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The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

In this work, we report the synthesis of three series of carbohydrate-based benzo[f]indole-4,9-diones and amino-1,4-naphthoquinone derivatives and evaluated their cytotoxic activity against eight human cancer cell lines. Several compounds showed a promising cytotoxic activity toward the tumor cell lines (half maximal inhibitory concentration (IC50) < 10.0 μM). The importance of the substitution pattern of the quinone derivatives on the antitumor activity was also discussed. 3-Carboethoxy-2-methyl-benzo[f]indole-4,9-dione derivatives were more cytotoxic than their parent compounds and amino-1,4-naphthoquinones. Unlike clinically useful anticancer agent doxorubicin, the majority of synthesized compounds did not exhibit any lytic effects against erythrocytes or normal human leukocytes.

Aims AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. Materials and methods A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. Key findings Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. Significance These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.

This work describes the first determination of the absolute configuration (AC) of (−)-cubebin by means of electronic circular dichroism (ECD), supported by quantum chemical calculations. The comparison of experimental ECD with the corresponding quantum chemical prediction for the proper diastereoisomer resulted in the definitive assignment of the AC of the naturally occurring (−)-cubebin as (8R,8aR,9S). The challenging determination of the relative configuration (RC) of cubebin based only on experimental nuclear magnetic resonance (NMR) methods is stressed. Computation of the 13C and 1H NMR chemical shifts for all the possible diastereoisomers leads to values of mean absolute error and root mean square deviation that do not allow distinguishing among them. Thus, errors in stereochemical determination can easily occur even when using two-dimensional methods, which clearly demonstrate the complexity of this special case. To determine the RC of this bioactive natural compound with high level of confidence, it was necessary to combine the DP4+ method with X-ray crystallography. Therefore, employing the commonly used empirical methods to determine the AC of (−)-cubebin can easily lead to misassignment of its stereochemistry.

Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4–32 μg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08–256 μg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.

1,2,3-triazole heterocycles stand out in medicinal chemistry for having great structural diversity and bioactivities. In this study, two series of triazoles were synthesized. One was obtained by the 1,3-dipolar cycloaddition reaction between ethyl cyanoacetate and several phenyl azides forming 1H-1,2,3-triazoles and the other by rearrangement of Dimroth forming and 2H-1,2,3-triazoles. Both series were shown to be active against the epimastigote form of Trypanosoma cruzi. The 1,2,3-triazoles 16d (S.I. between 100 and 200), 17d and 16f (S.I. > 200) were the most active compounds and capable of breaking the plasma membrane of trypomastigotes acting on CYP51 and inhibiting ergosterol synthesis. Candidate 16d exhibited the best and most favorable profile when interacting with CYP51.

We reported experimental and theoretical investigation of conformers of 1,2,3-triazole derivatives, substances of exclusively synthetic origin, subject of extensive studies, because of several biological properties, such as antiviral, antimicrobial and antileishmaniasis. We reported molecular/supramolecular X-ray structures of antiophidian compounds I and II. For I and II there are two crystallographic different molecules in the unit cell (A and B). To explore the causes of the similarities in the compound’s crystal structures, intermolecular interactions were explored using the Hirshfeld surface as the fingerprint plots. In addition, density functional theory (DFT) calculations were carried out at the ωB97x-D/6-31G(d,p)-PCM-CHCl3 level aiming to contribute to the interpretation of the experimental data and complement the experimental findings. Two structures named 2A and 5B were found in good agreement with the respective X-ray solid state ones (A and B). Theoretical 1H nuclear magnetic resonance (NMR) spectra calculated for 5B rotated structure (torsion angles deviation around 40° to 90°) was in fine agreement with experimental results (in CDCl3) indicating that the solution molecular structure is considerably different from optimized equilibrium geometries and solid-state structure. Therefore, care is needed when using X-ray structures or DFT geometries to model interaction of drugs with biological targets since significant conformational changes may take place in solution.

Candidiasis is a serious public health problem that currently affects not only immunodeficient patients with predisposing conditions, but also immunocompetent individuals. Thus, the search for new antifungal agents is required also due to the emergence of resistant strains and to the side effects of the available drugs. The aim of this study is to evaluate the in vitro antifungal profile of nine synthetic 1,2,3-triazole derivatives against four Candida species of medical importance (C. albicans, C. tropicalis, C. parapsilosis, and C. krusei), as well as to identify their in silico structure-activity relationship. Interestingly, the antifungal susceptibility tests showed the compound 5-methyl-1-(phenylamino)-1H-1,2,3-triazol-4-yl-methanol (2b) with the lowest minimal inhibitory concentration value against C. albicans strain (MIC = 8 μg/mL) similar to other promissing compounds described in the literature. According to our in silico evaluation, some stereoelectronic properties (e.g., higher values of log S and lowest unoccupied molecular orbital energy and lower number of atoms, rotatable bonds and Hydrogen bond acceptors) were correlated with the antifungal activity detected. This series reinforced the potential of 1,2,3-triazole as a promising nucleus in the search for new antifungals and may help on designing new drugs for candidiasis.

