Indole-2-Carboxamides Are Active against Mycobacterium abscessus in a Mouse Model of Acute Infection.

Nontuberculous mycobacteria (NTM) pathogens particularly infect patients with structural lung disorders. We previously reported novel indole-2-carboxamides (ICs) that are active against a wide panel of NTM pathogens. This study discloses in vivo data for two lead molecules (compounds 5 and 25) that were advanced for efficacy studies in Mycobacterium abscessus-infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial loads in lung and spleen of M. abscessus-infected mice.

Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A3 receptor antagonists: SAR and molecular modeling studies.

A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A1, A2A and A3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A1, A2A and A3 receptor subtypes.

Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors.

A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ±â€¯0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.

A Simple and Efficient Approach for the Synthesis of 2-Aminated Quinazoline Derivatives via Metal Free Oxidative Annulation.

A simple and efficient approach for the synthesis of 2-aminoquinazoline derivatives in moderate to good yields. This reaction employs mild reaction conditions, is metal-free and utilizes readily available starting materials making it a more viable reaction for the scale up synthesis and ligand diversity. Notably, this methodology allows the synthesis of 2-aminoquinazolines using a free amine or cyclic amine enabling structural diversity and good atom economy.

Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine.

OBJECTIVE: Prevalence of vitamin D (VD) deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of VD status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine. APPROACH AND RESULTS: Yucatan microswine were fed with VD-deficient (0 IU/d), VD-sufficient (1000 IU/d), or VD-supplemented (3000 IU/d) high-cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)2D3 on cholesterol metabolism was examined in human hepatocyte carcinoma cell line (HepG2) and human monocytic cell line (THP-1) macrophage-derived foam cells. VD deficiency decreased plasma high-density lipoprotein levels, expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. VD promoted nascent high-density lipoprotein formation in HepG2 cells via ATP-binding membrane cassette transporter A1-mediated cholesterol efflux. Cytochrome P450 (CYP)27B1 and VD receptor were predominantly present in the CD206(+) M2 macrophage foam cell-accumulated cores in coronary artery plaques. 1,25(OH)2D3 increased the expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol efflux in THP-1 macrophage-derived foam cells. 1,25(OH)2D3 decreased intracellular free cholesterol and polarized macrophages to M2 phenotype with decreased expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6 under lipopolysaccharide stimulation. 1,25(OH)2D3 markedly induced CYP27A1 expression via a VD receptor-dependent c-Jun N-terminal kinase (JNK) 1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 expression and stimulated cholesterol efflux that was inhibited by VD receptor antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage-derived foam cell. CONCLUSIONS: VD protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.

Novel thiazole-thiophene conjugates as adenosine receptor antagonists: synthesis, biological evaluation and docking studies.

Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3Ki value of 0.33µM with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode.

Implication of novel thiazolo-thiophene derivative (MCD-KV-10) for management of asthma.

CONTEXT: Asthma is multifaceted disease where many targets contribute towards its development and progression. Among these, adenosine receptor subtypes play a major role. OBJECTIVE: MCD-KV-10, a novel thiazolo-thiophene was designed and evaluated pre-clinically for its implication in management of asthma. MATERIALS AND METHODS: This compound showed good affinity and selectivity towards A(2A)/A3 adenosine receptor (AR) subtypes. Furthermore, MCD-KV-10 was evaluated for in vitro lipoxygenase inhibition activity; in vivo mast cell stabilization potential and in vivo anti-asthmatic activity was done in ovalbumin-induced airway inflammation model in guinea pigs. RESULTS: The compound showed good (>57%) inhibition of lipoxygenase enzyme and also effectively protected mast cell degranulation (>63%). The compound showed good anti-asthmatic activity as inferred from the in vivo studies. DISCUSSION: These results indicate that MCD-KV-10 has an inhibitory effect on airway inflammation. CONCLUSION: Though, we have identified a potential candidate for management of asthma, further mechanistic studies are needed.

Silver-Mediated Synthesis of Indolizines via Oxidative C-H functionalization and 5- endo-dig cyclization.

An efficient strategy for the synthesis of indolizines from readily available starting materials via oxidative C-H functionalization and 5-endo-dig cyclization in one step has been demonstrated. This protocol represents wide substrate scope, high functional group tolerance and selectivity. The structure of the product was confirmed by the X-ray crystallographic studies. The Ag2CO3 required of this tandem reaction can be recycled and reused after undergoing oxidative reaction.

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review.

INTRODUCTION: Triggering receptor expressed on myeloid cells (TREM) receptors and TREM-like transcript (TLT; or TREML) receptors of the immunoglobulin superfamily are known as key modulators of host immune responses. TREM-1 (CD354) and TREM-2 share the transmembrane adaptor DNAX-activation protein of 12 kDa (DAP12), but they possess separate stimulatory and inhibitory functional roles, especially in myeloid cells. AREAS COVERED: This review covers findings related to TREMs and TLTs published in patent applications from their discovery in 2000 to the present. New roles for TREM-1, TREM-2, TLT-1 and TLT-2 in maladies ranging from acute and chronic inflammatory disorders to cardiovascular diseases and cancers are discussed. Putative endogenous ligands and novel synthetic peptide blockers are also discussed. EXPERT OPINION: So far, therapeutic use of activators/blockers specific for TREMs and TLTs has been limited to preclinical animal models. TREM-1 is an immediate therapeutic target for acute and chronic inflammatory conditions, especially sepsis. Certain mutations in DAP12 and TREM-2 manifest into a disorder named polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, and newly identified TREM-2 variants confer a significant increase in risk of developing Alzheimer's disease. This makes TREM-2 an attractive therapeutic target for neurodegenerative diseases.

A concise synthesis of highly substituted imidazoles via copper-mediated oxidative C-H functionalization.

We herein report a simple and concise route for the synthesis of highly substituted imidazole derivatives via copper-mediated oxidative C-H functionalization in good to high yields. The advantage of the reaction lies in its mild reaction conditions and readily available starting materials.

Stability-indicating assay method for determination of actarit, its process related impurities and degradation products: Insight into stability profile and degradation pathways☆.

The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC-PDA-MS). A specific and sensitive stability-indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated.

Implication of novel bis-imidazopyridines for management of Alzheimer's disease and establishment of its role on protein phosphatase 2A activity in brain.

OBJECTIVES: The objective of this study was to synthesize and identify potential leads for the management of Alzheimer's disease (AD). METHODS: A series of bis-imidazopyridines were synthesized and assessed preclinically for anti-inflammatory and antioxidant activity in aluminium chloride-induced rat model for AD. The two targets, anti-inflammatory and antioxidant, hold a significant relevance in AD. The compounds were also screened for their role of protein phosphatase 2A (PP2A) activity in brain which is responsible for tau dephosphorylation and alleviation of AD. KEY FINDINGS: The results of our study identified NIPERAMCD-KTB7 (dose: 50 mg/kg bodyweight, orally), as a potential molecule with good inhibitory activity in acute (67% oedema protection) as well as chronic (61% oedema protection) model of inflammation. This compound also showed good antioxidant activity as inferred from the inhibition of lipid peroxidation and superoxide dismutase activity in rats at the dose mentioned above. More significantly, PP2A activity was found to be increased in the brains of the animals treated with NIPERAMCD-KTB7 suggesting its potential role in management of AD. CONCLUSIONS: These preliminary findings indicate that NIPERAMCD-KTB7 holds potential to serve as a basic lead for further structural modification and development of other new chemical entities for combating AD.

New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides.

A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.