Harnessing the benzyne insertion consequence to enable π-extended pyrido-acridine and quinazolino-phenanthridine.

Distinct protocols have been devised for the preparation of hybrid heterocyclic scaffolds like π-extended pyrido-acridines and quinazolino-phenanthridines duly materialized through Rh(III)- and Pd(II)-mediated catalytic courses commencing from acridine and quinazolimine scaffolds. Interestingly, the parent compounds (acridines and quinazolimines) are actualized from 2-aminobenzonitrile and anthranilic acid, where 2-aminobenzonitrile acts as the 1,4-dipolarophilic species and anthranilic acid as the benzyne precursor. The molecular assembly of acridine suggests the participation of two benzyne units. In addition, the structural motif of the quinazolimine ring features one benzyne unit. Further, indolizine ring containing the enaminonitrile skeleton upon exposure to benzyne forms an indolizine fused quinoline ring, decorated with three benzyne units.

Cascade [4 + 1] Annulation through Activation of the C(sp2)-H Bond Enabling Benzothiadiazinoisoindolcarboxylate, Benzothiadiazinoisoindole, and Benzothiadiazinoisoindolepyrrolidinedione as Hybrid Spiro-Heterocyclic Frameworks†.

Two structurally distinct and biologically privileged succinimide and isoindole heteroarenes bearing benzothiadiazinedioxide motif-centered hybrid conjugates are proficiently achieved through Rh(III)-catalyzed sequential C(sp2)-H bond activation, ortho-alkenylation and finally cascade intramolecular cyclization. The significant feature of this developed protocol is that the resulting diversely decorated heterocycles contain a quaternary carbon center and this has been coursed through atypical [4 + 1] annulation ignoring the prevalent [4 + 2]-cyclization pathway and interestingly the applied coupling partners (e.g., maleimide, maleate, and styrene) to materialize the protocol functioned only as C1 synthon. Furthermore, the selective reduction strategy enables to modify the hybrid conjugate of succinimide and benzothiazine dioxide to benzothiazine dioxide-based spirocyclic isoindolopyrrolidinedione skeleton following preferential reduction of one carbonyl group of imide functionality. Overall this methodology emerges to be easily handled, versatile, time-efficient, and manifests relatively unfamiliar spiro-cyclization and good functional group tolerance so easy to grab a library of the entirely new variant of decorated hybrid spiro-heterocyclic scaffolds.

Ru(II) catalyzed chelation assisted C(sp2)-H bond functionalization along with concomitant (4 + 2) annulation.

Efficacious protocols have been established to synthesize a structurally privileged Π-extended coumarin-fused pyridone nucleus by activating the vinylic C(sp2)-H bond of coumarin-3-carboxamide under the influence of inexpensive Ru(II)-metal. Here an N-methoxy carboxamide entity has been exploited as the chelating fragment to manifest C(sp2)-H bond functionalization with a concomitant (4 + 2) annulation reaction, resulting in heterocyclic ring-forming protocols along with sulfoxonium ylide and iodonium ylide as representative bench-stable carbene surrogates. This diverse heterocycle formation via carbene insertion strategies, is further expanded to activate the ortho-C(sp2)-H bonds of different heterocycles by employing the sp2-N moiety as the directing group to develop acyl-alkylated/alkenylated quinazolines, isoxazoles and highly fluorescent pyridone-N-oxides. Intriguingly, during an evaluation of the versatility of the current protocols, a one-pot double C-H activation has been rationalized in the presence of iodonium ylide, which results in biologically potent benzimidazole-fused coumarin-centered bridge-headed polycyclic heteroarenes. Furthermore, a chemo-selective late-stage synthetic transformation is being designed to develop differently substituted pyridone analogues by switching the nature of the reducing agent. In addition, a photophysical experiment was done on one pyridine-N-oxide compound (7e) and delightfully it exhibited fluorescence quenching activity selectively in the presence of Al3+ ions, which appears to be a unique feature of our methodology. Finally, upon correlation of the merit of the developed pathways, the iodonium ylide mediated strategy appears to be superior.

Fused Furan Moieties from Enol-like Compounds and ß-Keto Sulfoxonium Ylides Involving sp2 C-H Activation and Concomitant Tandem C-O Annulation.

