Ru(II)-Catalyzed [4 + 2]-Annulation of 2-Alkenyl/Arylimidazoles with N-Substituted Maleimides and 1,4-Naphthoquinones: Access to Imidazo-Fused Polyheterocycles.

Synthesis of imidazo-fused polyheterocyclic molecular frameworks, viz. imidazo[1,2-a]pyrrolo[3,4-e]pyridines, imidazo[2,1-a]pyrrolo[3,4-c]isoquinolines, and benzo[g]imidazo[1,2-a]quinoline-6,11-diones, has been achieved by the ruthenium(II)-catalyzed [4 + 2] C-H/N-H annulation of 2-alkenyl/2-arylimidazoles with N-substituted maleimides and 1,4-naphthoquinones. The developed protocol is operationally simple, exhibits broad substrate scope with excellent functional group tolerance, and provides the desired products in moderate to good yields. The mechanistic studies suggest that the reaction involves the formation of a C-C bond through Ru-catalyzed C(sp2)-H bond activation followed by intramolecular cyclization.

Rh(III)-catalyzed oxidative [4+2] annulation of 2-arylquinoxalines and 2-aryl-2H-indazoles with allyl alcohols.

Synthesis of functionalized benzo[a]phenazines and indazolo[2,3-a]quinolines has been developed through Rh(III)-catalyzed oxidative annulation of 2-arylquinoxalines and 2-aryl-2H-indazoles with allyl alcohols, respectively. The method features a broad substrate scope, excellent functional group tolerance, good to high yields of annulated products, and scaled-up synthesis capability. Based on a preliminary mechanistic investigation, a tentative mechanism of annulation reaction has been proposed.

Catalyst-Controlled Regiodivergent Oxidative Annulation of 2-Arylimidazo[1,2-a]pyridines with Cinnamaldehyde Derivatives for Construction of Fused N-Heterocyclic Frameworks.

Catalyst-dependent regioselective oxidative annulation of 2-arylimidazo[1,2-a]pyridines with cinnamaldehyde derivatives to construct fused N-heterocyclic frameworks has been described. The annulation reaction afforded 5-arylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine-6-carbaldehydes in the presence of [RhCp*Cl2]2 as catalyst while 1,7-diarylimidazo[5,1,2-cd]indolizine-6-carbaldehydes were obtained using Pd(OAc)2 as catalyst. The reaction produced annulated products in good yields and exhibited broad substrate scope and excellent functional group tolerance. The method provides two different isomeric annulated products bearing an aldehyde functionality which can be elaborated into an array of functionalities leading to valuable compounds.

Mono and Dinuclear Palladium Pincer Complexes of NNSe Ligand as a Catalyst for Decarboxylative Direct C-H Heteroarylation of (Hetero)arenes.

This report describes the synthesis of a new NNSe pincer ligand and its mono- and dinuclear palladium(II) pincer complexes. In the absence of a base, a dinuclear palladium pincer complex (C1) was isolated, while in the presence of Et3 N base a mononuclear palladium pincer complex (C2) was obtained. The new ligand and complexes were characterized using techniques like 1 H, 13 C{1 H} nuclear magnetic resonance (NMR), fourier transform infrared (FTIR), high-resolution mass spectrometry (HRMS), ultraviolet-visible (UV-Visible), and cyclic voltammetry. Both the complexes showed pincer coordination mode with a distorted square planar geometry. The complex C1 has two pincer ligands attached through a Pd-Pd bond in a dinuclear pincer fashion. The air and moisture-insensitive, thermally robust palladium pincer complexes were used as the catalyst for decarboxylative direct C-H heteroarylation of (hetero)arenes. Among the complexes, dinuclear pincer complex C1 showed better catalytic activity. A variety of (hetero)arenes were successfully activated (43-87 % yield) using only 2.5 mol % of catalyst loading under mild reaction conditions. The PPh3 and Hg poisoning experiments suggested a homogeneous nature of catalysis. A plausible reaction pathway was proposed for the dinuclear palladium pincer complex catalyzed decarboxylative C-H bond activation reaction of (hetero)arenes.

