Cascade Synthesis of New Indole-Containing Pentacyclic Scaffolds Mediated by Aryl and Iminyl Radicals.

A five-step approach, starting from simple 1,5-disubstituted indoles, has been implemented for the synthesis of diversely substituted indole-pyrido-indene pentacyclic compounds up to 54 % yield via domino radical-mediated processes in the presence of the radical reagents DLP/TTMSS and AIBN/TTMSS. Reactions proceeded with diverse key starting radical cyano-precursors strategically synthesized which were subsequently transformed into the target pentacyclic compounds through an aryl/iminyl radical-mediated domino reactions sequence. In addition to the routine spectroscopic techniques, the structure of radical precursors, as well as, the target pentacyclic products were unequivocally established by single crystal X-ray diffraction, confirming the effectiveness of the proposed synthetic sequence.

Analysis of adverse events in general surgery. Multicenter study.

Introduction: Knowledge of adverse events (AE) in acute care hospitals is a particularly relevant aspect of patient safety. Its incidence ranges from 3% to 17%, and surgery is related to the occurrence of 46%-65% of all AE.

Material And Methods: An observational, descriptive, retrospective, multicenter study was conducted with the participation of 31 Spanish acute-care hospitals to determine and analyze AE in general surgery services.

Synthesis, Anticancer and Antitubercular Properties of New Chalcones and Their Nitrogen-Containing Five-Membered Heterocyclic Hybrids Bearing Sulfonamide Moiety.

A new series of sulfonamides, , and , were synthesized by -sulfonation reaction with sulfonyl chlorides . Five new series of chalcone-sulfonamide hybrids were prepared via Claisen-Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (, () and carbothioamide derivatives.

Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel LDHA Inhibitors.

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24−31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24−31) were finally selected. These new pyrimidine-quinolone hybrids (24−31)(a−c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a−c) and 4-aryl-2-chloropyrimidines (1−4).

Design, synthesis, and molecular docking study of novel quinoline-based bis-chalcones as potential antitumor agents.

A novel series of quinoline-based symmetrical and unsymmetrical bis-chalcones was synthesized via a Claisen-Schmidt condensation reaction between 3-formyl-quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by using KOH/MeOH/H O as a reaction medium. Twelve of the obtained compounds were evaluated for their in vitro cytotoxic activity against 60 different human cancer cell lines according to the National Cancer Institute protocol. Among the screened compounds, the symmetrical N-butyl bis-quinolinyl-chalcone 14g and the unsymmetrical quinolinyl-bis-chalcone 17o bearing a 7-chloro-substitution on the N-benzylquinoline moiety and 4-hydroxy-3-methoxy substituent on the phenyl ring, respectively, exhibited the highest overall cytotoxicity against the evaluated cell lines with a GI range of 0.

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents.

A new series of N-substituted pyrazoline derivatives 6a-g, 7a-g, 8a-g, and 9a-g was synthetized by reaction of hydrazine derivatives and chalcone-thiazole hybrids bearing nitrogen mustard 5a-g. The chalcones 5a-g were obtained by Claisen-Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a-g. These new compounds 6/7/8/9a-g were screened for their antifungal activity against Cryptococcus neoformans, with IC values of 3.

Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors.

Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer.

New chalcone-sulfonamide hybrids exhibiting anticancer and antituberculosis activity.

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial).

Chloro-formyl steroids as precursors for hybrid heterosteroids: synthesis, spectroscopic characterization, and molecular and supramolecular structures.

Two new functionalized steroids containing both chloro and formyl substituents in ring A, and intended as precursors for the synthesis of hybrid systems, have been synthesized from ketosteroid precursors. 3-Chloro-2-formyl-17,17-dimethyl-18-nor-5α-androstane-2,13-diene, (I), and methyl 3-chloro-4-formyl-12-oxo-5β-cholan-3-ene-24-oate, CHClO, (IV), have been synthesized using Vilsmeier reactions with 17β-hydroxy-17α-methyl-5α-androstan-3-one and methyl 3,13-dioxo-5β-cholan-24-oate, respectively. These products have been fully characterized using IR spectroscopy, H and C NMR spectroscopy, and high-resolution mass spectrometry, and in the case of (IV), a single-crystal X-ray diffraction study.

