A dual-purpose polymerase engineered for direct sequencing of pseudouridine and queuosine.

More than 170 posttranscriptional RNA modifications are so far known on both coding and noncoding RNA species. Within this group, pseudouridine (Ψ) and queuosine (Q) represent conserved RNA modifications with fundamental functional roles in regulating translation. Current detection methods of these modifications, which both are reverse transcription (RT)-silent, are mostly based on the chemical treatment of RNA prior to analysis. To overcome the drawbacks associated with indirect detection strategies, we have engineered an RT-active DNA polymerase variant called RT-KTq I614Y that produces error RT signatures specific for Ψ or Q without prior chemical treatment of the RNA samples. Combining this polymerase with next-generation sequencing techniques allows the direct identification of Ψ and Q sites of untreated RNA samples using a single enzymatic tool.

Composites of sodium alginate based - Functional materials towards sustainable adsorption of benzene phenol derivatives - Bisphenol A/Triclosan.

The present study evaluates the adsorption efficiency of low-cost carbonaceous adsorbents as fly ash (FA), saw dust biochar (SDB) (untreated and alkali - treated), live/dead pulverized white rot fungus Hypocrea lixii biomass encapsulated in sodium alginate (SA) against the commercially available activated carbon (AC) and graphene oxide (GO) SA beads for removal of benzene phenol derivatives - Bisphenol A (BPA)/triclosan (TCS). Amongst bi - and tri - composites SA beads, tri-composite beads comprising of untreated flyash - dead fungal biomass - sodium alginate (UFA - DB - SA) showed at par results with commercial composite beads. The tri - composite beads with point zero charge (Ppzc) of 6.2 was characterized using FTIR, XRD, surface area BET and SEM-EDX. The batch adsorption using tri - composite beads revealed removal of 93% BPA with adsorption capacity of 16.6 mg/g (pH 6) and 83.72% TCS with adsorption capacity of 14.23 mg/g (pH 5), respectively at 50 ppm initial concentration with 6 % adsorbent dose in 5 h. Freundlich isotherm favoring multilayered adsorption provided a better fit with r2 of 0.9674 for BPA and 0.9605 for TCS respectively. Intraparticle diffusion model showed adsorption of BPA/TCS molecules to follow pseudo - second order kinetics with boundary layer diffusion governed by first step of fast adsorption and intraparticle diffusion within pores by second slow adsorption step. Thermodynamic parameters (ΔH°, ΔS°, ΔG°) revealed adsorption process as exothermic, orderly and spontaneous. Methanol showed better desorbing efficiency leading to five cycles reusability. The phytotoxicity assay revealed increased germination rate of mung bean (Vigna radiata) seeds, sprinkled with post adsorbed treated water (0 h, 5 h and 7 h) initially spiked with 50 ppm BPA/TCS. Overall, UFA - DB - SA tri - composite beads provides a cost effective and eco - friendly matrix for effective removal of hydrophobic recalcitrant compounds.

Functional integration of a semi-synthetic azido-queuosine derivative into translation and a tRNA modification circuit.

Substitution of the queuine nucleobase precursor preQ1 by an azide-containing derivative (azido-propyl-preQ1) led to incorporation of this clickable chemical entity into tRNA via transglycosylation in vitro as well as in vivo in Escherichia coli, Schizosaccharomyces pombe and human cells. The resulting semi-synthetic RNA modification, here termed Q-L1, was present in tRNAs on actively translating ribosomes, indicating functional integration into aminoacylation and recruitment to the ribosome. The azide moiety of Q-L1 facilitates analytics via click conjugation of a fluorescent dye, or of biotin for affinity purification. Combining the latter with RNAseq showed that TGT maintained its native tRNA substrate specificity in S. pombe cells. The semi-synthetic tRNA modification Q-L1 was also functional in tRNA maturation, in effectively replacing the natural queuosine in its stimulation of further modification of tRNAAsp with 5-methylcytosine at position 38 by the tRNA methyltransferase Dnmt2 in S. pombe. This is the first demonstrated in vivo integration of a synthetic moiety into an RNA modification circuit, where one RNA modification stimulates another. In summary, the scarcity of queuosinylation sites in cellular RNA, makes our synthetic q/Q system a 'minimally invasive' system for placement of a non-natural, clickable nucleobase within the total cellular RNA.