Novel Pyrido[2',1':2,3]imidazo[4,5-c]quinoline Derivative Selectively Poisons Leishmania donovani Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant Leishmania Infection in Vivo.

The unique bisubunit structure of Leishmania donovani topoisomerase 1B (LdTop1) is a potential drug target in the parasites unlike the monomeric Top1 from its human host counterpart. Here, we report the design, synthesis, and validation of a chimeric pyrido[2',1':2,3]imidazo[4,5-c]quinoline derivative (C17) as a novel antileishmanial agent that poisons topoisomerase 1-DNA covalent complexes (LdTop1cc) inside the parasites and inhibits Top1 religation activity both in the drug sensitive and antimony-resistant L. donovani clinical isolates. Importantly, the human Top1 is not sensitive to C17. Further, C17 overcomes the chemical instability of camptothecin (CPT) by generating persistent LdTop1cc-induced DNA breaks inside the parasites even after 12 h of drug removal. Intraperitoneal administration of C17 results in marked reduction of the Leishmania amastigotes from the infected spleen and liver of BALB/c mice. C17 confers a host protective immune-response up-regulating the Th1 cytokines facilitating parasite clearance which can be exploited for treating drug-resistant leishmaniasis.

Ball-Milling-Enabled Zn(OTf)2-Catalyzed Friedel-Crafts Hydroxyalkylation of Imidazo[1,2-a]pyridines and Indoles.

A facile and efficient synthetic method for the construction of C3-hydroxyalkylated imidazo[1,2-a]pyridines and indoles by a Zn(OTf)2-catalyzed Friedel-Crafts hydroxyalkylation of imidazo[1,2-a]pyridines and indoles with carbonyl compounds under mechanochemical conditions is reported. Good product selectivity, shorter reaction time, ambient reaction temperature, tolerance of a wide range of functional groups, broad substrate scope, moderate to good yield of products, and scalability are the salient features of the developed methodology.

Design and Syntheses of Ruthenium ENE (E = S, Se) Pincer Complexes: A Versatile System for Catalytic and Biological Applications.

This report describes the synthesis of two ruthenium(II) ENE pincer complexes (E = S, C1 and E = Se, C2) by the reaction of bis(2-(phenylchalcogenyl)ethyl)amine (L1, L2) with RuCl2 (PPh3 )3 . The complexes were characterized with the help of 1 H and 13 C{1 H} NMR, FTIR, HRMS, cyclic voltammetry and elemental analysis techniques. The structure and bonding mode of ligand with ruthenium in C2 was established with the help of single crystal X-ray diffraction. The complex showed distorted octahedral geometry with two chlorine atoms trans to each other. The Ru-Se bond distances (Å) are 2.4564(3)-2.4630(3), Ru-N distance is 2.181(2), Ru-P distance is 2.2999(6), and Ru-Cl distances are 2.4078(6)-2.4314(6). The complexes showed good to excellent catalytic activity for the N-alkylation of o-phenylenediamine with benzyl alcohol derivatives to synthesize 1,2-disubstituted benzimidazole derivatives. The complexes were also found to be efficient for aerobic oxidation of benzyl alcohols to corresponding aldehydes which are precursors to the bisimines generated in situ during the synthesis of 1,2-disubstituted benzimidazole derivatives. Complex C2 where selenium is coordinated with ruthenium was found to be more efficient as compared to sulfur coordinated ruthenium complex C1. Since ruthenium complexes are getting increasing attention for developing new anticancer agents, the preliminary studies like binding behavior of both the complexes towards CT-DNA were studied by competitive binding with ethidium bromide (EthBr) using emission spectroscopy. In addition, the interactions of C1-C2 were also studied with bovine serum albumin (BSA) using steady state fluorescence quenching and synchronous fluorescence studies. A good stability of Ru(II) state was observed by cyclic voltammetric studies of C1-C2. Overall these molecules are good examples of bio-organometallic systems for catalytic and biological applications.

Cobalt-catalyzed tandem one-pot synthesis of polysubstituted imidazo[1,5-a]pyridines and imidazo[1,5-a]isoquinolines.