Design of Two Alternative Routes for the Synthesis of Naftifine and Analogues as Potential Antifungal Agents.

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues and in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols and were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H₂SO₄ and HCl or Lewis acid like AlCl₃, respectively, led to naftifine, along with the target allylamines and . The antifungal assay results showed that intermediates (bearing both a β-aminoketo- and -methyl functionalities in their structures) and products were the most active.

A Schmidt rearrangement-mediated synthesis of novel tetrahydro-benzo[1,4]diazepin-5-ones as potential anticancer and antiprotozoal agents.

Novel tetrahydro-5H-benzo[e][1,4]diazepin-5-ones, several of them, containing the quinoline pharmacophore, were synthesized via a Schmidt rearrangement from their corresponding 1,2,3,4-tetrahydro-4-quinolones mediated by the NaN/HSO reaction conditions. Twelve of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where compound 24a presented a remarkable activity against 58 of the 60 cancer cell lines, with the most important GI values ranging from 0.047 to 8.

Microwave-Assisted Synthesis of Diversely Substituted Quinoline-Based Dihydropyridopyrimidine and Dihydropyrazolopyridine Hybrids.

An efficient, catalyst-free, and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro-1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products.

6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic Intermediates for the Synthesis of Pyrazolo[5,1-b]purines.

A microwave-assisted approach for the regioselective synthesis of functionalized 6-(aryldiazenyl)pyrazolo[1,5-a]pyrimidin-7-amines from the cyclization of 3-oxo-2-(2-arylhydrazinylidene)butanenitriles with 5-amino-1H-pyrazoles under solvent-free conditions has been developed. This methodology was distinguished by its broad substrate scope, operational simplicity, high atom economy, and high-yielding without requiring chromatographic purification. In addition, an efficient and versatile palladium-catalyzed reductive azo cleavage is disclosed for the synthesis of diverse heteroaromatic 1,2-diamines, a valuable synthetic building block to develop new fused heteroaromatic systems.

An efficient synthesis of new caffeine-based chalcones, pyrazolines and pyrazolo[3,4-b][1,4]diazepines as potential antimalarial, antitrypanosomal and antileishmanial agents.

A new series of chalcones 5a-f were synthesized from caffeine-based aldehyde 3 and substituted acetophenones 4a-f. Treatment of compounds 5a-f with hydrazine hydrate led to pyrazolines 6a-f, and their subsequent reaction with acetic anhydride or formic acid afforded the corresponding N-substituted pyrazolines 7a-f and 8a-f respectively. Additionally, the regioselective cyclocondensation reaction of chalcones 5a-f with 4,5-diaminopyrazole 9 afforded the diazepine derivatives 10a-f.

A new series of antibacterial nitrosopyrimidines: synthesis and structure-activity relationship.

New nitrosopyrimidines were synthesized and evaluated as potential antibacterial agents. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines displayed significant antibacterial activity against human pathogenic bacteria.

Synthesis and in vitro antitumor activity of a novel series of 2-pyrazoline derivatives bearing the 4-aryloxy-7-chloroquinoline fragment.

A new series of NH-pyrazoline derivatives 6 was synthesized by cyclocondensation reaction of novel [(7-chloroquinolin-4-yl)oxy]chalcones 5 with hydrazine hydrate. The treatment of pyrazolines 6 with acetic anhydride or formic acid yielded the N-acetyl- or N-formylpyrazoline derivatives 7-8, respectively. These novel 2-pyrazoline derivatives 6-8 were evaluated by the U.

Synthesis of novel polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-1,4-epoxy-1-benzazepines and cis-2-heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines as antiparasitic agents.

New series of polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-1,4-epoxy-1-benzazepines and cis-2-heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines were designed and synthesized in moderate to high yields using a three-step procedure from ortho-allylanilines. Their antiparasitic activity was evaluated against the extracellular and intracellular forms of Trypanosoma cruzi and Leishmania (Leishmania) infantum parasites. Their cytotoxicity was also determined on Vero and THP-1 mammalian cells.