Living donor liver paired exchange between pediatric and adult recipients due to donor graft size mismatch.

Living donor liver transplantation is an effective means to decrease organ shortage. However, many potential living donors are currently being denied due to ABO incompatibility or inadequate donor liver volume. Liver paired exchange (LPE) provides a practical solution to overcome these obstacles, and yet the first case of LPE in the United States was only recently reported in 2020. Here, we report world's first case of LPE involving pediatric and adult recipients to avoid surgical complexity of the pediatric recipient and to increase the graft-to-recipient weight ratio of the adult recipient between 2 ABO compatible pairs. As living donor liver transplantation becomes more widely adopted, the need for pair exchange to improve surgical safety and postoperative outcomes between 2 ABO compatible pairs is likely to increase.

Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.

Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.

Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder with complex etiology that eventually leads to dementia. The main culprit of AD is the extracellular deposition of ß-amyloid (Aß) and intracellular neurofibrillary tangles. The protein conformational change and protein misfolding are the key events of AD pathophysiology; therefore, endoplasmic reticulum (ER) stress is an apparent consequence. ER, stress-induced unfolded protein response (UPR) mediators (viz. PERK, IRE1, and ATF6) have been reported widely in the AD brain. Considering these factors, preventing protein misfolding or aggregation of tau or amyloidogenic proteins appears to be the best approach to halt its pathogenesis. Therefore, therapies through chemical and pharmacological chaperones came to light as an alternative for the treatment of AD. Diverse studies have demonstrated 4-phenylbutyric acid (4-PBA) as a potential therapeutic agent in AD. The current review outlined the mechanism of protein misfolding, different etiological features behind the progression of AD, the significance of ER stress in AD, and the potential therapeutic role of different chaperones to counter AD. The study also highlights the gaps in current knowledge of the chaperones-based therapeutic approach and the possibility of developing chaperones as a potential therapeutic agent for AD treatment.

Marginal bone loss around implants with platform switching and platform matched connection: A systematic review.

STATEMENT OF PROBLEM: Platform switching using narrower abutments than the implant platform has been used to reduce marginal bone loss (MBL) surrounding dental implants. While platform switching has been reported to prevent initial peri-implant bone loss, available data regarding the use of the platform-switching implant abutment configuration with long-term follow-up has been sparse; thus, the systematic review was planned to evaluate the best available evidence for the use of the platform switching technique. PURPOSE: The purpose of this systematic review was to answer the specific question, "Is there a difference between platform-matching implant abutment configurations and platform-switching implant abutment configurations in terms of MBL changes around endosseous implants"? MATERIAL AND METHODS: The PubMed/Medline, Scopus, Google Scholar, and Lilac databases were searched by 2 independent reviewers for articles published between January 2000 and July 2022. Platform-switched versus platform-matched implants were examined for changes in MBL in human randomized clinical trials (RCTs) and potential clinically controlled cohort studies (PCCS). RESULTS: Overall, 4 eligible studies were included and critically evaluated to summarize their findings. The follow-up period of the included studies was between 5 and 10 years. Two of the included studies showed a mean ±standard deviation of 0.6 ±0.20 mm MBL at 5 years and 1.20 ±0.21 mm at 10 years for the platform switched (PS) technique and 1.1 ±0.3 mm and 1.24 ±0.39 mm MBL for the platform matched (PM) technique. Another study showed marginal bone level changes for the platform-switched technique to be 0.18 ±0.14 mm as compared with the platform matched technique (0.80 ±0.40 mm). In one of the studies published in 2019, the mean estimated difference in the marginal bone levels of PS- and PM-restored implants after 5 years was reported to be 0.29 mm. The descriptive analysis of 4 RCTs indicated that platform-switched implant-to-abutment connections reduced average marginal bone loss surrounding implants compared with platform-matched implant-to-abutment connections, favoring the platform-switched approach. CONCLUSIONS: Platform switching appears to be a beneficial approach for retaining the crestal bone around dental implants.

Arterial Anastomosis Using Microsurgical Techniques in Adult Live Donor Liver Transplant: A Focus on Technique and Outcomes at a Single Institution.