An efficient cobalt-catalyzed tandem one-pot method has been developed for the synthesis of polysubstituted imidazo[1,5-a]-N-heteroaromatics. The method involves Knoevenagel condensation followed by cobalt-catalyzed direct alkenylation to give the desired polysubstituted imidazo[1,5-a]pyridines and imidazo[1,5-a]isoquinolines in a one-pot manner. This method exhibits a broad substrate scope, provides moderate to good (39-74%) yields and is amenable to scale-up to the gram scale.

Bulky Selenium Ligand Stabilized Trans-Palladium Dichloride Complexes as Catalyst for Silver-Free Decarboxylative Coupling of Coumarin-3-Carboxylic Acids.

This report describes the syntheses of three new trans-palladium dichloride complexes of bulky selenium ligands. These complexes possess a Cl-Pd-Cl rotor spoke attached to a Se-Pd-Se axle. The new ligands and palladium complexes (C1-C3) were characterized with the help of NMR, HRMS, UV-Vis., IR, and elemental analysis. The single-crystal structure of metal complex C2 confirmed a square planar geometry of complex with trans-orientation. The X-ray structure revealed intramolecular secondary interactions (SeCH-Cl) between chlorine of PdCl2 and CH2 proton of selenium ligand. Variable-temperature NMR data shows coalescence of diastereotopic protons, which indicates pyramidal inversion of selenium atom at elevated temperature. The relaxed potential energy scan of C2 suggests a rotational barrier of ∼12.5 kcal/mol for rotation of chlorine atom through Cl-Pd-Cl rotor. The complex C3 possesses dual intramolecular secondary interactions (OCH2 -Cl and SeCH2 -Cl) with stator ligand. Molecular rotor C2 was found to be a most efficient catalyst for the decarboxylative Heck-coupling under mild reaction conditions. The protocol is applicable to a broad range of substrates with large functional group tolerance and low catalyst loading (2.5 mol %). The mechanism of decarboxylative Heck-coupling reaction was investigated through experimental and computational studies. Importantly the reaction works under silver-free conditions which reduces the cost of overall protocol. Further, the catalyst also worked for decarboxylative arylation and decarboxylative Suzuki-Miyaura coupling reactions with good yields of the coupled products.

Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids.

A simple and straightforward approach has been realized for the direct benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids in the presence of K2S2O8 as an oxidant. Various functional groups were tolerated on both imidazoheterocycles and arylglyoxylic acids and a wide range of C5-benzoyl-imidazoheterocycles were obtained in good to high yields (50-84%). Radical trapping experiments confirmed the involvement of the radical pathway. The developed protocol is amenable for a scale-up reaction.

A selenium-coordinated palladium(ii) trans-dichloride molecular rotor as a catalyst for site-selective annulation of 2-arylimidazo[1,2-a]pyridines.

This report describes the synthesis of a new class of secondary interaction (SeCHCl)-controlled molecular rotor having a Cl-Pd-Cl rotor spoke attached onto a Se-Pd-Se axle. NMR data acquired at various temperatures established ΔG/ΔG values of 15.5 and 17.2 kcal mol-1 for a roughly 4.5 Å-long rotor. The molecular rotor showed excellent catalytic activity with reverse regioselectivity for annulation of 2-arylimidazo[1,2-a]pyridines (yields: ∼53-78%) with only 1.5 mol% catalyst loading.

Angiolymphoid Hyperplasia with Eosinophilia and its Response to the Combination of Radiofrequency Ablation and Topical Timolol.

Angiolymphoid hyperplasia with eosinophilia is a rare vascular disease characterized by multiple erythematous to violaceous papules, commonly present on the head and neck region. We report a case of a 23-year-old female who presented with multiple, erythematous asymptomatic papules on the preauricular region and pinna, which on biopsy was suggestive of angiolymphoid hyperplasia. The lesions were treated with a novel combination of radiofrequency ablation and topical timolol. The lesions healed without scarring and there was no recurrence on 1 year follow up.

Comparison of Q-switched Nd:YAG laser alone versus its combination with ultrapulse CO2 laser for the treatment of black tattoo.

