The Persistence of Hydrogen Bonds in Pyrimidinones: From Solution to Crystal.

Pyrimidinone scaffolds are present in a wide array of molecules with synthetic and pharmacological utility. The inherent properties of these compounds may be attributed to intermolecular interactions analogous to the interactions that molecules tend to establish with active sites. Pyrimidinones and their fused derivatives have garnered significant interest due to their structural features, which resemble nitrogenous bases, the foundational building blocks of DNA and RNA.

Synthesis and Antimycobacterial Evaluation of Novel Pyrazole-Isoxazolines and Pyrazole-Isoxazoles.

This study reports the synthesis of a new series of pyrazole-isoxazolines, at very good yields, from the cyclocondensation reaction of pyrazole-enaminones with hydroxylamine hydrochloride. Dehydration of the pyrazole-isoxazolines furnished another new series of the respective pyrazole-isoxazoles, at excellent yields. Both series of the obtained compounds were screened for antimycobacterial activity, and compounds 4 f and 5 c showed significant inhibition of bacterial growth with a time- and concentration-dependent bactericidal effect.

1,2,3-Triazolo[4,5-b]aminoquinolines: Design, synthesis, structure, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, and molecular docking of novel modified tacrines.

An efficient [4 + 2] cyclization protocol to synthesize a series of twelve examples of 1,2,3-triazolo[4,5-b]aminoquinolines (5) as novel structurally modified tacrines was obtained by reacting readily accessible precursors (i.e., 3-alky(aryl)-5-amino-1,2,3-triazole-4-carbonitriles (3)) and selected cycloalkanones (4) of five-, six-, and seven-membered rings.

Regiocontrolled Synthesis of 1-Substituted-3(5)-carboxyalkyl-1-pyrazoles Using Trichloromethyl Enones.

In this work, we present a regiocontrolled methodology to prepare 1-substituted-3(5)-carboxyalkyl-1-pyrazoles using trichloromethyl enones as starting materials. It was found that the selectivity of the reaction depends on the nature of the hydrazine: when using arylhydrazine hydrochlorides, synthesis of the 1,3-regioisomer was achieved (22 examples, 37-97% yields), while the corresponding free hydrazine led exclusively to the 1,5-regioisomer (12 examples, 52-83% yields). The trichloromethyl group was used as a precursor for the carboxyalkyl moiety, furnishing a one-pot three-component regioselective protocol suitable for preparing both isomers at moderate to excellent yields.

Intramacrophage potential of a tetrahydropyridine: A promising compound in combating Mycobacterium tuberculosis.

Due to several obstacles in treating tuberculosis (TB), the search for new therapeutic alternatives remains a global priority. The nitrogenous heterocyclic compounds are promising in searching for new anti-Mycobacterium tuberculosis molecules, and our previous results highlight the potential of tetrahydropyridines. After exploring the antimycobacterial potential and putative mechanism of action of a tetrahydropyridine derivative (NUNL02), we seek to measure the oxidative stress caused by NUNL02 inside the extracellular replicating M.

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.

Chemoselective -Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1)-ones Using 4-(Iodomethyl)pyrimidines.

This study reports two strategies for preparing -alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1)-ones: a linear protocol of alkylation, using a -building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective -alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70-98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.

Bromo-Substituted Diazenyl-pyrazolo[1,5-a]pyrimidin-2-amines: Sonogashira Cross-Coupling Reaction, Photophysical Properties, Bio-interaction and HSA Light-Up Sensor.

A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated.

Substituent-Driven Selective -/-Alkylation of 4-(Trihalomethyl)pyrimidin-2(1)-ones Using Brominated Enones.

The selective - or -alkylation of 4-(trihalomethyl)pyrimidin-2(1)-ones, using 5-bromo enones/enaminones as alkylating agents, is reported. It was found that the selectivity toward the - or -regioisomer is driven by the substituent present at the 6-position of the pyrimidine ring, thus enabling the preparation of each isomer as the sole product, in 60-95% yields. Subsequent cyclocondensation of the enaminone moiety with nitrogen dinucleophiles led to pyrimidine-azole conjugates in 55-83% yields.

Photophysical, photostability, and ROS generation properties of new trifluoromethylated quinoline-phenol Schiff bases.

A new series of ten examples of Schiff bases, namely ()-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols , was easily synthesized with yields of up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines and 4(5)-R-substituted salicylaldehydes - in which alkyl/aryl/heteroaryl for 2-R-substituents are Me, Ph, 4-MeCH, 4-FCH, 4-NOCH, and 2-furyl, and R-substituents are 5-NEt, 5-OCH, 4-Br, and 4-NO. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values in CHCl (Φ = 0.12-0.

Ultrasound-assisted synthesis of pyrimidines and their fused derivatives: A review.

The pyrimidine scaffold is present in many bioactive drugs; therefore, efficient synthetic routes that provide shorter reaction times, higher yields, and site-selective reactions are constantly being sought. Ultrasound (US) irradiation has emerged as an alternative energy source in the synthesis of these heterocyclic scaffolds, and over the last ten years there has been a significant increase in the number of publications mentioning US in either the construction or derivatization of the pyrimidine core. This review presents a detailed summary (with 140 references) of the effects of US (synergic or not) on the construction and derivatization of the pyrimidine core through classical reactions (e.

2,2,2-trifluoro-1-(1,4,5,6-tetrahydropyridin-3-yl)ethanone derivative as efflux pump inhibitor in Mycobacterium tuberculosis.

Although the administration of combined therapy is efficient to tuberculosis (TB) treatment caused by susceptible Mycobacterium tuberculosis strains, to overcome the multidrug resistance is still a challenge. Some studies have reported evidence about tetrahydropyridines as a putative efflux pump inhibitor, including in mycobacteria, being a promising strategy against M. tuberculosis.

