Guanidine-based ß amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors for the Alzheimer's disease (AD): A review.

Alzheimer's disease (AD) is an irreversible, progressive neurological disorder characterized by amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neuronal damage, memory loss, etc. Various factors, such as age, lifestyle, family history, environmental factors, and gene mutation, cause AD. BACE-1 is an interesting target to prevent or reverse AD progression. BACE-1 cleaves amyloid precursor protein (APP) into soluble amyloid precursor protein ß (sAPPß) and membrane-bound C-terminal fragment called C99, a rate-limiting step, and C99 is further cleaved by gamma-secretase to generate neurotoxic amyloid ß (Aß). Discovery and development of selective ß amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors have a great potential for the treatment and maintenance of Alzheimer's disease. In this review, we have compiled literature pertaining to guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of AD. We have also discussed role of BACE-1 substrates, and its crystal structure, BACE-1 inhibitors in the clinical trial, and essential points to overcome challenges associated with selective development of BACE-1 inhibitors. This paper provides valuable information for the design and discovery of selective new BACE-1 inhibitors against other aspartyl protease enzymes to treat AD.

Decolourisation of textile dye by laccase: Process evaluation and assessment of its degradation bioproducts.

Biodegradation of environmentally hazardous synthetic dyes by enzymes has been achieved the highest interest in recent years. In this work, we optimized Remazol Brilliant Blue R (RBBR) dye biodegradation by Arthrographis kalrae derived laccase via the Box-Behnken design (BBD) approach of the surface response methodology (RSM). Optimization of dye decolourisation by one variable at a time (OVAT) approach resulted in optimal dye decolourisation at laccase dose (2 IU mL-1), pH (7.0), temperature (35 °C), incubation time (240 min), and initial dye concentration (100 mg L-1). The optimized process through BBD enhanced dye decolourisation (97.18%). Fourier Transform Infrared Spectroscopy and UV-Visible Spectrophotometry have proven biodegradation. In addition, in comparison to untreated samples, the laccase-treated dye sample showed relatively less phyto- and cytotoxic effect on Allium cepa L. Extra Precision Glide docking exhibited the binding affinity score of -5.355 kcal mol-1, between laccase-RBBR complex.

Correction to: Novel xylanase producing Bacillus strain X2: molecular phylogenetic analysis and its application for production of xylooligosaccharides.

[This corrects the article DOI: 10.1007/s13205-020-02322-1.].

Evaluation of results of various tendon transfers in high and low radial nerve palsy.

BACKGROUND: Various combinations of tendon transfers are available for radial nerve palsy. However, the choice of which set of transfer to be performed in a patient remains an issue of varied opinions among surgeons. The study attempts to evaluate the results of various tendon transfers for radial nerve palsy quantitatively and subjectively. It also identifies which set of transfer is suitable for particular groups of patients. MATERIALS AND METHODS: The study was conducted between 2005 and 2007. A total of 15 tendon transfers were performed using various combinations and evaluated according to Bincaz's criteria, Kapandji scale and effect of tendon transfers on activities of daily living. RESULTS: 13 patients had excellent to fair outcome according to Bincaz's criteria. 2 patients had poor outcome. There was no hindrance in the activities of daily life in all patients. 93.4% of patients were satisfied with the results. CONCLUSION: Every combination of tendon transfers has its own set of merits and demerits. Selection of donor tendons as per occupational need of patients is utmost important. Patients in our series were satisfied with set of transfers using Pronator teres(PT) for wrist extension, Flexor carpi radialis (FCR) for finger extension and rerouted Palmaris longus (PL) for extension of thumb. Flexor carpi ulnaris (FCU) is important for power grip.

Novel xylanase producing Bacillus strain X2: molecular phylogenetic analysis and its application for production of xylooligosaccharides.

A Bacillus strain X2 that produced extracellular endo-xylanase (GH 11) (EC: 3.2.1.8) was isolated from the soil of the Northeast India region. This aerobic culture was Gram positive and endospore forming. Chemotaxonomic characterization showed variance with the fatty acid profile of related species in the Bacillus subtilis group. In Bacillus strain X2, distinct occurrence of iso-C14:0 lipids is absent in other related species. The 16S rRNA gene sequence homology showed 99% similarity with Bacillus subtilis subsp. inaquosorum. The phylogenetic analysis by the multilocus sequence analysis (MLSA) of the nucleotide sequence of six concatenated genes (16S rRNA, groEL, gyrA, polC, purH and rpoB) resolved the taxonomic position of the Bacillus strain X2 in the Bacillus subtilis subsp. group. The MLSA showed that it is a member of a clade that includes Bacillus subtilis subsp. stercoris. In in silico DNA-DNA hybridization (DDH), the highest matching score was obtained with Bacillus subtilis subsp. stercoris (87%). The in silico DDH of the genome (G + C 43.7 mol %) shared 48.5%, with Bacillus subtilis subsp. inaquosorum. The MLSA phylogenetic tree and the highest degree of DNA hybridization, indicating that it belongs to the Bacillus subtilis subspecies stercoris.