An efficient and fascinating protocol has been devised for the preparation of fused furan moieties involving a Rh(II) catalyzed one-pot C-H activation/concomitant tandem annulation process, employing an enolic compound and ß-keto sulfoxonium ylide as the reacting conjugates. The developed technique demands only Rh2(TFA)4 as the catalyst to proceed forward and is devoid of additional metallic or nonmetallic additives. The skeletal transformation of naphthoquinone fused furan to highly decorated naphthoquinone fused indolizines is a promising synthetic application.

Electrochemically Enabled C4-H and C3-H Functionalization of 2-Phenyl Quinazoline and Quinoxaline through Dehydrogenative C-H/C-H, C-H/P-H, and C-H/O-H Cross-Coupling.

Quinazoline moieties and particularly C4-substituted quinazoline scaffolds are widely distributed in biologically active molecules, and thus, direct C4-functionalization of quinazolines is the most convenient way to materialize new, straightforward, and sustainable strategies for the synthesis of useful medicinal targets. Retrospecting that, effort has been directed toward electrocatalytic C4-H bond diversification of quinazoline and related electron-deficient N-heterocycles (quinoxaline) offering C4 and C3 benzoyl-, acetyl-, phenol-, ether-, phosphonate-, and nitroalkane-incorporated N-heterocycles via a radical addition pathway under sacrificial oxidant- and additive-free conditions. Various coupling partners and quinazolines, as well as other structurally similar heterocyclic motifs, respond well, providing moderate to high yields of coupled products along with the gram-scale upgradation. Additionally, the performed control experiments and cyclic voltammetry investigations also nicely justified the proposed mechanism of the coupling process. Further, late-stage functionalization leading to the synthesis of indolo quinolines and vinyl-sulfonated products using the ruthenium-catalyzed skeletal transformation of benzoylated quinazoline 3b nicely appropriated the developed methodology. Finally, this reaction can be summarized as (a) anodic activation of the functionalized Hantzsch ester to furnish key radical species; (b) radical addition to an activated N-heterocycle; and (c) oxidation leading to the target product without the assistance of any metal chelation.

Risk factors associated with device embolisation or malposition during transcatheter closure of patent ductus arteriosus.

BACKGROUND: Device embolisation is a serious adverse event during transcatheter duct closure. This study analyses risk factors for embolisation. METHODS: Demographic parameters, echocardiographic anatomy, haemodynamics, and procedural characteristics of consecutive duct closures in a tertiary centre over 8 years were analysed. Procedures complicated by embolisation were compared to uncomplicated procedures. RESULTS: Fifteen embolisations occurred during 376 procedures. All except one embolisation were in infants. The pulmonary artery: aortic pressure ratio was 0.78 ± 0.22. Embolisation was seen significantly more commonly in Type C tubular ducts. Vascular plugs were more significantly associated with embolisations. Logistic regression analysis showed device embolisation was significantly higher in age group of < 6 months compared to 6-12 months (p = 0.02), higher in those with tubular ducts versus conical ducts (p = 0.003), use of vascular plugs compared to conventional duct occluders (p = 0.05), and in duct closure with undersized devices (p = 0.001). There was no in-hospital mortality. Three patients needed surgical retrieval while others were successfully managed in catheterisation laboratory. CONCLUSIONS: Device embolisation complicates 4% of transcatheter duct closures, with need for surgery in one-fifth of them. Larger ducts with high pulmonary artery pressures in younger and smaller infants are more often associated with device embolisation. Tubular ducts are more prone for embolisation compared to usual conical ducts. Softer vascular plugs are often associated with embolisations. Intentional device undersizing to avoid vascular obstruction in small patients is a frequent risk factor for embolisation. Precise echocardiographic measurements, correct occluder choice, proper technique and additional care in patients with high pulmonary artery pressures are mandatory to minimise embolisations.

Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors.

In recent days, the hike in obesity-mediated epidemics across the globe and the prevalence of obesity-induced cardiovascular disease has become one of the chief grounds for morbidity and mortality. This epidemic-driven detrimental events in the cardiac tissues start with the altered distribution and metabolism pattern of high-density lipoprotein and low-density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on the arterial wall and atherosclerotic plaque generation, followed by vascular spasms and infarction. Subsequently, obesity-triggered metabolic malfunctions induce free radical generation which may further trigger pro-inflammatory signaling and nuclear factor kappa-light-chain-enhancer of activated B cells transcriptional factor, thus inducing interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase. This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby making obese diabetic patients prone toward the development of myocardial infarction (MI) or stroke in comparison to their nondiabetic counterparts. The accelerated oxidative stress and pro-inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals, causing progression of athero-thrombotic vascular disease. Being an efficient antioxidative and anti-inflammatory indolamine, melatonin effectively inhibits lipid peroxidation, pro-inflammatory reactions, thereby resolving free radical-induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti-inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity-induced acute MI. This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity-diabetes correlation.