Pathogenic bacteria may cause serious infections, such as pneumonia, which can be fatal especially to immunosuppressed individuals. Hospitalized patients are particularly susceptible to antibiotic-resistant infections, which are worsened when caused by resistant Gram-negative pathogens due to there being few therapeutic options available. Thus, this work describes the synthesis and in vitro antimicrobial profile of 7-arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates and their halogenated aminoquinones against Gram-positive and Gram-negative bacteria. Interestingly, these bioactive substances have shown promising activity against Gram-negative pathogenic strains. Among these derivatives, two non-halogenated amino compounds exhibited promising MIC and MBC values (MIC = MBC = 1–2 μg mL−1) against Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853, two Gram-negative strains of clinical importance. In addition, mono- and di-brominated aminoquinones were also effective in preventing the growth of E. coli (MIC = MBC = 2–4 μg mL−1). The in vitro hemocompatibility evaluation showed a low toxicity profile for the active aminoquinones in hemolysis assays. These results suggest that these substances have potential for exploring the design of new antimicrobial prototypes against Gram-negative bacteria.

This work describes a new approach to obtain new β-vinylporphyrin derivatives through palladium-catalyzed cross-coupling reaction of 2-bromo-5,10,15,20-tetraphenylporphyrinatozinc(II) with N-tosylhydrazones. This is the first report of the use of such synthetic methodology in porphyrin chemistry allowing the synthesis of new derivatives, containing β-arylvinyl substituents.

A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed.

Aim: Cancer has emerged as a growing public health problem in many parts of the world. Methodology: We describe the synthesis of a series of carbohydrate-based isoquinoline-5,8-diones through the 1,4-addition reaction between 5,8-dioxo-5,8-dihydroisoquinoline and aminocarbohydrates. Halogenated quinones were also synthesized. Their inhibitory effects on the proliferation of human cancer cell lines were studied. Results & conclusion: The most promising compound, derived from isoquinoline-5,8-dione, containing ribofuranosidyl ring, was selectively active in vitro against H1299 cancer cells, with 1.7-fold higher activity than that of vinorelbine tartrate. This result suggests that the glycoconjugate in question may constitute a valuable lead compound to design and synthesize a more active and less toxic derivative with respect to the development of a new antitumor substance.

A novel series of carbohydrate-based naphthoquinones was synthesized and evaluated for cytotoxicity against different cancer cell lines. The compounds derived from 5-hydroxy-1,4-naphthoquinone (juglone) showed better cytotoxicity profiles against HCT-116, A-549 and MDA-MB 435 human cancer cells than the parent compound. The results suggest that the hydroxyl group on the aromatic ring increased the pro-oxidant activity of these new naphthoquinone derivatives. Furthermore, two derivatives were found to be more active against melanoma cells (MDA-MB435) than the clinically useful anticancer agent doxorubicin, and none of the compounds caused mouse erythrocyte lysis.

Starting from 2-hydroxy-1,4-naphthoquinone (lawsone), we synthesized eight new 6H-dibenzo[b,h]xanthene derivatives selectively under solvent-free conditions. Spectroscopic investigations confirmed that only the isomer 6H-dibenzo[b,h]xanthene was obtained in all eight cases. Computational studies provide a rationalization for the selective appearance of these isomers having as an intermediate an addition product.

A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed.

Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO(2), N-Br-FUR-NO(2), N-F-FUR-NO(2), N-Cl-FUR-NO(2)) showed promising MIC and MBC values (MIC = MBC = 1-16 μg/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials (e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds.

The aim of this paper was to revive the accurate determination of the boiling point of organic compounds using the percolator technique developed in the 1960s. Although this method is simple, fast and efficient it is omitted from current textbooks. This method has several advantages over Siwoloboff such as high reproducibility and direct measurement of the boiling point of the sample obtained by observing the temperature of the vapor-liquid equilibrium. The experiments were performed in the organic chemistry laboratory but allow interdisciplinary integration with other disciplines of several academic areas.

Bromoquinones have been attracted considerable interest from the scientific community as versatile intermediates in organic synthesis and as antitumor agents 1 . On the other hand, many sugar-containing naphthoquinones 2 or naphthoquinones having Nheterocyclic moiety also have been found to be compounds with antitumor activity. In this context, we describe the synthesis of a new class of brominated sugar-based naphthoquinone derivatives 1a–c (Scheme 2).