Antimicrobial and Toxicity Evaluation of Imidazolium-Based Dicationic Ionic Liquids with Dicarboxylate Anions.

Imidazolium-based dicationic ILs (DILs) presenting antimicrobial activity and relatively low toxicity are highly desirable and are envisioned for use in live tissue to prevent bacterial or fungal infections. In this context, we present here DILs with dicarboxylate anions [C(MIM)[C(MIM)][CO-(CH)CO], in which = 4, 6, 8, and 10, and m = 0, 1, 2, 3, 4, and 5. The results showed that DILs with an alkyl chain spacer of ten carbons were active against yeasts and the bacterial strains tested.

A novel 1-((3-(2-toluyl)-4,5-dihydroisoxazol-5-yl)methyl)-4-(trifluoromethyl)pyrimidin-2(1H)-one activates intrinsic mitochondria-dependent pathway and decreases angiogenesis in PC-3 cells.

Prostate cancer is among the most common cancer diagnoses in men, and the best treatment for patients with metastatic disease in advanced stages is still unclear. Previously, we have demonstrated that the three 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2- ones derivatives (8a, 8e and 9c) present important cytotoxicity and selectivity for tumoral cells. Considering that various cytotoxic drugs have been assessed in patients with prostate cancer, but few drugs show survival advantage, we decided to study these three compounds (8a, 8e and 9c) in prostate cancer cells, androgen receptor (AR)-positive 22Rv-1 and AR-negative PC-3 cells.

Chitin-psyllium based aerogel for the efficient removal of crystal violet from aqueous solutions.

A new alternative aerogel was prepared from low-cost chitin and psyllium biopolymers to adsorb crystal violet (CV) dye from liquid media and possibly treat effluents containing other dyes. The aerogel was characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM), which demonstrated that aerogel has a typical structure of amorphous materials and presented a randomly interconnected porous structure that resembles an open pore network. 2.

7-Amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes]: Synthesis and cholinesterase inhibitory activity of structurally modified tacrines.

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC = 3.

Novel Alkyl(aryl)-Substituted 2,2-Difluoro-6-(trichloromethyl)-2-1,3,2-oxazaborinin-3-ium-2-uides: Synthesis, Antimicrobial Activity, and CT-DNA Binding Evaluations.

The synthesis, antimicrobial activity evaluations, biomolecule-binding properties (DNA), and absorption and emission properties of a new series of ()-1,1,1-trichloro-4-alkyl(aryl)amino-4-arylbut-3-en-2-ones and 2,2-difluoro-3-alkyl(aryl)amino-4-aryl-6-(trichloromethyl)-2-1,3,2-oxazaborinin-3-ium-2-uides in which 3(4)-alkyl(aryl) = H, Me, -propyl, -butyl, CH, 4-CHCH, 4-CHOCH, 4-NOCH, 4-FCH, 4-BrCH, 2-naphthyl, is reported. A series of β-enaminoketones is synthesized from the O,N-exchange reaction of some amines with ()-1,1,1-trichloro-4-methoxy-4-aryl-but-3-en-2-ones at 61-90% yields. Subsequently, reactions of the resulting β-enaminoketones with an appropriate source of boron (BF.

Biological assays of BF-naphthyridine compounds: Tyrosinase and acetylcholinesterase activity, CT-DNA and HSA binding property evaluations.

The present work reports the biological assays between synthetic BF-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA.

Abnormal ankle-brachial index (ABI) predicts primary and secondary cardiovascular risk and cancer mortality.

Background: An abnormal ankle-brachial pressure index (ABI) is a marker of the risk for increased total and cardiovascular (CV) mortality. However, it is not clear whether it is associated with an even worse prognosis in patients with previous CV events or with cancer mortality.

Materials And Methods: Consecutive subjects undergoing ABI assessment for suspected peripheral artery disease or for stratification of CV risk in ten centers in the Veneto Region (northeast Italy), between 2011 and 2014 were enrolled.

The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants.

The novel direct oral anticoagulants (DOAC) have been shown to be at least as effective as and safer than conventional anticoagulants for the initial and long-term treatment of venous thromboembolic disorders. However, the rate of post-thrombotic syndrome (PTS) in patients with deep-vein thrombosis (DVT) treated with the DOACs is unknown. With the adoption of the Villalta scale, we assessed the rate of PTS at the end of the follow-up period in a consecutive series of 309 outpatients with acute proximal DVT who had received at least 3 months of treatment with a DOAC and had been followed-up for up to 3 years.

Supramolecular Similarity in Polymorphs: Use of Similarity Indices (I).

A systematic investigation to assess the degree of similarity between polymorphs was carried out. A similarity indices (I) approach was applied in ten series of polymorphs with different characteristics and number of molecules in the asymmetric unit. Geometric (I), contact area (I), and stabilization energy (I) parameters were used.

Supramolecular Packing of a Series of -Phenylamides and the Role of NH···O=C Interactions.

A series of seven -phenylamides [R-C(O)NHPh, in which R: CH, C(CH), Ph, CF, CCl, CBr, and H] were used as models in this study. Molecular packing and intermolecular interactions were evaluated by theoretical calculations, solution NMR, and quantum theory of atoms in molecules analyses. Crystallization mechanisms were proposed based on the energetic and topological parameters using the supramolecular cluster as demarcation.

In silico and in vitro evaluation of tetrahydropyridine compounds as efflux inhibitors in Mycobacterium abscessus.

Herein, we evaluated tetrahydropyridine (THP) compounds (NUNM) as antimicrobials and inhibitors of the efflux mechanism in M. abscessus. subsp.