Development of novel 9H-carbazole-4H-chromene hybrids as dual cholinesterase inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease affecting mental ability and neurocognitive functions. Cholinesterase enzymes affect concentration of acetylcholine in the brain, leading to dementia. Thus, there is an urgent need to develop novel dual cholinesterase inhibitors as possible anti-AD drugs. Herein, we have designed and synthesized a novel series of 9H-carbazole-4H-chromenes 4(a-l) through a one-pot three-component reaction of salicylaldehydes (1), hydroxycarbazole (2) and N-methyl-1-(methylthio)-2-nitroethenamine (3) using triethylamine as a catalyst in ethanol. Synthetic transformation involves the formation of two C-C bonds and one C-O bond in a single step to obtain desired analogs. The rapid one-pot reaction does not require chromatographic purification, proceeds under mild conditions, and exhibits good tolerance toward various functional groups with high synthetic yields. Synthesized compounds were screened for cytotoxicity using MTT assay in BV-2 microglial cells. These compounds were then in-vitro screened against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes. Most of these ligands have shown dual cholinesterase inhibitory activity compared to the standard drug. In-vitro results showed that the compounds 4a and 4d have promising anticholinesterase response against both cholinesterase enzymes (4a, AChE IC50: 5.76 µM, BuChE IC50: 48.98 µM; 4d, AChE IC50: 3.58 µM, BuChE IC50: 42.73 µM). In-vitro results were validated by molecular docking and dynamic simulation at 100 ns. Molecular docking and molecular dynamics simulation study strongly supported structural features present in these analogs. Together, these analogs could be exploited to develop dual anti-cholinesterase candidates to treat AD in combination with other drugs.

Selective C-H Activation of Unprotected Allylamines by Control of Catalyst Speciation.

An outstanding challenge in the Pd-catalyzed functionalization of allylamines is the control of stereochemistry. Terminal alkenes preferentially undergo Heck-type reactions, while internal alkenes may undergo a mixture of Heck and C-H activation reactions that give mixtures of stereochemical products. In the case of unprotected allylamines, the challenge in achieving C-H activation is that facile in situ formation of Pd nanoparticles leads to preferential formation of trans rather than cis-substituted products. In this study we have demonstrated the feasibility of using mono-protected amino acid (MPAA) ligands as metal protecting groups to prevent aggregation and reduction, allowing the selective synthesis of free cis-arylated allylamines. This method complements Heck-selective methods, allowing complete stereochemical control over the synthesis of cinnamylamines, an important class of amine that can serve as therapeutics directly or as advanced intermediates. To highlight the utility of the methodology, we have demonstrated rapid access to mu opioid receptor ligands.

Identification of structural scaffold from interbioscreen (IBS) database to inhibit 3CLpro, PLpro, and RdRp of SARS-CoV-2 using molecular docking and dynamic simulation studies.

A novel coronavirus SARS-CoV-2 has caused a worldwide pandemic and remained a severe threat to the entire human population. Researchers worldwide are struggling to find an effective drug treatment to combat this deadly disease. Many FDA-approved drugs from varying inhibitory classes and plant-derived compounds are screened to combat this virus. Still, due to the lack of structural information and several mutations of this virus, initial drug discovery efforts have limited success. A high-resolution crystal structure of important proteins like the main protease (3CLpro) that are required for SARS-CoV-2 viral replication and polymerase (RdRp) and papain-like protease (PLpro) as a vital target in other coronaviruses still presents important targets for the drug discovery. With this knowledge, scaffold library of Interbioscreen (IBS) database was explored through molecular docking, MD simulation and postdynamic binding free energy studies. The 3D docking structures and simulation data for the IBS compounds was studied and articulated. The compounds were further evaluated for ADMET studies using QikProp and SwissADME tools. The results revealed that the natural compounds STOCK2N-00385, STOCK2N-00244, and STOCK2N-00331 interacted strongly with 3CLpro, PLpro, and RdRp, respectively, and ADMET data was also observed in the range of limits for almost all the compounds with few exceptions. Thus, it suggests that these compounds may be potential inhibitors of selected target proteins, or their structural scaffolds can be further optimized to obtain effective drug candidates for SARS-CoV-2. The findings of in-silico data need to be supported by in-vivo studies which could shed light on understanding the exact mode of inhibitory action.Communicated by Ramaswamy H. Sarma.

Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents.

An efficient one-pot three-component reaction for the synthesis of [1,3]dioxolo[4',5':6,7]chromeno[2,3-b]pyridines 4(a-i) has been developed. Synthesis was achieved by reacting sesamol (1), aromatic aldehydes 2(a-i), and 2-aminopropene-1,1,3-tricarbonitrile (3) in the presence of triethylamine at 100 °C under neat reaction condition. Simple operational procedure, broad substrate scope, column chromatography free separations, and high yield of products make it an efficient and largely acceptable synthetic strategy. Synthesized compounds 4(a-i) were further screened for preliminary anticonvulsant activity using MES and scPTZ tests. These analogs were also checked for neurotoxicity and hepatotoxicity. Selected active compounds have been then screened quantitatively to determine ED50 and TD50 values. Analog 4h was found effective in both preclinical seizure models with significant therapeutic/toxicity profile (4h: ED50 = 34.7 mg/kg, MES test; ED50 = 37.9 mg/kg, scPTZ test; TD50 = 308.7 mg/kg). Molecular dynamic simulation for 100 ns of compound 4h-complexed with GABAA receptor revealed good thermodynamic behavior and fairly stable interactions (4h, Docking score = - 10.94). In conclusion, effective synthetic strategy, significant anticonvulsant activity with good toxicity profile and detailed molecular modeling studies led us to anticipate the emergence of these analogs as valid leads for the development of future effective neurotherapeutic agents.

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis.

Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole (IIIa-m) and aziridine (VIa and VIc) were afforded through a modified Schiff base green synthesis using ß-cyclodextrin-SO3H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with ß-cyclodextrin-SO3H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids (IIIa-m) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones (IVa-m) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C-S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC50 = 1.47 µM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC50 = 1.40 µM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc, and the results suggested that these two compounds could be potential leads for the treatment of cancer.

Arylidenemalononitriles as Versatile Synthons in Heterocyclic Synthesis.

BACKGROUND: Arylidenemalononitriles are valuable synthons for the construction of a variety of novel complex heterocyclic motifs, fused heterocycle derivatives, and spirocyclic compounds. They are versatile chemical intermediates and have increasing applications in industry, agriculture, medicine, and biological science. OBJECTIVE: The aim of this review is to highlight the preparation methods and reactions of arylidenemalononitriles in the synthesis of various heterocyclic compounds. CONCLUSION: In this review, we have presented the application of arylidenemalononitriles to construct a variety of heterocycles. Various catalysts for the preparation of arylidnemalononitriles have been described.

Why do subcutaneous ports get stuck? A case-control study.

PURPOSE: We sought to identify clinical features associated with difficult subcutaneous port removals in children. METHODS: Ports placed between April 2014 and September 2017 at our institution were prospectively tracked for difficult removals. A case-control analysis was performed. Patients with ports that were difficult to remove (stuck; cases) were compared to biological sex and age-matched controls in a ratio of 1:3. Logistic regression determined the association between case/control status and clinical features adjusting for biological sex and age as covariates. A multivariable analysis was performed to identify independent associations. RESULTS: 57 stuck ports (28 extreme [10 endovascular intervention] and 29 moderate) and 171 controls were analyzed. Stuck ports were associated with a diagnosis of acute lymphoblastic leukemia (86% cases versus 22.2% controls; p < 0.001) and a longer placement duration (median 2.6 years [interquartile range (IQR) 2.5-2.6] versus 0.8 years [IQR 0.5-1.4]; p < 0.001). On univariate analysis, procedural and device features associated with stuck ports included subclavian access (71.9% cases versus 48.5% controls; p = 0.0126), a polyurethane versus silicone catheter (96.5% cases versus 79.9% controls; p = 0.001), and a rough catheter appearance at removal (92.6% cases versus 9.4% controls; p < 0.0001). A diagnosis of ALL and duration of line placement were associated with having a stuck port on multivariate analysis. CONCLUSION: Polyurethane central venous catheters placed for the two-year treatment of acute lymphoblastic leukemia may become difficult to remove. This constellation of factors warrants more extensive preoperative discussion of risk, endovascular backup availability, and scheduling for longer operating room time.