BACKGROUND: Q-switched lasers are conventionally used for the treatment of black tattoo. However, they require multiple sittings, and the response may be slow due to competing epidermal pigment in dark skin. OBJECTIVE: To compare the efficacy of Q-switched Nd:YAG laser alone with its combination with ultrapulse CO2 for the removal of black tattoo. MATERIALS AND METHODS: Sixty patients with black tattoo were randomized into two groups viz., group A and group B. Group A was treated with QS Nd:YAG laser (1064 nm) alone, and group B received combination of ablative ultrapulse CO2 followed by fixed-dose QS Nd:YAG laser (1064 nm), at 6-week interval for a maximum of 6 sittings. After each sitting, 3 independent physicians noted percentage of improvement that was evaluated using visual analogue scale (VAS) and grading system for tattoo ink lightening (TIL). RESULTS: Combination laser (group B) showed statistically significant improvement in mean VAS score in the last 2 noted visits as compared to 1st session (p < 0.007, p < 0.001) and TIL mean score in last three noted visits as compared to 1st session (p < 0.008, p < 0.020, and p < 0.004). There was no statistically significant difference in the side effect profile of both the groups. CONCLUSION: For refractory professional tattoos, combination of ultrapulse CO2 laser and QS Nd:YAG laser is superior to QS Nd:YAG laser alone.

Splenic Vein Thrombosis as a Rare Complication of Disseminated Tuberculosis - Imaging Diagnosis and Case Report.

BACKGROUND: Venous thromboembolism is a known but rare complication associated with Mycobacterium tuberculosis infection. The reported incidence of venous thromboembolism is 1.5-3.4% of infected patients, and it occurs due to a hypercoagulable state induced by the associated inflammation. CASE REPORT: A young woman with pulmonary tuberculosis was found to have disseminated tuberculosis and a clinically unsuspected partial thrombus in the splenic vein on imaging. Ultrasound demonstrated hepato-splenomegaly with multiple granulomas as well as ascites and a left-sided pleural effusion. An increased calibre of the splenic vein with a hyperechogenicity within it raised the suspicion of a thrombus, which was confirmed on a contrast-enhanced CT examination. CECT of the abdomen also showed a small peripheral splenic infarct, while CECT of the chest revealed bilateral miliary lesions in the lungs along with necrotic mediastinal lymphadenopathy. The final imaging diagnosis was disseminated tuberculosis complicated by splenic vein thrombosis. A timely institution of anti-coagulant and anti-tubercular treatment led to a complete resolution of the splenic vein thrombosis. CONCLUSIONS: Contrast-enhanced CT serves as a useful imaging tool for the detection of venous thrombosis and for the estimation of a complete burden of the disease. This condition should be kept in mind by both clinicians and radiologists and looked for in order to prevent life-threatening complications.

Glomus vagale tumour, can it be diagnosed only on sonography?

Vagal paragangliomas are rare benign tumors accounting for only 3% of head and neck paragangliomas and arise from vagal ganglions, predominately the nodose ganglion in the carotid sheath. Imaging plays an important role in their diagnosis, differentiation from more common lesions presenting in the carotid space, and management. MRI is the method of choice for investigation when paragangliomas are clinically suspected. The typical salt-and-pepper appearance in T1-weighted images is well known but not specific to paragangliomas. Demonstration of the continuity of the lesion with the vagus nerve on magnetic resonance imaging (MRI) further asserts the diagnosis of glomus vagale. Although this tumor can be diagnosed on a contrast-enhanced computed tomography (CECT) examination, it is limited by the non-demonstration of its neural origin. Sonography is considered only a preliminary investigation in patients, and a CECT and/or MRI study of the neck is conducted before treatment planning. This case is unique as a confident diagnosis of glomus vagale was made on high-resolution sonography of the neck. A middle-aged male patient presenting with a neck swelling was diagnosed with a glomus vagale tumor on USG by the direct demonstration of its continuity with the vagus nerve, and Doppler examination confirmed its vascularity. The diagnosis was confirmed on histopathology after surgical excision. The sonographic appearance, Doppler characteristics, and imaging differential diagnosis of glomus vagale are discussed in detail.

