In Silico Design and Investigation of Novel Thiazetidine Derivatives as Potent Inhibitors of PrpR in Mycobacterium tuberculosis.

Tuberculosis is one of the most life-threatening acute infectious diseases diagnosed in humans. In the present investigation, a series of 16 new disubstituted 1,3-thiazetidines derivatives is designed, and investigated via various in silico methods for their potential as anti-tubercular agent by evaluating their ability to block the active site of PrpR transcription factor protein of Mycobacterium tuberculosis. The efficacy of the molecules was initially assessed with the help of AutoDock Vina algorithm. Further Glide module is used to redock the previously docked complexes. The binding energies and other physiochemical properties of the designed molecules were evaluated using the Prime-MM/GBSA and the QikProp module, respectively. The results of docking revealed the nature, site of interaction and the binding affinity between the proposed candidates and the active site of PrpR. Further the inhibitory effect of the scaffolds was predicted and evaluated employing a machine learning-based algorithm and was used accordingly. Further, the molecular dynamics simulation studies ascertained the binding characteristics of the unique 13, when analysed across a time frame of 100 ns with GROMACS software. The results show that the proposed 1,3-thiazetidine derivatives such as 10, 11, 13 and 14 could be potent and selective anti-tubercular agents as compared to the standard drug Pyrazinamide. Finally, this study concludes that designed thiazetidines can be employed as anti-tubercular agents. Undeniably, the results may guide the experimental biologists to develop safe and non-toxic drugs against tuberculosis by demanding further in vivo and in vitro analyses.

Anti-cancer property and DNA binding interaction of first row transition metal complexes: A decade update.

Metal ions carry out a wide variety of functions, including acid-base/redox catalysis, structural functions, signaling, and electron transport. Understanding the interactions of transition metal complexes with biomacromolecules is essential for biology, medicinal chemistry, and the production of synthetic metalloenzymes. After the coincidental discovery of cisplatin, importance of the metal complexes in biochemistry became a top priority for inquiry. In this review, a decade update on various synthetic strategies to first row transition metal complex and their interaction with DNA through non-covalent binding are explored. Moreover, this effort provides an excellent analysis on the efficacy of theoretical and practical approaches to the systematic generation of new non-platinum based metallodrugs for anti-cancer therapeutics.

Histopathological Profile of Central Nervous System Tumors in a Peripheral Tertiary Care Centre of West Bengal.

Introduction Central nervous system (CNS) tumor incidence is very low in comparison to other organ neoplasm. Recent increase in the incidence may be due to exposure of the population to various risk factors, genetic mutation, or improved diagnosis with advancement in diagnostic modalities. This study aims to observe the histopathological spectrum of CNS tumors with their clinical profile and basic demography at a single center in a peripheral region in West Bengal. Material and Methods A retrospective study was conducted in the department of pathology, Gouridevi Institute of Medical Sciences and Hospital (GIMSH), Durgapur, West Bengal, over a period of 2 years from October 2018 to September 2020 on CNS tumors. Basic demographic data, tumor site, and histopathological profile were obtained from medical records and further analyzed and graded according to the World Health Organization (WHO) classification. Result Among 42 cases of CNS tumors, 29 cases were from different regions of the brain and 13 cases were from the spinal cord, with a male to female ratio (1.21:1); the commonest age group was the sixth decade and most common tumor was meningioma, followed by astrocytic tumors. Conclusion The present study helps provide information regarding the burden of disease in our area. Despite the use of modern imaging techniques that help in the provisional diagnosis of disease, histological examination is the gold standard in diagnosis of varied types.

H2O2-Mediated Synthesis of a Quinazolin-4(3H)-one Scaffold: A Sustainable Approach.

A quinazolin-4(3H)-one ring system is a privileged heterocyclic moiety with distinctive biological properties. From this perspective, the development of an efficient strategy for the synthesis of quinazolin-4(3H)-one has always been in demand for the synthetic chemistry community. In this report, we envisaged an efficient protocol for the synthesis of quinazolin-4(3H)-one using substituted 2-amino benzamide with dimethyl sulfoxide (DMSO) as a carbon source and H2O2 as an effective oxidant. Mechanistically, the reaction proceeds through the radical approach with DMSO as one carbon source. To further substantiate the synthetic claim, the synthetic protocol has been extended to the synthesis of the anti-endotoxic active compound 3-(2-carboxyphenyl)-4-(3H)-quinazolinone.