Strategic analyses to identify key structural features of antiviral/antimalarial compounds for their binding interactions with 3CLpro, PLpro and RdRp of SARS-CoV-2: in silico molecular docking and dynamic simulation studies.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel member of the betacoronavirus family is a single-stranded RNA virus that has spread worldwide prompting the World Health Organization to declare a global pandemic. This creates an alarming situation and generates an urgent need to develop innovative therapeutic agents. In this context, an in silico molecular docking and molecular dynamics (MD) simulation study on the existing 58 antiviral and antimalarial compounds was performed on 3CLpro, PLpro and RdRp SARS-CoV-2 proteins. The antiviral compounds are best fitted in the binding pockets and interact more profoundly with the amino acid residues compared to antimalarial compounds. An HIV protease inhibitor, saquinavir showed a good dock score and binding free energy with varied binding interactions against 3CLpro and PLpro. While, adefovir, a nucleotide HBV DNA polymerase inhibitor exhibited good dock score and binding interactions against RdRp. Although, the antimalarial compounds showed relatively less dock score but were found to be crucial in displaying essential binding interactions with these proteins. The MD simulation runs for 100 ns on 3CLpro-saquinavir, PLpro-saquinavir and RdRp-adefovir complexes using Desmond revealed fairly stable nature of interactions. This study helped in understanding the key interactions of the vital functionalities that provide a concrete base to develop lead molecules effective against SARS-CoV-2.

Extraperitoneal Laparoscopy in Severe Intra-abdominal Adhesions: A Safe Alternative to Laparotomy.

Surgery in a frozen abdomen can be difficult and dangerous with a significant risk of visceral injuries. We report a case of a 26-year-old lady with chronic pelvic pain diagnosed to have large bilateral adnexal cysts on magnetic resonance imaging with normal tumor markers. She had previous two laparotomies for benign conditions. Laparoscopy was planned, but pneumoperitoneum could not be created due to dense intraperitoneal adhesions. Direct entry was done into the preperitoneal space followed by insufflation of gas in this space. Blunt and sharp dissection of this space was done without breaching the peritoneum to reach the adnexa. The adnexal cyst was found to be encysted collection due to adhesions from previous surgeries. Deroofing was done followed by the visualization of pelvic structures intraperitoneally. Extraperitoneal laparoscopy may be used as a safe alternative to laparotomy in patients with dense intra-abdominal adhesions with the advantage of faster postoperative recovery.

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines.

Palladium-catalyzed organometallic transformations of free amines are often unsuccessful due to side reactions, such as oxidation, that can occur. However, the ability to furnish the free amine products from these reactions is important for improving the utility and sustainability of these processes, especially for accessing their potential as medicinal and agrochemical agents. Notably, the 3,3-diarylallylamine motif is prevalent in a variety of biologically relevant structures, yet there are few catalytic approaches to their synthesis, and none involving the free amine. Herein, we describe a simple protocol for the arylation of cinnamylamines and the diarylation of terminal allylamines to generate a diverse group of 3,3-diarylallylamine products using a PdII precatalyst. Key features of the method are the ability to access relatively mild conditions that facilitate a broad substrate scope as well as direct diarylation of terminal allylamine substrates. In addition, several complex and therapeutically relevant molecules are included to demonstrate the utility of the transformation.

Palladium-Catalyzed γ,γ'-Diarylation of Free Alkenyl Amines.