BACKGROUND: Microvascular hepatic artery reconstruction (MHAR) is associated with decreased rates of hepatic artery thrombosis (HAT) in living donor liver transplantation (LDLT). There is a paucity of literature describing the learning points and initiation of this technique at the institutional level. The objective of this study is to report our institutional experience using MHAR in adult LDLT with a focus on technique and outcomes. METHODS: A retrospective review of adult patients who underwent LDLT from January 2012 to December 2020 was conducted. Patients were divided into two groups, those who underwent LDLT without MHAR and with MHAR. We analyzed cases for technical data including donor and recipient artery characteristics, anastomotic techniques, intraop events, and postop complications. A Mann-Whitney test was performed to compare outcomes between non-MHAR and MHAR patients. RESULTS: Fifty non-MHAR and 50 MHAR patients met inclusion criteria. Median age at transplantation was 58 (interquartile range [IQR] 11.8) and 57.5 years (IQR 14.5), respectively. Median follow-up for MHAR patients was 12.8 months (IQR 11.6). The most common recipient arteries were the right hepatic artery (HA) (58%) and left HA (20%). Median size of recipient and donor arteries were 3.3 mm (IQR 0.7) and 3.1 mm (IQR 0.7), resulting in a median mismatch size of 0.3 mm (IQR 0.4). Median microanastomosis time was 44 minutes (IQR 0). HAT, graft failure, and mortality rates were higher in the non-MHAR cohort (6% vs. 0%, 8% vs. 0%, and 16% vs. 6%, respectively); however, these did not reach statistical significance. CONCLUSION: This study found lower rates of HAT and graft failure after implementing MHAR, though statistical significance was not achieved. Larger cohort studies are needed to further assess the potential benefit of MHAR in adult LDLT. From our experience, MHAR requires cooperation between the transplant and microsurgical teams, with technical challenges overcome with appropriate instrumentation and planning.

Detrimental influence of industrial effluents, especially heavy metals, on limnological parameters of water and nutritional profile in addition to enzymatic activities of fish, Sperata seenghala (Sykes, 1839) from diverse Ramsar sites, India (Punjab).

The present research was designed to determine the nutritive value of the liver and intestine of fish, Sperata seenghala, the impact of effluence load on limnological parameters of water and proximate composition of fish organs, especially on fatty acids, liver enzymatic activities, seasonal variations in the nutritional profile of fish, and to check and compare the pollution status of Ramsar sites in Punjab by calculating the water quality index, heavy metal pollution index, and metal index from June 2018 to August 2020. WQI of Harike wetland was found to be 53.95, which depicts that water quality in this region is "poor". At Nangal wetland, water quality index was reported to be "excellent" quality water and fit for the whole ecological unit. Overall heavy metal pollution index for Harike wetland was reported 174.569, whereas for Nangal wetland it was 5.994, depicting massive contaminant loads in a polluted region. MI value was also recorded as being higher (6.9336) in polluted habitat than in control habitat (0.8175). In fish liver, significant (p < 0.05) higher mean total lipids (6.73%), total proteins (3.98%), moisture (77.69%), ash (3.56%), and carbohydrates (3.79%) were observed in the samples from Nangal wetland than Harike wetland. A similar trend was reported in all biochemical contents of the fish intestine. Enzyme activities such as aspartate-aminotransferase and alanine-aminotransferase were significantly elevated (p < 0.05) in the specimens collected from the polluted region. The mean total n-3 (except in spring), n-6 polyunsaturated fatty acids (except in winter), and average monounsaturated and saturated fatty acids diminished significantly (p < 0.05) in the liver of fish from contaminated habitat than control site. In the intestine of fish collected from the polluted region, significant reductions in the mean total n-3 (except in autumn as well as summer), total n-6 PUFAs (in autumn and winter), and total SFAs were reported than control site.

Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution.

Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

Accessing Complex Tetrahydrofurobenzo-Pyran/Furan Scaffolds via Lewis-Acid Catalyzed Bicyclization of Cyclopropane Carbaldehydes with Quinone Methides/Esters.

Herein, we report a straightforward one-pot synthesis of tetrahydrofurobenzopyran and tetrahydrofurobenzofuran systems via an in situ ring-expansion of the cyclopropane carbaldehydes followed by a [2 + n] cycloaddition with the quinone derivatives. The transformation not only unveils a new reaction mode of cyclopropane carbaldehydes with quinone methides/esters, but also promotes a step-efficient diastereoselective route to the sophisticatedly fused oxygen tricycles that can be further dehydrogenated to access the valued dihydro-2H-furo[2,3-b]chromene frameworks.