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver-specific enzyme, inhibits oxidation of phospholipids and prevents lipid-mediated oxidative damage. However, its functional contribution in macrophage-mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku-Hospital-Pediatrics-1 (THP1)-derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up-regulated and 176 down-regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut-off, <18 µg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low-density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate-binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28-day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential.

The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-ß kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.

Design, synthesis, and structure-activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells.

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2-8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2-8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the ßIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.

Janus Compounds, 5-Chloro-N4-methyl-N4-aryl-9H-pyrimido[4,5-b]indole-2,4-diamines, Cause Both Microtubule Depolymerizing and Stabilizing Effects.

While evaluating a large library of compounds designed to inhibit microtubule polymerization, we identified four compounds that have unique effects on microtubules. These compounds cause mixed effects reminiscent of both microtubule depolymerizers and stabilizers. Immunofluorescence evaluations showed that each compound initially caused microtubule depolymerization and, surprisingly, with higher concentrations, microtubule bundles were also observed. There were subtle differences in the propensity to cause these competing effects among the compounds with a continuum of stabilizing and destabilizing effects. Tubulin polymerization experiments confirmed the differential effects and, while each of the compounds increased the initial rate of tubulin polymerization at high concentrations, total tubulin polymer was not enhanced at equilibrium, likely because of the dueling depolymerization effects. Modeling studies predict that the compounds bind to tubulin within the colchicine site and confirm that there are differences in their potential interactions that might underlie their distinct effects on microtubules. Due to their dual properties of microtubule stabilization and destabilization, we propose the name Janus for these compounds after the two-faced Roman god. The identification of synthetically tractable, small molecules that elicit microtubule stabilizing effects is a significant finding with the potential to identify new mechanisms of microtubule stabilization.

Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells.

The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N(4)-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4, and 9 showed potent microtubule depolymerizing activities, while compounds 6-8 had slightly lower potency. Compounds 4, 6, 7, and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 6-9 circumvented Pgp and ßIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI50 values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity.

Synthesis of N(4)-(substituted phenyl)-N(4)-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells.

A series of fourteen N(4)-(substituted phenyl)-N(4)-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI(50) values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [(3)H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the ßIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.

Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections.

Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii, and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9H-pyrimido[4,5-b]indoles 1-3 with single-digit nanomolar Ki for tgTS, two of which, 2 and 3, are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.

Therapeutic potential of snake venom in cancer therapy: current perspectives

Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity.

Synthesis and preliminary pharmacological evaluation of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents.

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.

Switching of friction by binary polymer brushes.

Surface force studies on polystyrene-poly(2-vinylpyridine) (1 : 1) mixed polymer brushes and corresponding monobrushes were carried out in dried state under a controlled environment. The aim was to explore possibilities to control adhesion and friction between inorganic or polymeric surfaces by use of polymer brushes. The effect of switching of chemical composition of binary brush surfaces (on treatment with suitable solvents) on wettability, surface roughness, and hence the adhesion and friction properties of the surfaces were determined. Atomic force microscopy (AFM) with silicon tips, silicon nitride tips, and colloidal probes with silica particles were employed to investigate the interactions between inorganic surfaces and polymer brushes. To study the interactions between different polymer brush surfaces colloidal probes were covered with polystyrene and poly(acrylic acid) brushes on the surface. For all the dry polymer brushes samples, surface roughness values were in the range of 0.35-1.0 nm only. Adhesion and friction forces of polymer brush samples were reduced in comparison to the silicon wafer and were correlated with each other (except for the silicon tip). Switching in adhesion and friction forces up to a factor of 4.5 was possible by switching of the conformation of mixed brushes on treatment with selective solvents. The friction force on a PS + P2VP gradient polymer brush layer varied laterally and increased with increase in the P2VP content. Friction depends on wettability, scan velocity of the AFM tip, grafting density, and composition gradient of polymer brushes. Moreover, for PS and P2VP monobrushes, friction forces were shown to increase with increasing grafting density. Polymer brush layers thus may be used to control the adhesion and friction behavior of solid surfaces in different ways.