The direct difunctionalization of alkenes is an effective way to construct multiple C-C bonds in one-pot using a single functional group. The regioselective dicarbofunctionalization of alkenes is therefore an important area of research to rapidly obtain complex organic molecules. Herein, we report a palladium-catalyzed γ,γ'-diarylation of free alkenyl amines through interrupted chain walking for the synthesis of Z-selective alkenyl amines. Notably, while 1,3-dicarbofunctionalization of allyl groups is well precedented, the present disclosure allows 1,3-dicarbofunctionalization of highly substituted allylamines to give highly Z-selective trisubsubstituted olefin products. This cascade reaction operates via an unprotected amine-directed Mizoroki-Heck (MH) pathway featuring a ß-hydride elimination to selectively chain walk to furnish a new terminal olefin which then generates the cis-selective alkenyl amines around the sterically crowded allyl moiety. This operationally simple protocol is applicable to a variety of cyclic, branched, and linear secondary and tertiary alkenylamines, and has a broad substrate scope with regard to the arene coupling partner as well. Mechanistic studies have been performed to help elucidate the mechanism, including the presence of a likely unproductive side C-H activation pathway.

Educational Utility of Social Media for Laparoscopic Surgery in India: A Cross-Sectional Survey of Popular Indian Communities on Facebook.

INTRODUCTION: The Covid pandemic and social distancing has adversely impacted the conventional apprenticeship method of postgraduate training in laparoscopic surgery. Social media may be a useful adjunct for laparoscopic training, but its utility in developing countries like India has not been studied carefully. This paper describes an observational, cross-sectional study on the educational utility of Facebook groups based in India and which focus on laparoscopic gynecologic surgery. METHODS: The most popular Facebook groups involving Indians and focusing on laparoscopic gynecology were identified using appropriate search terms as well as inclusion and exclusion criteria. Demographic data related to the groups, the authors of posts as well as descriptive statistics of all the posts during the study period were collected and appropriate statistical analysis was performed. RESULTS: All the groups in this study were large and growing steadily. Posts related to laparoscopy were more likely to be videos, dealing with operative techniques and having educational value for postgraduate residents (p value < 0.001) compared to posts unrelated to laparoscopic surgery. The majority of posts (88.2%) presented original content created by group members rather than material shared from other sources. Members preferred to share laparoscopic content using links to their personal YouTube channels rather than using institutional YouTube channels, dedicated websites for laparoscopic surgery or direct posts on Facebook. Group members liked educational content and laparoscopic surgery-related content significantly more than other content. Only 16.7% of the laparoscopic surgeons could be identified to be working in academic institutes. CONCLUSION: Social media for medical education has inherent advantages and disadvantages. This article provides objective data regarding its utilisation in a developing country in the midst of the Covid pandemic, and provides a guide for further research and development of innovative teaching methods.

A Review on Thiocyanation of Indoles.

BACKGROUND: The thiocyanation of indoles is a direct way for carbon-sulfur bond formation to access 3-thiocyanato-indoles. 3-thiocyanato-indoles exhibit potent biological and pharmacological activities and also serve as building blocks to synthesize many biologically active sulfur-containing indole derivatives. OBJECTIVE: The aim of this review is to highlight different approaches for the thiocyanation of indoles focusing on its scope and mechanism. CONCLUSION: In this review, we have summarized various methods for the thiocyanation of indoles. Selection of new methods for the preparation of 3-thiocyanato-indoles will be done. The mechanistic aspects and significance of the methods are also briefly discussed.

Regioselective α-Deuteration of Michael Acceptors Mediated by Isopropylamine in D2O/AcOD.

Site-specific hydrogen/deuterium exchange is an important method to access deuterated compounds for chemical and biological studies. Herein is reported the first method for the regioselective α-deuteration of enals and enones. The transformation features D2O and AcOD as deuterium sources and amines as organocatalysts. The deuteration strategy is scalable and works on enals with a variety of substituted arene or heterocycle motifs as well as enones. The method has been applied to the synthesis of deuterated drug precursors.

Effectiveness of Misoprostol in Office Hysteroscopy in Premenopausal Nulliparous Women: A Prospective Randomized Double-Blind Placebo-Controlled Trial.

