Synthesis and in vivo analgesic and anti-inflammatory activity of some bi heterocyclic coumarin derivatives

Sets of coumarinyl ethers having chromone, benzofuranyl and 4-hydroxy coumarins (4, 5, 6) were prepared and tested for analgesic and antiinflammatory activity. The 4-(4'-acetyl-3'-hydroxy-phenoxymethyl)-coumarin 3 were synthesised by the reaction of 4-bromo methyl coumarin with 2, 4-dihydroxy acetophenones, were found to less active. Further compound 3 having the ortho hydroxy moiety was cyclised to chromones 4 and benzofurans 5 were found to enhance the analgesic and anti-inflammatory activity. The cyclisation to 4-hydroxy coumarin 6 was found to be reducing the anti-inflammatory and analgesic activity in this series. These newly synthesized compounds were found to produce less toxicity and less ulcerogenic effects.     

Human cardiac gap junctions: isolation, ultrastructure, and protein composition

Recent experiments from our laboratory have shown that the ultrastructure and protein composition of gap junctions isolated from rat ventricles are tissue specific, i.e., markedly different from gap junctions of liver and lens. The differences include a cytoplasmic surface component characteristic for cardiac gap junctions; this component can be visualized by two ultrastructural techniques: as a fuzzy layer in electron micrographs of thin-sectioned junctional pellets and as cytoplasmic surface particles in deep-etched freeze-fractured junctions. The component corresponds to a Mr 17,500 cytoplasmic surface domain of each of the six (Mr 47,000) rat heart gap junctional channel protein subunits that make up the gap junctional channel hexamer known as a connexon. The cytoplasmic surface component is localized at the carboxy-terminal of the subunit. Within the cytoplasmic surface component, rat cardiac gap junctions are cross-linked by disulfide linkages between subunits of the same connexon and between subunits of adjacent connexons. By contrast, the Mr 28,000 liver gap junctional subunit lacks a comparably large cytoplasmic surface component, cytoplasmic surface fuzz, cytoplasmic surface particles, and intra- and interconnexon disulfide linkages. Most of these unique characteristics of cardiac gap junctions were discovered in junctions isolated from rat ventricles. Unlike liver and lens gap junctions, cardiac gap junctions from humans, non-human primates, or other large mammals have not previously been isolated and characterized. Here we report the isolation of unproteolyzed gap junctions from the ventricle of a 24 year-old man with advanced cardiomyopathy whose heart was removed for replacement by a transplanted heart.(ABSTRACT TRUNCATED AT 250 WORDS)     

3D QSAR studies on 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

Malaria is currently one of the world’s most severe endemic diseases, responsible for majority of morbidity and mortality. A large number of drugs are available for its treatment; however, the development of resistance has become more widespread with most of the frontline drug therapies. Inhibitors of PfDHODH have proven efficacy for the treatment of malaria. 3D QSAR studies on some 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as PfDHODH inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The alignment strategy was used for these compounds by means of Distill function defined in SYBYL x 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with q ² of 0.669 and 0.727, cross-validated coefficient (r ² _cv) of 0.603 and 0.698, and conventional coefficients (r ²) of 0.971 and 0.966, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r ² _pred) of 0.799 and 0.815 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with better PfDHODH inhibitory activity.     

Computational studies on structurally diverse dipeptidyl peptidase IV inhibitors: an approach for new antidiabetic drug development

Dipeptidyl peptidase IV (DPP-IV) deactivates the natural hypoglycemic incretin hormone GLP-1. Inhibition of this enzyme restores glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, we suggested an in silico work flow for the identification of novel DPP-IV inhibitors. Ligand-based and structure-based pharmacophores were designed using HipHop program provided in catalyst and ligandScout 3.0 software, respectively. Generated models were validated by receiver operating characteristic curve analysis, Guner–Henry scoring method and by pharmacophore-based screening of marketed DPP-IV inhibitors. Ligand-based pharmacophore model A scored 0.8 AUC value, 0.865 Guner–Henry score and gave all marketed DPP-IV inhibitors as hits through screening while structure-based pharmacophore B scored 0.77 AUC value, 0.66 Guner–Henry score and gave four marketed DPP-IV inhibitors as hits (except alogliptin) out of five. These validated pharmacophores have effectively been used in search of three databases, Maybridge hitfinder collection, Chemdiv, and Asinex. Resulting hits were subjected to molecular docking using ligandfit program. Five hit compounds namely Asinex ASN 09417841, AW 00785, ChemDiv 0173-0023, ChemDiv 0276-0112, and ChemDiv 8010-1357 scored high Ligscore1 and ?PLP1 score comparable to standard drug sitagliptin. Good interactions were found with important residues like Glu205, Glu206, Tyr662, Phe357, Arg358, Tyr666 etc. They were reported as novel virtual leads to design potent DPP-IV inhibitors.     

