing alpha-ethylation, which is often observed with whole cell biocatalysts. By choosing suitable recombinant carbonyl reductase, the reduction of beta-ketonitriles afforded (R)- or (S)-beta-hydroxy nitriles with excellent optical purity and yield. Subsequently, nitrilase-catalyzed hydrolysis of the obtained optically pure beta-hydroxy nitriles led to the corresponding beta-hydroxy carboxylic acids in high yields. More importantly, the sequential enzymatic reduction and hydrolysis could be carried out in "two-step-one-pot" fashion without the isolation of intermediates beta-hydroxy nitriles, lowering the cost and minimizing the environmental impact. This allows ready access to both antipodes of chiral beta-hydroxy nitriles and beta-hydroxy carboxylic acids of pharmaceutical importance with excellent optical purity.

(E)-5-Bromo-3-(2,6-dichloro-benzyl-idene)indolin-2-one.

The title compound, C(15)H(8)BrCl(2)NO, crystallizes with two independent mol-ecules in the asymmetric unit. The dihedral angles between the two aromatic rings are 62.74 (9) and 63.50 (6)° in the two independent molecules. In the crystal, the mol-ecules are connected by N-H⋯O hydrogen bonds, forming two centrosymmetric dimers.

(E)-3-(2,6-Dichloro-benzyl-idene)indolin-2-one.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(15)H(9)Cl(2)NO. The dihedral angles between the oxindolyl and dichloro-phenyl rings are essentially identical for the two independent mol-ecules [63.4 (1) and 63.2 (1)°]. Dimers linked by amide-carbonyl N-H⋯O hydrogen bonds are formed from each symmetry-independent mol-ecule and the respective symmetry equivalent created by inversion.

(Z)-3-[(E)-3-Phenyl-allyl-idene]indolin-2-one.

The title compound, C(17)H(13)NO, synthesized to be tested for neuroprotective activities, consists of an indoline and a phenyl-allyl-idene unit with a dihedral angle of 9.0 (1)° between the two ring systems. There are two independent mol-ecules in the asymmetric unit which are connected into a dimer by inter-molecular N-H⋯O hydrogen bonds.

Synthesis and structure-activity relationship studies of 3-substituted indolin-2-ones as effective neuroprotective agents.

Neurodegenerative diseases are a major health problem particularly among the elderly. Drugs to prevent or slow down the death of neurons are urgently needed but are currently unavailable. We previously reported that the c-Raf inhibitor, GW5074 {5-iodo-3-[(3',5'-dibromo-4'-hydroxyphenyl) methylene]-2-indolinone}, is protective in tissue culture and in vivo paradigms of neurodegeneration. However, at doses slightly higher than those at which it is protective, GW5074 displays toxicity when tested in neuronal cultures. We report herein the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of novel 3-substituted indolin-2-one compounds that are highly neuroprotective but lack the toxicity of GW5074. Of the 45 analogs tested in this study, compounds 7, 37, 39, and 45 were found to be the most potent neuroprotective and thus represent promising lead compounds for preclinical development for the treatment of neurodegenerative disorders.

Synthesis of optically pure 2-azido-1-arylethanols with isolated enzymes and conversion to triazole-containing beta-blocker analogues employing click chemistry.

Both antipodes of 2-azido-1-arylethanols were synthesized with excellent optical purity via enzymatic reduction of the corresponding alpha-azidoacetophenone derivatives catalyzed by a recombinant carbonyl reductase from Candida magnoliae ( CMCR) or an alcohol dehydrogenase from Saccharomyces cerevisiae ( Ymr226c). This provides an effective route to this class of important compounds in optically pure form. ( S)-2-Azido-1-( p-chlorophenyl)ethanols reacted with alkynes employing click chemistry to afford high yields of optically pure triazole-containing beta-adrenergic receptor blocker analogues with potential biological activity.

(E)-5-Chloro-3-(2,6-dichloro-benzyl-idene)-indolin-2-one.

There are two independent mol-ecules of the title compound, C(15)H(8)Cl(3)NO, in the asymmetric unit. Both form inversion dimers via pairs of hydrazide-carbonyl N-H⋯O hydrogen bonds.

(Z)-5-Fluoro-3-[(1H-pyrrol-2-yl)methyl-ene]indolin-2-one.

The title compound, C(13)H(9)FN(2)O, a potential neuroprotective agent, consists of an indolinone and a pyrrolyl unit [dihedral angle between the ring planes = 4.9 (1)°]. An intra-molecular hydrogen bond between the carbonyl O atom and the NH group of pyrrole correlates with the Z arrangement of the substituents at the C=C bond. In the crystal, inversion dimers occur, linked by pairs of N-H⋯O bonds.

Asymmetric reduction of beta-ketonitriles with a recombinant carbonyl reductase and enzymatic transformation to optically pure beta-hydroxy carboxylic acids.

Alpha-ethylation is concomitant with the reduction of aromatic beta-ketonitriles catalyzed by whole-cell biocatalysts. Use of isolated carbonyl reductase has completely eliminated this competing reaction. (R)-beta-Hydroxy nitriles were obtained via a reduction catalyzed by a recombinant carbonyl reductase with excellent optical purity and were further converted to (R)-beta-hydroxy carboxylic acids via a nitrilase-catalyzed hydrolysis. The present study allows ready access to both chiral beta-hydroxy nitriles and beta-hydroxy carboxylic acids of pharmaceutical importance.