Access to π-Extended Heterocycles Containing Pyrrolo-Coumarin Cores Involving -COCH3 as a Traceless Directing Group and Materializing Two Successive sp2C-H/sp3N-H and sp2C-H/sp2N-H Activations.

An efficient protocol has been developed for the preparation of π-extended N-heterocycles involving a Rh(III)-catalyzed C-H activation reaction starting from 3-acetamidocoumarins and internal alkynes. The isolation of the intermediate pyrrolo-coumarin suggests that the -COCH3 group in acetamidocoumarins performs the role of a traceless directing group. Besides, the use of commercially available [Cp*RhCl2]2 adds more importance as no additional modification of the catalyst is required. A two-step protocol bearing intermediate pyrrolo-coumarin can be further functionalized to highly decorated heterocyclic moieties materializing sp2 C-H and sp2 N-H coupling. Moreover, one of the pyrrolo-coumarin compounds (3da) is capable of differentiating between Cr(III) and Cr(VI) ions as revealed via fluorescence spectroscopy. In addition, intermediate pyrrolo-coumarin is further functionalized to spirocyclic N-heterocycles.

Correction: Accessing oxy-functionalized N-heterocycles through rose bengal and TBHP integrated photoredox C(sp3)-O cross-coupling.

Correction for 'Accessing oxy-functionalized N-heterocycles through rose bengal and TBHP integrated photoredox C(sp3)-O cross-coupling' by Rahul Dev Mandal et al., Org. Biomol. Chem., 2022, 20, 2939-2963, https://doi.org/10.1039/D2OB00381C.

Accessing oxy-functionalized N-heterocycles through rose bengal and TBHP integrated photoredox C(sp3)-O cross-coupling.

Herein, we report a practical and simple mono- and di-C(sp3)-O cross-coupling of tautomerizable N-heterocycles (dihydrophthalazine-1,4-diones, pyridone, quinoxalinone and pyrimidinone) with ketones, ß-dicarbonyl compounds and nitroalkane, leading to substituted imidate derivatives under visible-light conditions. The combination of rose bengal as the photocatalyst and TBHP enables sustainable reaction conditions, operational simplicity, and high chemo- and regioselectivity with exceptional yields (up to 94%), good functional group tolerance and substrate generality. In the case of unsymmetrical ketones, the less substituted end is functionalized selectively. The di-C-O coupling products are generally obtained with ketones containing three enolizable 'H' at the reaction site while ketones with two enolizable 'H' furnished only single coupling products. Radical inhibition experiments revealed the involvement of a radical pathway in this coupling strategy. The coupling products are also scaled up to the gram scale, offering scope for further functionalizations via C-H bond activation.

An iron-catalyzed domino reaction of donor-acceptor cyclopropanes: a diastereoselective approach towards diversely functionalized pyrrolo-quinazolines.

An expeditious synthetic route to access functionalized pyrrolo[2,1-b]quinazoline scaffolds has been achieved via domino ring opening cyclization (DROC) reactions of donor-acceptor (D-A) cyclopropanes and 2-amino(methyl)aniline derivatives. This novel iron catalyzed transformation is amenable to a wide range of substrates. Three new C-N bonds and two rings were sequentially constructed in this divergent one-pot process. The advantages of simple operation, high yields and general applicability make this procedure highly attractive and practical too.

Unusual right pulmonary artery-to-left atrial communication associated with scimitar syndrome.

Right pulmonary artery to left atrial fistula is classified based on the right pulmonary artery branching, individual right pulmonary venous drainage, and presence of an aneurysmal segment. A rare association with scimitar syndrome and right lung devoid of blood supply from right pulmonary artery is described in this report. The anatomical and management differences between the different types are highlighted.

Cobra-head and other shape-memory abnormalities of nitinol atrial septal occluders: incidence, predisposing factors, and outcomes.