Highly efficient and diastereoselective synthesis of new pyrazolylpyrrolizine and pyrazolylpyrrolidine derivates by a three-component domino process.

Diastereoselective reactions between 4-formylpyrazoles, N-substituted maleimides and glycine derivates led to new series of pyrazolyldipyrrolo [3,4-a:3',4'-f]pyrrolizines and pyrazolylpyrrolo[3,4-c]pyrroles in good yields. The reactions proceeded by a domino process through azomethine ylides formed in situ via a 1,3-dipolar cycloaddition reaction.

Microwave induced three-component synthesis and antimycobacterial activity of benzopyrazolo[3,4-b]quinolindiones.

Three series of novel 4-arylbenzo[h]pyrazolo[3,4-b]quinolin-5,6-diones 4, 7 and 9 have been efficiently obtained in good yields by three-component microwave assisted reaction between aminopyrazoles 1 or 6 (both 1-phenyl and 1-H substituted), 2-hydroxynaphthoquinone 2 and benzaldehydes 3. Compounds 4, 7 and 9 have been evaluated against fifteen Mycobacterium spp strains, and six of them have shown antimycobacterial activity. The highest inhibitory activity with MIC ≤2 μg/mL for three of these compounds (4a, 4b and 4g) was related with their highest lipophilicity and lesser polarity within these series.

Synthesis of novel analogs of 2-pyrazoline obtained from [(7-chloroquinolin-4-yl)amino]chalcones and hydrazine as potential antitumor and antimalarial agents.

A new series of N-acetyl and N-formyl-pyrazoline derivatives 6 and 7-8 were synthesized by cyclocondensation reaction of [(7-chloroquinolin-4-yl)amino]chalcones with hydrazine hydrate in acetic acid and hydrazine hydrate in formic acid respectively. These compounds were evaluated in vitro as antitumor and as antimalarial agents. Compounds 7b and 8b-e showed remarkable antitumor activity against cancer cell lines, with the most important GI50 values ranging from 0.

Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.

A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used.

Synthesis, antifungal and antitumor activity of novel (Z)-5-hetarylmethylidene-1,3-thiazol-4-ones and (z)-5-ethylidene-1,3-thiazol-4-ones.

New hetaryl- and alkylidenerhodanine derivatives 3a-d, 3e, and 4a-d were prepared from heterocyclic aldehydes 1a-d or acetaldehyde 1e. The treatment of several rhodanine derivatives 3a-d and 3e with piperidine or morpholine in THF under reflux, afforded (Z)-5-(hetarylmethylidene)-2-(piperidin-1-yl)thiazol-4(5H)-ones and 2-morpholinothiazol-4(5H)-ones 5a-d, 6a-d, and (Z)-5-ethylidene-2-morpholinothiazol-4(5H)-one (5e), respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry.

Microwave-assisted synthesis of pyrimido[4,5-b][1,6]naphthyridin-4(3H)-ones with potential antitumor activity.

The 6,7,8,9-tetrahydropyrimido[4,5-b][1,6]naphthyridin-4(3H,5H,10H)-ones 4,5a-g and their oxidized forms 6,7a-g were obtained from the catalyst-free reaction of 6-amino-2-methylthiopyrimidin-4(3H)-one 3 and (E)-3,5-bis(benzylidene)-1-alkyl-4-piperidones 1,2a-g under Microwave irradiation and their subsequent oxidation process with p-chloranil. Eighteen of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 4g presented a remarkable activity against 57 cancer cell lines, with the most important GI(50) values ranging from 1.48 to 9.

Efficient catalyst-free four-component synthesis of novel γ-aminoethers mediated by a Mannich type reaction.

Herein, it is provided an efficient and one-pot procedure for the synthesis of novel and diversely substituted γ-aminoethers in good yields through a four-component process by treatment of benzylamines with polyformaldehyde and activated alkenes in aliphatic alcohols acting both as solvent and as etherificant agents. Reactions proceeded via a Mannich-type reaction, where the formation of iminium ions and aminals was identified as the key intermediates to obtain the target products.