α,ß-Unsaturated Carbonyls for One-Pot Transition-Metal-Free Access to 3,6-Dihydro-2H-pyrans.

An efficient protocol has been developed for accessing mono-, di-, and trisubstituted 3,6-dihydro-2H-pyran derivatives by simply subjecting α,ß-unsaturated carbonyls to the carefully optimized Corey-Chaykovsky reaction conditions. The strategy provides selectively substituted dihydropyran derivatives in good to excellent yields with a broad substrate scope under very mild reaction conditions. Easy transformation of the final 3,6-dihydro-2H-pyran to the valued 5,6-dihydro-2H-pyran-2-one and tetrahydro-2H-pyran derivatives expanded the scope of this methodology to diverse oxacycles. Further, the developed strategy also found application in a two-step route to racemic goniothalamin, which is widely studied for its cytotoxic behavior.

Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization.

Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.

Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate.

A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O). LSP-excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug-excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.

Capitalist agriculture, COVID-19 and agrarian labour relations in Punjab, India.

In the state of Punjab, the heart of the green revolution in India, a large fraction of agricultural labour is expended by migrant workers. The unplanned lockdown imposed by the Indian government affected paddy transplantation, a labour-intensive activity in Punjab primarily due to interstate restrictions on movement. Drawing on a primary survey in a village from the Malwa region of Punjab, the paper examines the changes in agrarian relations in rural Punjab due to the Covid-19 pandemic by critically analysing the dynamics of capital labour relations. The restriction on labour movement and unilateral imposition of transplantation wage rates by a few Panchayats in Punjab (dominated by capitalist landlords and rich peasants) has intensified class conflict in the state. The Punjab government's policies, which are driven by the capitalist landlords and rich peasants, have played a significant role in the increased exploitation of workers. The paper concludes with a brief evaluation of the changes induced by Covid-19 in the agrarian political economy of Punjab.

Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability.

Levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O) gradually loses one molecule of water of crystallization as the water vapor pressure is decreased from 90% to 15% RH (40 °C), a behavior characteristic of nonstoichiometric hydrates. LSP loses four molecules of water of crystallization to form levothyroxine sodium monohydrate (LSM; C15H10I4NNaO4·H2O) under realistic storage conditions (40 °C/0% RH for 3 h). The crystal structure of LSP was determined following which the specimen was partially dehydrated in situ to form LSM. The crystal structure of LSM provided insight into its potential for high reactivity. Thus, its presence in a drug product is undesirable. In LSP-oxalic acid mixtures stored in a hermetic container at 40 °C, there was moisture transfer from drug to excipient. Synchrotron X-ray diffractometry revealed dehydration of LSP resulting in LSM, while anhydrous oxalic acid transformed to its dihydrate. In formulations of LSP, chemical degradation of levothyroxine sodium may be preceded by its partial dehydration.

One-Dimensional Nanostructured Oxide Chemoresistive Sensors.

Day by day, the demand for portable, low cost, and efficient chemical/gas-sensing devices is increasing due to worldwide industrial growth for various purposes such as environmental monitoring and health care. To fulfill this demand, nanostructured metal oxides can be used as active materials for chemical/gas sensors due to their high crystallinity, remarkable physical/chemical properties, ease of synthesis, and low cost. In particular, (1D) one-dimensional metal oxides nanostructures, such as nanowires, exhibit a fast response, selectivity, and stability due to their high surface-to-volume ratio, well-defined crystal orientations, controlled unidirectional electrical properties, and self-heating phenomenon. Moreover, with the availability of large-scale production methods for nanowire growth such as thermal oxidation and evaporation-condensation growth, the development of highly efficient, low cost, portable, and stable chemical sensing devices is possible. In the last two decades, tremendous advances have been achieved in 1D nanostructured gas sensors ever since the pioneering work by Comini on the development of a SnO2 nanobelt for gas sensor applications in 2002, which is one such example from which many researchers began to explore the field of 1D-nanostructure-based chemical/gas sensors. The Sensor Laboratory (University of Brescia) has made major contributions to the field of metal oxide nanowire chemical/gas-sensing devices. Over the years, different metal oxides such as SnO2, ZnO, WO3, NiO, CuO, and their heterostructures have been grown for their nanowire morphology and successfully integrated into chemoresistive gas-sensing devices. Hence in this invited feature article, Sensor Laboratory research on the synthesis of metal oxide nanowires and novel heterostructures and their characterization and gas-sensing performance during exposure to different gas analytes has been presented. Moreover, some new strategies such as branched-like nanowire heterostructures and core-shell nanowire structures adopted to enhance the performance of nanowire-based chemical sensor are presented in detail.