Appraisal of radiation dose with 64-slice computed tomography perfusion in lung cancer patients with special reference to SSDE: An initial experience in a tertiary care hospital.

CONTEXT: Computed tomography perfusion (CTP) is an important functional tool for lung cancer. It is expected to deliver high radiation dose, making its accurate estimation important. Size-specific dose estimate (SSDE) is a new dose metric, which includes the scanner output as well as the patient size. AIMS: To determine radiation dose [CT dose index (CTDIvol), dose length product (DLP), effective dose (ED), and SSDE] for CTP in lung cancer and the correlation of CTDIvol, DLP, and SSDE with effective diameter and SSDE with weight, body mass index (BMI), and the scan length. SETTINGS AND DESIGN: Cross-sectional study in the Department of Radio-diagnosis from October 2015 to March 2016. PATIENTS AND METHODS: Due ethical approval and informed consent was taken. Thirty consecutive adult patients of lung cancer undergoing CTP study were included; various radiation dose parameters were determined and presented as mean ± SD. STATISTICAL ANALYSIS USED: Paired Student's t-test and Pearson correlation using Statistical Package for the Social Sciences, Version 16. RESULTS: Mean radiation dose was CTDIvol = 270.138 ± 1.627 mGy, DLP = 681 ± 53.496 mGy.cm, ED = 12.501 ± 0.923 mSv, SSDE = 388.90 ± 81.27 mGy. The CTDIvol and DLP had significant positive correlation (r = 0.556, P = 0.000 and r = 0.522, P = 0.003, respectively) with effective diameter. SSDE had strong negative correlation (r = -0.997, P = 0.000) with effective diameter, significant negative correlation with the BMI (r = -0.889; P = 0.000) and weight (r = -0.910, P = 0.000) of patients. Scan length was not significantly correlated in SSDE (r = -0.012, P = 0.951). CONCLUSIONS: Smaller sized patients had greater SSDE.

Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis have reduced exercise tolerance, measured objectively as decreased peak exercise oxygen uptake (peak VO2). Reduced peak VO2 is associated with decreased survival time. The effect of aerobic exercise training on peak VO2 has not been well studied in patients with cirrhosis. We evaluated the safety and efficacy of 8 weeks of supervised exercise on peak VO2, quadriceps muscle thickness, and quality of life. METHODS: In a prospective pilot study, stable patients (79% male, 57.6 ± 6.7 years old) with Child-Pugh class A or B cirrhosis (mean Model for End-Stage Liver Disease score, 10 ± 2.2) were randomly assigned to groups that received exercise training (n = 9) or usual care (controls, n = 10) at the University of Alberta Hospital in Canada from February through June 2013. Supervised exercise was performed on a cycle ergometer 3 days/week for 8 weeks at 60%-80% of baseline peak VO2. Peak VO2, quadriceps muscle thickness (measured by ultrasound), thigh circumference, answers from Chronic Liver Disease Questionnaires, EQ-visual analogue scales, 6-minute walk distance, and Model for End-Stage Liver Disease scores were evaluated at baseline and at week 8. Analysis of covariance was used to compare variables. RESULTS: At week 8, peak VO2 was 5.3 mL/kg/min higher in the exercise group compared with controls (95% confidence interval, 2.9-7.8; P = .001). Thigh circumference (P = .001), thigh muscle thickness (P = .01), and EQ-visual analogue scale determined self-perceived health status (P = .01) was also significantly higher in the exercise group compared with controls at week 8; fatigue subscores of the Chronic Liver Disease Questionnaires were lower in the exercise group compared with controls (P = .01). No adverse events occurred during cardiopulmonary exercise testing or training. CONCLUSIONS: In a controlled prospective pilot trial, 8 weeks of supervised aerobic exercise training increased peak VO2 and muscle mass and reduced fatigue in patients with cirrhosis. No relevant adverse effects were observed. Larger trials are needed to evaluate the effects of exercise in patients with cirrhosis. ClinicalTrials.gov number: NCT01799785.