STUDY OBJECTIVE: The objective of this was to evaluate the effectiveness of misoprostol in premenopausal nulliparous women with 200-mcg single vaginal dose 4 h before the procedure. DESIGN: This was a prospective randomized double-blind placebo-controlled trial. SETTING: This study was conducted in a tertiary care and academic research center. PATIENTS: One hundred patients were included in the study: 50 in misoprostol group and 50 in placebo. INTERVENTIONS: Patients underwent office hysteroscopy 4 h after vaginal application of misoprostol or placebo. MEASUREMENTS AND MAIN RESULTS: Ease of doing hysteroscopy was significantly better in the misoprostol group (difficulty score: 2.74 ± 1.20) as compared to placebo (difficulty score: 4.20 ± 1.10), P = 0.001. The time taken for negotiating the internal os (cervical passage time) was found to be significantly shorter in the misoprostol group (6.20 ± 5.21 s) as compared to placebo (14.78 ± 11.84 s), P = 0.001. The overall Visual Analog Scale (VAS) score was significantly lower in the intervention group (2.64 ± 1.62) as compared to placebo (4.90 ± 1.90), P = 0.001. Moreover, the VAS score at the point of passing internal os was significantly lower in the misoprostol group (2.82 ± 1.39) as compared to placebo (4.94 ± 1.96), P = 0.001. Misoprostol had a significant positive effect on satisfaction level of patients; 76% (n = 38) of women in the misoprostol group expressed their willingness to undergo the procedure again if required versus 18% (n = 9) in placebo, P = 0.001. Furthermore, 78% (n = 39) of women in the misoprostol group would recommend the procedure to their friends and relatives versus 36% (n = 18) in placebo, P = 0.001. CONCLUSION: Preoperative cervical preparation with 200 mcg of misoprostol vaginal application 4 h before office hysteroscopy in premenopausal nulliparous women significantly reduces the difficulty encountered in negotiating the cervical canal. Further, it significantly reduces the pain experienced by the patient at the point of passage through internal os as well as throughout the entire procedure.

Iron-Catalyzed Direct Julia-Type Olefination of Alcohols.

Herein, we report an iron-catalyzed, convenient, and expedient strategy for the synthesis of styrene and naphthalene derivatives with the liberation of dihydrogen. The use of a catalyst derived from an earth-abundant metal provides a sustainable strategy to olefins. This method exhibits wide substrate scope (primary and secondary alcohols) functional group tolerance (amino, nitro, halo, alkoxy, thiomethoxy, and S- and N-heterocyclic compounds) that can be scaled up. The unprecedented synthesis of 1-methyl naphthalenes proceeds via tandem methenylation/double dehydrogenation. Mechanistic study shows that the cleavage of the C-H bond of alcohol is the rate-determining step.

One-Pot C-H Arylation/Lactamization Cascade Reaction of Free Benzylamines.

An efficient method has been developed for the synthesis of seven-membered biaryl lactams involving Pd-catalyzed, native amine-directed, ortho-arylation of benzylamines followed by in situ lactamization. This cascade sequence is enabled by the use of 2-iodobenzoates, which facilitates C-H arylation from the free amine under conditions that typically require an improved directing group approach. This reaction is characterized by a broad substrate scope with good functional group tolerance. The need for an ester versus carboxylic acid-functionalized coupling partner is also explored, as is the potential for synthesizing eight-membered biaryl lactams. Various applications are also investigated, including access to the aza-brassinolide core.

Molecular Cobalt(II) Complexes for Tau Polymerization in Alzheimer's Disease.

Tau is an axonal protein known to form abnormal aggregates and is the biomarker of Alzheimer's disease. Metal-based therapeutics for inhibition of Tau aggregation is limited and rarely reported in contemporary science. Here, we report the first example of rationally designed molecular cobalt(II)-complexes for effective inhibition of Tau and disaggregation of preformed Tau fibrils. The mechanistic studies reveal that prevention of Tau aggregation by cobalt-based metal complexes (CBMCs) is concentration-dependent and Tau seldom exhibits conformational changes. Interestingly, CBMCs play dual role in causing disassembly of preformed aggregates as well as inhibition of complete Tau aggregation. Furthermore, CBMCs were nontoxic and maintained the tubulin network intact. CBMCs also prevented okadaic acid-induced toxicity in SH-SY5Y cells thus, preventing hyperphosphorylation of Tau. We believe that this unprecedented finding by the newly developed molecular complexes has a potential toward metal-based therapeutics for Alzheimer's disease.