Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids.

Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer's disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC50 of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.

Design, synthesis and cholinesterase inhibitory activity of novel spiropyrrolidine tethered imidazole heterocyclic hybrids.

A small library of structurally fascinating spiropyrrolidine tethered imidazole heterocylic hybrids has been synthesized regioselectively in good yields employing [bmim]Br mediated 1,3-diplar cycloaddition strategy. The new class of azomethine ylide generated in situ from l-histidine and 11H-indeno[1,2-b]quinoxalin-11-one reacts with various substituted ß-nitrostyrenes affording the spiropyrrolidine tethered imidazole heterocylic hybrids. Compounds thus synthesized were assessed for their in vitro cholinesterase (ChEs) inhibitory activities, among them compounds possessing 4-methyl and 4-methoxy substituents on the aryl ring showed potent activities with IC50 values of 2.02 ±â€¯0.05 and 2.05 ±â€¯0.06 µM against AChE and 12.40 ±â€¯0.14 and 11.45 ±â€¯0.28 µM against BChE enzyme, respectively. In addition, the most active compounds were performed for their molecular docking simulation and the results revealed interesting binding templates to the active site channel of cholinesterase enzymes.

Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and their molecular docking simulation.

A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-b]quinoxaline heterocyclic hybrids 7a-j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomethine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and l-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a-j were evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 7h and 7j displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC50 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.

Highly functionalized 2-amino-4H-pyrans as potent cholinesterase inhibitors.

Novel highly functionalized 2-amino-4H-pyrans were achieved in excellent yields under simple grinding at ambient temperature and were assessed for their potential for treating Alzheimer's disease (AD). The 2-amino-4H-pyran bearing nitro groups on both the aryl rings showed the highest activity, with an IC50 of 1.98 ±â€¯0.09 µM against acetylcholinesterase (AChE) and 10.62 ±â€¯0.21 µM against butyrylcholinesterase (BChE), the inhibition mechanisms on AChE and BChE receptors were revealed by means of molecular docking simulations.

Spiropyrrolidine/spiroindolizino[6,7-b]indole heterocyclic hybrids: Stereoselective synthesis, cholinesterase inhibitory activity and their molecular docking study.

A regio and stereo- selective synthesis of hitherto unexplored hybrid heterocyclic system comprising spiropyrrolidine, indolizino[6,7-b]indole units in good to excellent yields, has been developed via three component 1,3-dipolar cycloaddition and concomitant trifluoroacetic acid catalyzed Pictet-Spengler cyclization with paraformaldehyde. The newly synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) and butylcholinesterase (BChE) enzyme inhibitory activities. Most of the synthesized compounds showed good inhibitory activity, among them, compounds 4d and 4g displayed highest potency against AChE (IC50 1.88 and 1.98 µM), and BChE (IC50 18.32 and 10.21 µM) enzyme, respectively than the standard drug, galanthamine. Molecular modeling simulation was investigated for the most active compounds 4d and 4g on AChE and BChE enzymes to disclose the binding and orientation of these molecules into active site of respective receptors.

Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug.

Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.

Heat shock protein 90 regulates development in Dictyostelium discoideum.

Cytosolic heat shock protein 90 (Hsp90) has been implicated in diverse biological processes such as protein folding, cell cycle control, signal transduction, development, and morphological evolution. Model systems available for studying Hsp90 function either allow ease of manipulation for biochemical studies or facilitate a phenomenological study of its role in influencing phenotype. In this work, we have explored the use of the cellular slime mold Dictyostelium discoideum to examine cellular functions of Hsp90 in relation to its multicellular development. In addition to cloning, purification, biochemical characterization, and examination of its crystal structure, our studies, using a pharmacological inhibitor of Hsp90, demonstrate a role for the cytoplasmic isoform (HspD) in D. discoideum development. Inhibition of HspD function using geldanamycin (GA) resulted in delayed aggregation and arrest of D. discoideum development at the 'mound' stage. Crystal structure of the amino-terminal domain of HspD showed a binding pocket similar to that described for yeast Hsp90. Fluorescence spectroscopy, as well as GA-coupled beads affinity pulldown, confirmed a specific interaction between HspD and GA. The results presented here provide an important insight into the function of HspD in D. discoideum development and emphasize the potential of the cellular slime mold to serve as an effective model for studying the many roles of Hsp90 at cellular and organismal levels.

Properties, potentials, and prospects of antifreeze proteins.

Antifreeze proteins (AFPs) are a group of proteins that protect organisms from deep freezing temperatures and are expressed in vertebrates, invertebrates, plants, bacteria, and fungi. The nuclear magnetic resonance, x-ray structure, and many spectroscopic studies with AFPs have been instrumental in determining the structure-function relationship. Mutational studies have indicated the importance of hydrophobic residues in ice binding. Various studies have pointed out that the mechanism of AFP action is through its adsorption on the ice surface, which leads to a curved surface, preventing further growth of ice by the "Kelvin effect." The AFPs have potential industrial, medical, and agricultural application in different fields, such as food technology, preservation of cell lines, organs, cryosurgery, and cold hardy transgenic plants and animals. However, the applications of AFPs are marred by high cost due to low yield. This review deals with the source and properties of AFPs from an angle of their application and their potential. The possibility of production using different molecular biological techniques, which will help increase the yield, is also dealt with.

Paraoxonase (PON1) activity in north west Indian Punjabis with coronary artery disease & type 2 diabetes mellitus.

BACKGROUND & OBJECTIVE: Paraoxonase (PON1), an arylesterase is associated with high density lipoprotein cholesterol (HDL-C). PON1 prevents low density lipo-protein cholesterol (LDL-C) from peroxidation and can also hydrolyze lipid peroxides, thereby providing protection against atherosclerosis and coronary artery disease (CAD). The incidence of CAD is known to be high in north western Indian Punjabis. Though many factors may play a role in its pathogenesis, low PON1 activity could be an independent risk factor. We carried out this study to determine PON1 activity in north-west Indian Punjabi patients with CAD with and without type 2 diabetes mellitus and compared with healthy individuals. METHODS: A total of 120 patients with angiographically proven CAD (57 with and 63 without type II diabetes mellitus) and 19 healthy controls were studied for plasma PON1 activity and lipid variables. Comparison was undertaken between CAD patients and healthy controls and between CAD patients with and without type II DM. RESULTS: Significantly lower plasma PON1 activity (P<0.05) along with lower HDL-C (P<0.001) and higher LDL-C (P<0.05) levels were observed in CAD patients as compared to healthy controls. On univariate analysis of variance after adjusting for age and sex, no significant difference could be observed between PON1 activity and age and sex. On discriminant analysis, no clear cut-off could be observed in PON1 activity between patients CAD and controls. Similarly between CAD with and without patients type II diabetes mellitus, there was no significant difference in PON1 activity and lipids. INTERPRETATION & CONCLUSION: The low plasma PON1 activity irrespective of being diabetic may be an independent risk factor for CAD in north-western Indian Punjabi population. Similar studies involving larger samples in different ethnic groups in India need to be done to find out the role of PON1 activity in CAD.