Evaluation of tetrahydropyridazine-based peripherally restricted dual inhibitors of CB1R and inducible nitric oxide synthase (iNOS) for treating metabolic syndrome disorders.

Background And Purpose: The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB). This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration.

Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH.

Does an intrinsic strain contribute to the effect of quantum confinement phenomenon? An alloyed transition metal dichalcogenide series, Mo(SSe) as a case study.

It is well known that the bandgap of 2D transition metal dichalcogenides (TMDs) in the quantum confinement regime increases with a decrease in the number of layers. In this work, we show the effect of lattice strain on the dependence of the gap. We have designed an ideal system in the form of common-cationic alloyed-TMDs, Mo(SSe), for such studies.

A patent review on aldehyde dehydrogenase inhibitors: an overview of small molecule inhibitors from the last decade.

Introduction: Physiological and pathophysiological effects arising from detoxification of aldehydes in humans implicate the enzyme aldehyde dehydrogenase (ALDH) gene family comprising of 19 isoforms. The main function of this enzyme family is to metabolize reactive aldehydes to carboxylic acids. Dysregulation of ALDH activity has been associated with various diseases.

One-Pot Synthesis of Thio-Augmented Sulfonylureas via a Modified Bunte's Reaction.

We report the development of a one-pot Bunte's reaction-enabled expeditious platform under aqueous conditions for the scalable conversion of sulfonylureas to synthetically versatile thio-sulfonylureas. The reaction was further propagated in the same pot to yield diverse chiral and achiral isothiosulfonyl analogs. The protocol enabled the synthesis of various drug-like molecules and was applied to an enantiomeric synthesis of a cannabinoid receptor antagonist SLV326.

Colloidal Quantum Dot Light Emitting Diodes at Telecom Wavelength with 18% Quantum Efficiency and Over 1 MHz Bandwidth.

Developing high performance, low-cost solid-state light emitters in the telecom wavelength bandwidth is of paramount importance for infrared light-based communications. Colloidal quantum dot (CQD) based light emitting diodes (LEDs) have shown tremendous advances in recent times through improvement in synthesis chemistry, surface property, and device structures. Despite the tremendous advancements of CQD based LEDs in the visible range with efficiency reaching theoretical limits, their short-wave infrared (SWIR) counterparts mainly based on lead chalcogenide CQDs, have shown lower performance (≈8%).

Topoisomerase I inhibitors: Challenges, progress and the road ahead.

Topoisomerase IB (Top1), a subcategory of DNA topoisomerase enzymes is expressed much higher in several tumor cells. Therefore, modulating the activity of Top1 in tumor cells to prevent DNA replication and subsequent cell division made it an important drug target for anticancer therapy. FDA-approved camptothecin (CPT) derivatives topotecan and irinotecan exert anticancer activity through stabilization of enzyme-mediated DNA cleavage complex forming a ternary complex between DNA-Top1-drug.

Soluble epoxide hydrolase inhibitors: an overview and patent review from the last decade.

Introduction: Biological effects mediated by the CYP450 arm of arachidonate cascade implicate the enzyme-soluble epoxide hydrolase (sEH) in hydrolyzing anti-inflammatory epoxy fatty acids to pro-inflammatory diols. Hence, inhibiting the sEH offers a therapeutic approach to treating inflammatory diseases. Over three decades of work has shown the role of sEH inhibitors (sEHis) in treating various disorders in rodents and larger veterinary subjects.

Systematic Optimization of Potent and Orally Bioavailable Purine Scaffold as a Dual Inhibitor of Toll-Like Receptors 7 and 9.

Several toll-like receptors (TLRs) reside inside endosomes of specific immune cells-among them, aberrant activation of TLR7 and TLR9 is implicated in myriad contexts of autoimmune diseases, making them promising therapeutic targets. However, small-molecule TLR7 and TLR9 antagonists are not yet available for clinical use. We illustrate here the importance of C2, C6, and N9 substitutions in the purine scaffold for antagonism to TLR7 and TLR9 through structure-activity relationship studies using cellular reporter assays and functional studies on primary human immune cells.

Development of a metabolically stable topoisomerase I poison as anticancer agent.

We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1, we report design and synthesis of metabolically stable Top1 poison 3.

Size- and Temperature-Dependent Intraband Optical Properties of Heavily n-Doped PbS Colloidal Quantum Dot Solid-State Films.