Liver Transplantation in Patients with Sickle Cell Disease in the United States.

BACKGROUND: Up to 30% of patients with sickle cell disease (SCD) develop chronic liver disease via etiologies including sickle cell hepatopathy, acquired viral hepatitis, or secondary hemochromatosis. It is unclear how many patients with SCD ultimately undergo liver transplantation (LT) and what factors are associated with survival after LT. In this study, we examined LT outcomes in these patients by reviewing the Scientific Registry of Transplant Recipients (SRTR) and our institutional experience. METHODS: Analysis of the SRTR identified 23 LT recipients and five simultaneous liver and kidney transplantation (SLKT) recipients with SCD. Patient demographics and graft and patient survival were analyzed. Two patients with SCD at our institution underwent SLKT. RESULTS: Review of the SRTR revealed that recipients with SCD had significantly higher model for end-stage liver disease scores (33 versus 21, P = 0.004), preoperative intensive care unit admission (43.5% versus 19.1%, P = 0.007), preoperative dialysis (17.4% versus 4.9%, P = 0.009), and were more likely to be status 1 (26.1% versus 12.1%, P = 0.041) when compared with the reference population of African American LT recipients. Despite being higher risk at the time of LT, patients with SCD had equivalent posttransplant graft and patient survival when compared with the reference population (P = 0.5 and P = 0.2, respectively) and a 2:1 propensity score-matched group (P = 0.5 and P = 0.2, respectively). Two recent SLKT recipients with SCD from our institution have performed well with stable allograft function. CONCLUSIONS: Data from the SRTR demonstrate that patients with SCD can expect equivalent graft and patient survival after LT despite exhibiting more comorbidities at the time of LT. The low number of patients with SCD who underwent LT in the SRTR in comparison with the rate of chronic liver disease in this population raises the question as to whether a disparity in access to LT exists for this complex population.

Global experience and perspective on anonymous nondirected live donation in living donor liver transplantation.

Anonymous nondirected living liver donation (ANLLD), sometimes referred to as "altruistic" donation, occurs when a biologically unrelated person comes forward to donate a portion of his/her liver to a transplant candidate who is unknown to the donor. Here, we explore the current status of ANLLD with special consideration of published reports; US experience; impact on donor psychosocial outcomes; barriers to donation; and current global trends with respect to ethical considerations. Between 1998 and 2019, 105 anonymous nondirected living liver donor (ND-LLD) transplants have been documented in the US Scientific Registry of Transplant Recipients. Sixteen donors (15%) were reported to experience a postoperative complication. Currently, 89 donors remain alive (85%), 16 (15%) have unknown status, and none are confirmed deceased. Although there are only a handful of case series, these data suggest that ANLLD is a feasible option. While there are no liver-specific data, studies involving anonymous nondirected kidney donors suggest that anonymous donation does not adversely impact psychosocial outcomes in donors or recipients. There are substantial financial burdens and ethical considerations related to ANLLD. Further studies are required to assess donor demographics, psychosocial motivations, long-term health-related quality of life, and financial impact of ANLLD.

Regioselective Brønsted Acid-Catalyzed Annulation of Cyclopropane Aldehydes with N'-Aryl Anthranil Hydrazides: Domino Construction of Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones.

A highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives was achieved by reacting cyclopropane aldehydes with N'-aryl anthranil hydrazides in the presence of p-toluene sulfonic acid (PTSA). The transformation involves domino imine formation and intramolecular cyclization to form 2-arylcyclopropyl-2,3-dihydroquinolin-4(1H)-one, followed by nucleophilic ring opening of the cyclopropyl ring to form desired tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one in good to excellent yield with complete regioselectivity. This protocol tolerates a great variety of functional groups and thus provides a simple and step-efficient method for pyrroloquinazolinone synthesis.