[CMMIM][BF4 -] Ionic Liquid-Catalyzed Facile, One-Pot Synthesis of Chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6-ones: Evaluation of Their Photophysical Properties and Theoretical Calculations.

Herein, we have developed a novel synthetic route for the synthesis of chromeno[4,3-d]pyrido[1,2-a]pyrimidin-6-one derivatives 8a-q using an acid ionic liquid [CMMIM][BF4 -] 4 via one-pot, three-component synthesis in aqueous ethanol at room temperature. A series of 17 derivatives have been successfully prepared with up to 93% yield. All the synthesized derivatives were well characterized using 1H-NMR, 13C-NMR, and FT-IR spectral techniques. Additionally, the photophysical properties of 12 selected derivatives including molar extinction coefficient (ε), Stokes shift (Δυ̅), and quantum yield (Φ) varying from 0.52095 × 104 to 0.93248 × 104, 4216 to 4668 cm-1, and 0.0088 to 0.0459, respectively, have been determined. Furthermore, the experimental data are supported by density functional theory (DFT) and time-dependent DFT calculations. Theoretical investigations showed a trend similar to experimental results.

Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: in vitro evaluation of VEGFR-3 kinase inhibition activity.

An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3-nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 µM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.

1,3-Bis(carboxymethyl)imidazolium Chloride as a Sustainable, Recyclable, and Metal-Free Ionic Catalyst for the Biginelli Multicomponent Reaction in Neat Condition.

A simple and novel methodology has been developed for the synthesis of 1,3-bis(carboxymethyl)imidazolium chloride [BCMIM][Cl] salt. The ionic salt [BCMIM][Cl] catalyzed the reaction among arylaldehydes; the substituted 1,3-dicarbonyl compounds and urea/thiourea at 80 °C with 5 mol % under neat condition provided the substituted dihydropyrimidin-2(1H)-one/thiones in the synthesis step with yields of up to 96%. In addition, we synthesized the commercially available drug Monastrol by employing this methodology. The new synthesis method employs the benefits of a broad substrate scope, short reaction time, and high atom economy along with low catalyst loading in neat conditions, and is devoid of chromatographic purification. The ionic salt [BCMIM][Cl] was recycled and reused up to six cycles without substantial damage of its catalytic efficiency.

On water catalyst-free synthesis of benzo[d]imidazo[2,1-b] thiazoles and novel N-alkylated 2-aminobenzo[d]oxazoles under microwave irradiation.

A highly efficient unprecedented catalyst-free microwave-assisted procedure for synthesizing benzo[d]imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazol in green media was developed. The transformation provided rapid access to functionalized benzo[d]imidazo[2,1-b]thiazoles from 2-aminobenzothiazole and N-alkylated 2-aminobenzo[d]oxazole from 2-aminobenzoxazole scaffolds under mild transition-metal-free conditions. This synthetic manipulation is expected to greatly expand the repertoire of reaction types in heterocyclic chemistry and pave the way for new syntheses of bioactive compounds.

A Facile Microwave-Assisted Synthesis of Oxazoles and Diastereoselective Oxazolines Using Aryl-Aldehydes, p-Toluenesulfonylmethyl Isocyanide under Controlled Basic Conditions.

In this study, a highly efficient two-component [3 + 2] cycloaddition reaction of substituted aryl aldehydes with 4-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of 2 equiv of potassium phosphate as a base to 5-substituted oxazoles were established in a isopropanol medium under microwave irradiation. However, using 1 equiv of K3PO4 as a base resulted in the diastereoselective synthesis of 4,5-disubstituted oxazolines under identical reaction conditions. The foremost benefits of these protocols are the moderate-to-excellent yields with good functional group compatibility, simple experimental procedure, inexpensive readily available starting materials, nonchromatographic purification, and high bond-forming efficiency. The synthetic manipulation reported herein represents a cleaner route to the sustainable preparation of 5-substituted oxazoles and diastereoselective 4,5-disubstituted oxazolines derivatives.

Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-Assisted One-Pot, Telescopic Approach and Its Interaction with Biomacromolecules.

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach. The synthetic procedure reported herein represents a cleaner route toward thiazolidine-2-imines as compared to traditional methodologies. Moreover, the biological significance of combinatorially synthesized thiazolidin-2-imines has been investigated for their use as possible inhibitors for acetyl cholinesterase through molecular docking studies.

Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates.