BACKGROUND: Shape-memory abnormalities are seen in some nitinol atrial septal occluders. Variably described as cobra-head, tulip, and others, their incidence, mechanisms, clinical impact, and outcome have not been systematically analysed. METHODS: We retrospectively reviewed all consecutive device closures in the last 6 years for deformations. Type and size of the occluder, deployment technique, size, and angulation/kinking of the delivery sheath were analysed. Procedural success, duration, and other complications were studied. RESULTS: A total of 112 devices (11.8%) among 950 occluders used in 936 patients showed deformities. Fourteen of 936 received 2 devices. Deformities were transient and self-correcting in 40%. Multivariate analysis showed significant associations with oversized sheaths (p = 0.004), kinked/angulated sheaths (p < 0.001), special deployment techniques (p < 0.001), and twist in the device waist (p = 0.011). Despite more frequent deformities with Figulla (15.6%) and Amplatzer (13.9%) occluders than Cera occluders (6.6%) and larger devices (>24 mm - 14.6%) than smaller devices (less than or equal to 24 mm - 9.7%), they were not significant on multivariate analysis. In vivo manipulations corrected most deformities; nineteen needed in vitro reformations and four needed a change of device. Despite prolongation of the procedure, repeated attempts (mean 2.76 ± 1.7 attempts, with a range from 1 to 9 attempts), and supraventricular tachycardia in two patients, there were no serious adverse effects. CONCLUSIONS: Deformations were frequent in 11.8% of atrial septal occluders on a targeted search. Oversized and angulated/kinked sheaths, special techniques like pulmonary vein deployment and twist in device waist during procedure predisposed to deformities. While most deformities were corrected with manipulations, removal of the device was infrequently needed and change of device was rarely required. Long procedural time and multiple attempts for deployment did not affect procedural success.

Are early palliative procedures providing an adequate long-term benefit in young cyanotic infants from developing countries, despite advances in surgery and interventions?

OBJECTIVES: Ductal stents, right ventricular outflow tract stents, and aortopulmonary shunts are used to palliate newborns and infants with reduced pulmonary blood flow. Current long-term outcomes of these palliations from resource-restricted countries are unknown. METHODS: This single-centre, retrospective, observational study analysed the technical success, immediate and late mortality, re-interventions, and length of palliation in infants ≤5 kg who underwent aortopulmonary shunts, ductal, and pulmonary outflow stents. Patients were grouped by their anatomy. RESULTS: There were 69 infants who underwent one of the palliations. Technical success was 90% for aortopulmonary shunts (n = 10), 91% for pulmonary outflow stents (n = 11) and 100% for ductal stents (n = 48). Early mortality within 30 days in 12/69 patients was observed in 20% after shunts, 9% after pulmonary outflow stents, and 19% after ductal stents. Late mortality in 11 patients was seen in 20% after shunts, 18% after outflow stents, and 15% after ductal stents. Seven patients needed re-interventions; two following shunts, one following outflow stent, and four following ductal stents for hypoxia. Among the anatomical groups, 10/12 patients with pulmonary atresia, intact ventricular septum survived after valvotomy and ductal stenting. Survival to Glenn shunt after ductal stent for pulmonary atresia, intact ventricular septum and diminutive right ventricle was very low in two out of eight patients, but very good (100%) for other univentricular hearts. Among 35 patients with biventricular lesions, 22 survived to the next stage. CONCLUSIONS: Cyanotic infants, despite undergoing technically successful palliation had a high inter-stage mortality irrespective of the type of palliation. Duct stenting in univentricular hearts and in pulmonary atresia with an intact ventricular septum and adequate sized right ventricle tended to have low mortality and better long-term outcome. Completion of biventricular repair after palliation was achieved only in 63% of patients, reflecting unique challenges in developing countries despite advances in intensive care and interventions.

Activation of SIRT1/PGC 1α/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

AIMS: Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction. MAIN METHODS: Rats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out. KEY FINDINGS: Melatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves. SIGNIFICANCE: Activation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.

"On water" palladium catalyzed diastereoselective boronic acid addition to structurally diverse cyclopropane nitriles.

An efficient palladium catalyzed diastereoselective addition of arylboronic acids to complex spirocyclopropyl dinitriles is developed in the presence of a catalytic amount of 4-dodecylbenzenesulphonic acid (DBSA) as a Brønsted acid surfactant in aqueous media. The protocol is also found to be highly effective when different types of nitrile compounds and organo-boron compounds are used. The overall reaction has been found to be very cost efficient since it requires low catalyst loading, mild thermal energy and short reaction time. Wide substrate scope, operational simplicity, good to excellent product yield, and use of green solvents make the reaction a practical route to transform nitrile into a keto functionality in biorelevant heterocyclic scaffolds. The scale-up synthesis of the target scaffolds can also be achieved with ease which also signifies the practicability of this protocol.