Juglone (3) is a natural compound isolated from nogueira plants (Juglans nigra) which has shown important cytotoxic activity 1 .Quinones fused to Nheterocyclic aromatic rings have been reported in the literature 2 as potential anticancer agents. On the basis of our experience in the field of the synthesis and biological evaluation of new quinonecarbohydrate conjugates 3 and 1,2,3-triazole derivatives, we described the synthesis and in vitro anticancer activity studies of new compounds type 1 in which Juglone and 1,2,3-triazole frameworks are directly attached (Scheme). RESULTS AND DISCUSSION The thermal 1,3-dipolar cycloaddition reaction between glycosyl azides 2a-b and juglone (3) afforded corresponding 5-hydroxy-1-substituted-1Hnaphtho[2,3-d][1,2,3-]triazole-4,9-diones 1a-b, in moderated yields, and unexpected naphthoquinone derivatives 4a-b, which possess an aminocarbohydrate chain at the C-2 position of the quinone ring.

INTRODUCTION Recently, we described the synthesis and pharmacological evaluation of 1,2,3-triazole derivatives. 1 In this study, it was found that the compounds 1-[(5 -methyl-1 -(4 fluorophenylamino)-1H-1,2,3-triazol-4 -yl)carbonyl]2-(4 methylphenylsulfonyl)hydrazine and 1-[(5 methyl-1 -(2 ,5 -dichlorophenylamino)-1H-1,2,3triazol-4 -yl)carbonyl]-2-(phenylsulfonyl)hydrazine exhibited a significant effect against HSV-1 replication in cell culture. In an effort to optimize the antiviral activity of these structurally triazole compounds, we now described the synthesis of a new family of triazol derivates 1a-f.

INTRODUCTION The synthesis of aminoquinones and related compounds has attracted considerable attention, because they exhibit a wide spectrum of pharmaceutical activities including antitumor and antimalarial properties 1 . Two general methods are available for the synthesis of aminoquinones 2 : nucleophilic substitution reaction of halo-derivative quinones with amines and direct 1,4-type addition of amines to quinones, with or without Lewis acid conditions under ultrasonic irradiation. As part of an ongoing research program on the synthesis of new quinone derivatives and on the basis of our experience in the field of the use of carbohydrates in organic synthesis, we herein report an extension of the second approach 3 which led to three novel isoquinoline-5,8-quinone derivatives 1a-c, possessing a carbohydrate chain at C-7position of the quinone ring.

Snake venoms are complex mixtures of proteins of both enzymes and nonenzymes, which are responsible for producing several biological effects. Human envenomation by snake bites particularly those of the viperid family induces a complex pathophysiological picture characterized by spectacular changes in hemostasis and frequently hemorrhage is also seen. The present work reports the ability of six of a series of 1,2,3-triazole derivatives to inhibit some pharmacological effects caused by the venoms ofBothrops jararacaandLachesis muta.In vitroassays showed that these compounds were impaired in a concentration-dependent manner, the fibrinogen or plasma clotting, hemolysis, and proteolysis produced by both venoms. Moreover, these compounds inhibited biological effectsin vivoas well. Mice treated with these compounds were fully protected from hemorrhagic lesions caused by such venoms. But, only theB. jararacaedema-inducing activity was neutralized by the triazoles. So the inhibitory effect of triazoles derivatives against somein vitroandin vivobiological assays of snake venoms points to promising aspects that may indicate them as molecular models to improve the production of effective antivenom or to complement antivenom neutralization, especially the local pathological effects, which are partially neutralized by antivenoms.

The current treatment used against envenomation by Lachesis muta venom still presents several side effects. This paper describes the synthesis, pharmacological and theoretical evaluations of new 1-arylsulfonylamino-5-methyl-1 H -[1,2,3]-triazole-4-carboxylic acid ethyl esters ( 8a – f) tested against the hemolytic profile of the L. muta snake venom. Their structures were elucidated by one- and two-dimensional NMR techniques ( 1 H, APT, HETCOR 1 J CH and n J CH , n = 2, 3) and high-resolution electrospray ionization mass spectrometry. The series of triazole derivatives significantly neutralized the hemolysis induced by L. muta crude venom presenting a dose-dependent inhibitory profile (IC 50 = 30−83 μM) with 1-(4′-chlorophenylsulfonylamino)-5-methyl-1 H -[1,2,3]-triazole-4-carboxylic acid ethyl ester (8e) being the most potent compound. The theoretical evaluation revealed the correlation of the antiophidian profile with the coefficient distribution and density map of the Highest Occupied Molecular Orbitals (HOMO) of these molecules. The elucidation of this new series may help on designing new and more efficient antiophidian molecules.

Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1 H -1,2,3-triazole-4-carbohydrazides ( 8a–b , 8e–f , 8i–j and 8n–o) and new analogues ( 8c–d , 8g–h , 8l–m and 8p–q) . These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone ( NAH ) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC = 2.5 μg/mL) similar to or better than the current drugs on the market. The theoretical structure–activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO 2 ) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.