INTRODUCTION: There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox-Gastaut syndrome (LGS). Areas covered: 1,4-disubstituted triazole ring formed by 1,3-dipolar cycloaddition reaction is an important structural motif widely used to construct diverse chemotypes in chemical, biological, and material fields. 1,2,3-triazole ring containing rufinamide, an antiepileptic drug developed by Novartis, is useful in combination with other antiepileptic medicaments for the treatment of childhood-onset epilepsy known as LGS. There are numerous synthetic methods used to construct the rufinamide through 1,3-dipolar cycloaddition. The application claims processes for the preparation of rufinamide and their intermediates. The synthetic strategy covered for the synthesis of rufinamide using activated acetylenic esters. The activation is done using N-hydroxy succinimide, N-hydroxyphthalimide, 1-hydroxy benzotriazole, and 4-nitro phenol. Expert opinion: The manufacturing route appears to follow the regioselective Cu catalyzed cycloaddtion of 2,6-difluro benzyl azide with or without isolated activated acetylenic esters in three steps that provide a good lead for new synthetic strategy for the rufinamide synthesis.

Rapid Construction of an Imidazo[4,5-b]pyridine Skeleton from 2-Chloro-3-nitropyridine via Tandem Reaction in H2O-IPA Medium.

A highly efficient, clean, and simple procedure for the synthesis of a privilege imidazo[4,5-b]pyridine scaffold from 2-chloro-3-nitropyridine in combination with environmentally benign H2O-IPA as a green solvent is presented. The scope of the novel method has been demonstrated through the tandem sequence of SNAr reaction with substituted primary amines followed by the in situ nitro group reduction and subsequent heteroannulation with substituted aromatic aldehydes to obtain functionalized imidazo[4,5-b]pyridines with only one chromatographic purification step. The synthesis pathway appears to be green, simple, and superior compared with other already reported procedures, with the high abundance of reagents and great ability in expanding the structural diversity.

Efficient Access to Imidazo[1,2- a]pyridines/pyrazines/pyrimidines via Catalyst-Free Annulation Reaction under Microwave Irradiation in Green Solvent.

An expeditious catalyst-free heteroannulation reaction for imidazo[1,2- a]pyridines/pyrimidines/pyrazines was developed in green solvent under microwave irradiation. Using H2O-IPA as the reaction medium, various substituted 2-aminopyridines/pyrazines/pyrimidines underwent annulation reaction with α-bromoketones under microwave irradiation to provide the corresponding imidazo[1,2- a]pyridines/pyrimidines/pyrazines in excellent yields. The synthetic methodology appears to be very simple and superior to the already reported procedures with the high abundance of commercial reagents and great ability in expanding the molecular diversity. The present synthetic sequence is visualized as an environmentally benign process which allows the introduction of three points of structural diversity to expand chemical space with excellent purity and yields. The anti-inflammatory and antimicrobial activities of the derivatives were evaluated. Screening results uncovered three derivatives with strong inhibition of albumin denaturation and two derivatives were active on Proteus and Klebsiella bacteria. These positive bioassay results implied that the library of potential anti-inflammatory agents could be rapidly prepared in an ecofriendly manner, and provided new insights into drug discovery for medicinal chemists.

Application of Pictet-Spengler Reaction to Indole-Based Alkaloids Containing Tetrahydro-ß-carboline Scaffold in Combinatorial Chemistry.

Indole-based alkaloids are well-known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-ß-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole-based alkaloids, as well as highly marketed drugs. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of these privileged tetrahydro-ß-carboline scaffolds. To date, there are numerous research reports that have been published on the synthesis of the tetrahydro-ß-carboline scaffold both on solid phase, as well as in solution phase. Moreover rapid growth has been observed for the enantioselective synthesis of tetrahydro-ß-carboline scaffold using chiral organocatalysts. In this Review, efforts have been taken to shed light on the latest information available on different strategies to synthesize tetrahydro-ß-carboline both on solid phase and in solution phase during the last 20 years. Furthermore, we believe that the present synthetic methodologies covered in this Review will help to improve the status of this privileged tetrahydro-ß-carboline scaffold in its use for drug discovery.

Calcified amyloid tumor of neck with exuberant giant cell reaction.

Amyloidosis is a group of disorders characterized by an extracellular deposition of an abnormal amount of proteins in a variety of organs resulting from abnormal folding of protein. It typically presents as disseminated deposits. Tumor like localized presentation of amyloidosis in the absence of systemic amyloidosis is referred to as amyloidoma or amyloid tumor. Amyloidoma is the least common presentation of tissue amyloid deposition. Amyloidoma of soft tissue is again a very rare entity, especially in the neck region. Calcification and minimum giant cell reaction can occur in amyloidoma. However, extensive calcification and exuberant giant cell reaction in amyloidoma of soft tissue neck make it difficult to diagnose. In this report, we discuss such a rare case with its differential diagnoses.

