Haribabu Ankati

Synthesis of Optically Pure 2-Azido-1-arylethanols with Isolated Enzymes and Conversion to Triazole-Containing β-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.

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

Neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, and Huntingtons 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 Huntingtons 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 Aβ toxicity, suggesting that protection against HCA and Aβ depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.

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 Novel Pyridobenzimidazoles Bonded to Indoleorbenzo[b]thio-phenestructures

Pyridobenzimidazoles 6a-iwere synthesized in very good to excellent yields (81-96%) by the condensation of substituted N-phenyl-o-phenylenediamines 4a-d with indole/benzo(b)thiophene-3-aldehydes 5a-t inmethoxyethanol under reflux conditions. The diamines 4a-d were prepared byfirst treating 2-chloro-3-nitropyridine (1)with suitably substituted anilines 2a-d then reducing the resulting3-nitro-N-phenylpyridin-2-amines 3a-d with tin(II)chloride using microwave heating in each case.

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.

Synthesis of 3- Benzylidene, 5-Substituted 3-Benzylidene, 3- Hetarylmethylene and 5-Substituted Hetarylmethylene Derivatives of Indolin- 2-ones

A wide variety of titled compounds, several of which have neuro-protecting properties has been prepared in yields ranging between 70 to 90%. The compounds were identified by 1 HNMR, 13 C NMR, 1D and 2D NOE analysis, and HRMS. An investigation of the effect of certain 5-substitutuents on the E to Z ratios in DMSO-d6 was carried out. The 5- nitro and 5-acetyl substituents were not isomerized, whereas the 5-fluoro, 5-chloro and 5-bromo underwent significant isomerization. In the former cases resonance interaction of the lone pair electrons of NH group of the indolin-2-one with the 5-nitro or 5-acetyl of the indolin-2-one prevents rotation of the benzylidene C=C bond whereas in the case of the latter 5-halo substituent, the lone pair electrons on the NH group interacts with the benzylidene C=C bond giving rise to anionic C-C - bond in which rotation about this bond can occur.

Synthesis of 2-Benzylidene and 2-Hetarylmethyl Derivatives of 2H-1,4-Benzoxazin-3-(4H)-ones as Neuroprotecting Agents

A wide variety of the title compounds were synthesized by conventional and microwave methods in which the main step is a condensation of an aldehyde with a 1,4-benzoxazin-3-(4H)-one. In all cases, the Z diasteromers were the major products. Of particular importance is the synthesis of novel 2-(3,5-dibromo-4-hydroxy) and 2-(4-acetoxy-3,5-dibromobenzylidene derivatives of 2H-1,4-benzoxazin-3-(4H)-ones, four of which were shown in a previous publication to exhibit potent neuroprotecting properties. The yields of titled compounds ranged from 25 to 83%.

(E)-5-Chloro-3-(2,6-dichloro­benzyl­idene)­indolin-2-one

There are two independent molecules of the title compound, C15H8Cl3NO, in the asymmetric unit. Both form inversion dimers via pairs of hydrazide–carbonyl N—H⋯O hydrogen bonds.

MICROWAVE-ASSISTED SYNTHESIS OF 3-METHYLISOTHIAZOLO[5,4-b]PYRIDINE AND VARIOUS 2-AMINO DERIVATIVES OF THIENO[2,3-b]PYRIDINE AND 1-(2-AMINOPYRIDIN-3-YL)ETHANONE

Various 2-amino derivatives of thieno[2,3-b]pyridin-2-amine (3a-g) were prepared in fair to good yields (30-76%) by subjecting 1-(2-chloropyridin-3-yl)ethanone (1) and appropriate primary amine (2a-g) to microwave heating at 90-120 °C for 15-20 min in the presence of elemental sulfur, NaOAc, and DMF. Lower yields (4-15%) of the secondary 2-amino derivatives of 1-(pyridin-3-yl)ethanone product (4a-g) were also obtained. However, when the microwave-assisted reactions were carried out on primary (2b-h) and secondary amines (2i-o) in the absence of elemental S at 100-200 °C for 15-20 min, the respective secondary 2-amines (4b-h) and tertiary 2-amines (4i-o) of 1-(pyridin-3-yl)ethanones were obtained in good to excellent yields (61-98%). Finally, when 1 subjected to microwave heating at 120 °C for 15 min in the presence of elemental sulfur, NH 4 Cl, NaOAc, and DMF, 3-methylisothiazolo[5,4-b]pyridine (5) was obtained in 79% yield. Possible mechanisms for the formation of compounds 3-5 are presented.

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

The title compound, C13H9FN2O, a potential neuroprotective agent, consists of an indolinone and a pyrrolyl unit [dihedral angle between the ring planes = 4.9 (1)°]. An intramolecular 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.