Steady-state access to intraband transitions in colloidal quantum dots (CQDs), doping, permits exploitation of the electromagnetic spectrum at energies below the band gap. CQD intraband optoelectronics allows envisaging cheap mid- and long-wavelength infrared photodetectors and light-emitting devices, which today employ epitaxial materials. As intraband devices start to emerge, thorough studies of the basic properties of intraband transitions in different CQD materials are needed to guide technological research.

A Chemical Switch for Transforming a Purine Agonist for Toll-like Receptor 7 to a Clinically Relevant Antagonist.

Toll-like receptor 7 (TLR7) is an established therapeutic target in myriad autoimmune disorders, but no TLR7 antagonist is available for clinical use to date. Herein, we report a purine scaffold TLR7 antagonist, first-of-its-kind to our knowledge, which was developed by rationally dissecting the structural requirements for TLR7-targeted activity for a purine scaffold. Specifically, we identified a singular chemical switch at C-2 that could make a potent purine scaffold TLR7 agonist to lose agonism and acquire antagonist activity, which could further be potentiated by the introduction of an additional basic center at C-6.

Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents.

Life on earth depends on the biosynthesis of riboflavin, which plays a vital role in biological electron transport processes. Higher mammals obtain riboflavin from dietary sources; however, various microorganisms, including Gram-negative pathogenic bacteria and yeast, lack an efficient riboflavin-uptake system and are dependent on endogenous riboflavin biosynthesis. Consequently, the inhibition of enzymes in the riboflavin biosynthesis pathway would allow selective toxicity to a pathogen and not the host.

Discovery and Mechanistic Study of Tailor-Made Quinoline Derivatives as Topoisomerase 1 Poison with Potent Anticancer Activity.

To overcome chemical limitations of camptothecin (CPT), we report design, synthesis, and validation of a quinoline-based novel class of topoisomerase 1 (Top1) inhibitors and establish that compound 28 ( N-(3-(1 H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-3-(1,3,4-oxadiazol-2-yl)quinolin-4-amine) exhibits the highest potency in inhibiting human Top1 activity with an IC value of 29 ± 0.04 nM. Compound 28 traps Top1-DNA cleavage complexes (Top1ccs) both in the in vitro cleavage assays and in live cells.

Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors.

Camptothecin (CPT), a natural product and its synthetic derivatives exert potent anticancer activity by selectively targeting DNA Topoisomerase I (Top1) enzyme. CPT and its clinically approved derivatives are used as Top1 poisons for cancer therapy suffer from many limitations related to stability and toxicity. In order to envisage structurally diverse novel chemical entity as Top1 poison with better efficacy, Ligand-based-pharmacophore model was developed using 3D QSAR pharmacophore generation ( algorithm) methodology in Discovery studio 4.

Stability and Performance of CsPbIBr Thin Films and Solar Cell Devices.

In this manuscript, the inorganic perovskite CsPbIBr is investigated as a photovoltaic material that offers higher stability than the organic-inorganic hybrid perovskite materials. It is demonstrated that CsPbIBr does not irreversibly degrade to its component salts as in the case of methylammonium lead iodide but instead is induced (by water vapor) to transform from its metastable brown cubic (1.92 eV band gap) phase to a yellow phase having a higher band gap (2.

Hybrid heterojunctions between a 2D transition metal dichalcogenide and metal phthalocyanines: their energy levels vis-à-vis current rectification.

We form junctions between a monolayer of a range of metal-phthalocyanines and a monolayer of 2D transition metal dichalcogenides (TMD) through an electrostatic adsorption process. The energy levels of the components, as drawn from scanning tunneling spectroscopy (STS) and the density of states (DOS) thereof, indicated that the hybrid junctions would act as current rectifiers. We have observed that the central metal atom affected the energies of the metalorganics and thereby the rectification ratio of the junctions.

Differential conductance (dI/dV) imaging of a heterojunction-nanorod.

Through scanning tunneling spectroscopy, we envisage imaging a heterostructure, namely a junction formed in a single nanorod. While the differential conductance spectrum provides location of conduction and valence band edges, dI/dV images record energy levels of materials. Such dI/dV images at different voltages allowed us to view p- and n-sections of heterojunction nanorods and more importantly the depletion region in such a junction that has a type-II band alignment.

F. N. A. C. of salivary glands.

During a period of 12 years, 874 salivary gland lesions were aspirated of which 740 (86.85%) were from parotid gland. Cystic, inflammatory & neoplastic lesions were 25.