Microwave Controlled Reductive Cyclization: A Selective Synthesis of Novel Benzimidazole-alkyloxypyrrolo[1,2-a]quinoxalinones.

An efficient cascade synthesis of novel benzimidazole linked alkyloxypyrrolo[1,2-a]quinoxalinones was explored on soluble polymer support under microwave irradiation. Two exclusive protocols have been developed for the partial and full reductive cyclization by controlling the microwave energy. Commencing from the same substrate, ortho nitro pyrrol carboxylates, N-hydroxy pyrroloquinoxalinones were obtained by partial reductive cyclization (60 °C, 7 min), and the synthesis of pyrroloquinoxalinones was accomplished by full reductive cyclization (85 °C, 12 min). This method represents the first synthesis of N-hydroxy pyrroloquinoxalinones using Pd/C and ammonium formate as reducing agents. Further employing a variety of alkyl bromides, the obtained pyrroloquinoxalinones were transformed to their corresponding O- and N-alkylated analogues to deliver the diversified, novel molecular entities.

Nanoparticles with dual responses to oxidative stress and reduced ph for drug release and anti-inflammatory applications.

Oxidative stress and reduced pH are involved in many inflammatory diseases. This study describes a nanoparticle-based system that is responsive to both oxidative stress and reduced pH in an inflammatory environment to effectively release its encapsulated curcumin, an immune-modulatory agent with potent anti-inflammatory and antioxidant capabilities. Because of the presence of Förster resonance energy transfer between curcumin and the carrier, this system also allowed us to monitor the intracellular release behavior. The curcumin released upon triggering could efficiently reduce the excess oxidants produced by the lipopolysaccharide (LPS)-stimulated macrophages. The feasibility of using the curcumin-loaded nanoparticles for anti-inflammatory applications was further validated in a mouse model with ankle inflammation induced by LPS. The results of these studies demonstrate that the proposed nanoparticle system is promising for treating oxidative stress-related diseases.

Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy.

Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.

Multicomponent solvent-free synthesis of benzimidazolyl imidazo[1,2-a]-pyridine under microwave irradiation.

A novel one-pot, three-component reaction employing variously substituted benzimidazole-linked amino pyridines, aldehydes, and isonitriles catalyzed by scandium(III) triflate under solvent-free conditions were accomplished. This new synthetic methodology facilitates the rapid generation of intricate molecular frameworks in three-dimensional fashion leading to benzimidazole-imidazo[1,2-a] pyridines. This approach is envisioned as an environmentally benign process and a simple operation to the biological interesting compounds. The present synthetic sequence permits the introduction of three points of structural diversity to expand chemical space with high purity and excellent yields.

Calcium depletion-mediated protease inhibition and apical-junctional-complex disassembly via an EGTA-conjugated carrier for oral insulin delivery.

Calcium (Ca(2+)) has a crucial role in maintaining the intestinal protease activity and in forming the apical junctional complex (AJC) that preserves epithelial barrier function. Ethylene glycol tetraacetic acid (EGTA) is a Ca(2+)-specific chelating agent. To maintain the concentration of this chelator in areas where enzyme inhibition and paracellular permeation enhancement are needed, this study synthesized a poly(γ-glutamic acid)-EGTA conjugate (γPGA-EGTA) to form nanoparticles (NPs) with chitosan (CS) for oral insulin delivery. The results of our molecular dynamic (MD) simulations indicate that Ca(2+) ions could be specifically chelated to the nitrogen atoms, ether oxygen atoms, and carboxylate oxygen atoms in [Ca(EGTA)](2-) anions. By chelating Ca(2+), γPGA-EGTA conferred a significant insulin protection effect against proteases in intestinal tracts isolated from rats. Additionally, calcium depletion by γPGA-EGTA could stimulate the endocytosis of AJC components in Caco-2 cell monolayers, which led to a reversible opening of AJCs and thus increased their paracellular permeability. Single-photon emission computed tomography images performed in the biodistribution study clearly show the (123)I-insulin orally delivered by CS/γPGA-EGTA NPs in the heart, aorta, renal cortex, renal pelvis and liver, which ultimately produced a significant and prolonged hypoglycemic effect in diabetic rats. The above results confirm that this γPGA-EGTA conjugate is a promising candidate for oral insulin delivery.