Hypervalent iodine promoted ortho diversification: 2-aryl benzimidazole, quinazoline and imidazopyridine as directing templates.

The mild and efficient palladium-catalyzed ortho C(sp2)-H diversification of (NH)-free 2-substituted benzimidazole, quinazoline, and imidazopyridine is reported using hypervalent iodine as the key reagent. Acetoxy, aryl, iodide and nitro functional groups were introduced on the same substrate by simply shifting the reaction conditions in the presence of inorganic additives (Cs2CO3, I2, NaNO2) and the hypervalent iodine reagent (diacetoxyiodo)benzene (PIDA) under aerobic conditions. The combination of NaNO2 with PIDA was successfully employed in Pd-catalyzed C-H bond nitration to achieve a library of nitrated 1,3 N-heterocycles. This versatile ortho C(sp2)-H activation strategy features operational simplicity, short reaction times, and ample substrate possibilities, it requires no ligands or silver salts as additives, and it shows good tolerance of oxidation prone functional groups.

Cervical Lymph Node Evaluation in Oral Squamous Cell Carcinoma Patients Using Ultrasound-Guided Fine-Needle Aspiration Cytology - A Descriptive Diagnostic Evaluation Study in a Tertiary Care Center.

BACKGROUND: Oral cancer is the most frequent type of cancer of the head and neck area, with squamous cell carcinoma (SCC) being the most common single entity. Worldwide, oral cancer accounts for 2%-4% of all cancer cases, the prevalence being highest in India. Lymph node metastases occur in about 40% of patients with oral cancer. Clinically, their manifestations are hidden in rates of 15% to 34%. More accurate imaging techniques can reduce the risk of undiagnosed metastasis. Ultrasonography has gained wide acceptance as a diagnostic aid in the evaluation of reactive and metastatic lymph nodes. The present study is an attempt to assess the earliest evaluation of the cervical lymph nodes by ultrasound-guided fine-needle aspiration cytology (FNAC). METHODOLOGY: A descriptive diagnostic evaluation study was carried out to find out the sensitivity and specificity of ultrasound-guided FNAC in detecting metastasis to cervical lymph nodes from oral SCC in the Department of Oral Medicine and Radiology, Government Dental College, Thiruvananthapuram, in collaboration with the Department of Imageology, Regional Cancer Centre, Thiruvananthapuram during the time period from July 2015 to September 2016. RESULTS: A total of 112 patients with histologically proven oral SCC having palpable lymph nodes were evaluated clinically and ultrasonographically. In this study, sensitivity and specificity of >90% were obtained for ultrasonographic criteria such as the long axis to short axis ratio <2, the absence of hilum, heterogeneous architecture, and altered vascularity in the evaluation of metastatic lymph nodes. The diagnostic yield in the detection of metastatic lymph nodes was much higher in the ultrasonographic examination. CONCLUSION: Ultrasound-guided FNAC offers an opportunity to enhance patient prognosis through early detection and a specific diagnosis (92.5%) when compared to clinical examination (78.6%) in the current study.

Clues to echocardiographic diagnosis of isolation of right subclavian artery in a patient with DiGeorge syndrome and its transcatheter management with its associated anomalies.

Isolated subclavian artery is a rare anomaly. A second steal due to a patent arterial duct further reduces arm perfusion. Surgical anastomosis of the isolated vessel to aorta normalises arm perfusion. Simple echocardiographic clues aid in the diagnosis. An associated moderate sized ventricular septal defect was non-surgically closed along with catheter closure of the duct resulting in improved arm perfusion.

Synthesis of Novel tricyclic pyrazolo(1,4)oxathiinopyrazines and Evaluation of Their Competency Towards the Inhibition of Lactate Dehydrogenase Activity-Inhibition of LDH Activity.

We have evaluated the LDH inhibitory property of novel pyrazolo[4',3':5,6][1,4]oxathiino[2,3-b]pyrazine derivatives which have been synthesized from easily available starting materials through a one-pot protocol that offers the use of elemental sulfur as the sulfur source. These newly synthesized compounds may aid to drug development for neoplastic and non-neoplastic diseases characterized by increased glucose metabolism. Additionally, they may act as suitable starting materials which can be further structurally modified for the development of new LDH inhibitors with higher efficacy and specificity.