Homology modeling,binding site identification,and docking study of human β-arrestin: an adaptor protein involved in apoptosis

β-Arrestins are well-known negative regulators of G-protein-coupled receptors (GPCRs) signaling. The present study is aimed to build human β-arrestins 3D structures by homology modeling followed by identification and characterization of binding sites and there by assessing druggability of the proteins. Based upon BLAST results, bovine β-arrestin (PDB ID:1G4M) was considered as a template for homology modeling. Homology models were constructed using MODELLER program, refined and validated using PROCHECK in which >97 % of residues present in the favored regions of the Ramachandran plots. Since there are no co-ordinates of ligands available in the template, we used various binding site prediction algorithms to predict different binding pockets on the modeled proteins. To examine the response of proteins toward various apoptosis inducers, molecular docking study was carried out. The identification of 3D structures, binding sites for various signaling molecules will guide us designing molecular tools for therapeutic intervention that may prove useful in numerous disorders associated with β-arrestin-GPCRs signaling.     

Inhibition of thrombin-induced platelet aggregation by uteroglobin

Uteroglobin, a steroid-dependent, small molecular weight (15K) protein in the rabbit, inhibited thrombin-induced aggregation of both rabbit and human gel-filtered platelets (GFP). GFP aggregation by arachidonic acid was not affected by uteroglobin. There were no effects of uteroglobin on thrombin-induced clotting of plasma or purified fibrinogen, or inhibition of thrombin by antithrombin III. Additionally, preliminary results suggest that uteroglobin does not interfere with binding of thrombin to platelets. We suggest that inhibition of platelet aggregation by uteroglobin may function in preventing thrombosis and ensuring free flow of blood through the microvasculature of the uterus and the placenta and may induce some of the antimotility effects of progesterone on the uterus.     

Cassia tora prevents Aβ1-42 aggregation,inhibits acetylcholinesterase activity and protects against Aβ1-42-induced cell death and oxidative stress in human neuroblastoma cells

BackgroundAlzheimer’s is a complex neurodegenerative disease and is characterized by extraneuronal accumulation of β-amyloid peptide. Because of its complex nature, multi-target directed ligands (MTDLs) are increasingly being considered as promising anti-Alzheimer therapeutic agents. This study is aimed at determining the effects of Cassia tora ethyl acetate fraction on several Alzheimer-associated deleterious events in test tubes as well as in human neuroblastoma SK-N-SH and SH-SY5Y cell lines.MethodEthyl acetate fraction of C. tora was purified by chromatography, characterized by ¹H and ¹³C NMR, and tested for its ability to prevent Aβ _1-42 aggregation by thioflavin-T fluorescence and transmission electron microscopy. We also analyzed the intracellular ROS level and cytotoxicity in SK-N-SH and SH-SY5Y cell lines.ResultsThe extract inhibits the formation of Aβ _1-42 aggregation from monomers and oligomers, as also acetylcholinesterase activity, Aβ _1-42 -induced cell death, and Aβ _1-42 -dependent intracellular ROS production in both SK-N-SH and SH-SY5Y cells. In-depth chromatographic and spectroscopic analysis of the extract revealed that the active molecules are most likely triglycerides of oleic acid (C₁₈H₃₄O₂).ConclusionWe demonstrate for the first time that Cassia tora fraction prevents Aβ _1-42 aggregation, inhibits acetylcholinesterase and alleviates Aβ _1-42 -induced oxidative stress in human neuroblastoma cells. We further suggest the possible use of triglycerides of oleic acid as efficient anti-Alzheimer agents.     

2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

ABSTRACT: BACKGROUND: The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors the quantitative structure-activity relationship (QSAR) approach became very useful and largely widespread technique for ligand based drug design. METHODS: We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-Thiadiazole thioacetanilides Analogues to elucidate the structural properties required for HIV-RT inhibitory activity. RESULTS: The 2D-QSAR studies were performed using multiple linear regression method (MLR), giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.89 and a non-cross-validated correlation coefficient r2=0.97 were obtained. Docking analysis suggests the new series have comparable binding affinity with the standard compounds. CONCLUSIONS: This approach showed that hydrophobic & electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.     

Response from lieberman and colleagues

Respond on comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165