Chemistry and anti-herpes simplex virus type 1 evaluation of 4-substituted-1H-1,2,3-triazole-nitroxyl-linked hybrids.

HSV disease is distributed worldwide. Anti-herpesvirus drugs are a problem in clinical settings, particularly in immunocompromised individuals undergoing herpes simplex virus type 1 infection. In this work, 4-substituted-1,2,3-1H-1,2,3-triazole linked nitroxyl radical derived from TEMPOL were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. The nitroxide derivatives were characterized by infrared spectroscopy and elemental analysis, and three of them had their crystal structures determined by single-crystal X-ray diffraction. Four hybrid molecules showed important anti-HSV-1 activity with IC50 values ranged from 0.80 to 1.32 µM. In particular, one of the nitroxide derivatives was more active than Acyclovir (IC50 = 0.99 µM). All compounds tested were more selective inhibitors than the reference antiviral drug. Among them, two compounds were 4.5 (IC50 0.80 µM; selectivity index CC50/IC50 3886) and 7.7 times (IC50 1.10 µM; selectivity index CC50/IC50 6698) more selective than acyclovir (IC50 0.99 µM; selectivity index CC50/IC50: 869). These nitroxide derivatives may be elected as leading compounds due to their antiherpetic activities and good selectivity.

Molecular modeling of a series of dehydroquinate dehydratase type II inhibitors of Mycobacterium tuberculosis and design of new binders.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), is still responsible for a large number of fatal cases, especially in developing countries with alarming rates of incidence and prevalence worldwide. Mycobacterium tuberculosis has a remarkable ability to develop new resistance mechanisms to the conventional antimicrobials treatment. Because of this, there is an urgent need for novel bioactive compounds for its treatment. The dehydroquinate dehydratase II (DHQase II) is considered a key enzyme of shikimate pathway, and it can be used as a promising target for the design of new bioactive compounds with antibacterial action. The aim of this work was the construction of QSAR models to aid the design of new potential DHQase II inhibitors. For that purpose, various molecular modeling approaches, such as activity cliff, QSAR models and computer-aided ligand design were utilized. A predictive in silico 4D-QSAR model was built using a database comprising 86 inhibitors of DHQase II, and the model was used to predict the activity of the designed ligands. The obtained model proved to predict well the DHQase II inhibition for an external validation dataset ([Formula: see text] = 0.72). Also, the Activity Cliff analysis shed light on important structural features applied to the ligand design.

Crystal structure of 1-anilino-5-methyl-1H-1,2,3-triazole-4-carb-oxy-lic acid monohydrate.

In the mol-ecular structure of the title compound, C10H10N4O2·H2O, the angle between the triazole and arene rings is 87.39 (5)°. The water of crystallization connects the mol-ecules in the crystal packing. The crystal structure exhibits N-H⋯O, O-H⋯O and O-H⋯N inter-actions, resulting in the formation of a three-dimensional framework. The inter-molecular inter-actions were identified and qu-anti-fied using Hirshfeld surface analysis.

Identification of a Selective PDE4B Inhibitor From Bryophyllum pinnatum by Target Fishing Study and In Vitro Evaluation of Quercetin 3-O-α-L-Arabinopyranosyl-(1→2)-O-α-L-Rhamnopyranoside.

Natural products are considered an important source of bioactive compounds especially in biodiversity-rich countries like Brazil. The identification of potential targets is crucial to the development of drugs from natural sources. In this context, in silico methodologies, such as inverse virtual screening (target fishing), are interesting tools as they are a rational and direct method that reduces costs and experimental time. Among the species of Brazilian biomes, Bryophyllum pinnatum (Lam.) Oken, native to Madagascar, is widely used by the population to treat inflammation conditions. It has a remarkable presence of flavonoids, including quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside (1), considered one of its major compounds. However, until now there were no studies addressing its putative mechanism of action and explaining its pharmacological action. The enzyme PDE4B, known as an antiinflammatory protein, was indicated as a promising target by target fishing methods. This activity was confirmed by in vitro enzymatic inhibition, and an expressive selectivity of PDE4B over PDE4A was demonstrated. The interactions were investigated through molecular dynamics simulations. The results were pioneering, representing an advance in the investigation of the antiinflammatory action of B. pinnatum and confirm the potential of the flavonoid as a chemical extract marker. Also, the flavonoid was shown to be a promising lead for the design of other selective PDE4B blockers to treat inflammatory diseases.

Tempol, a superoxide dismutase-mimetic drug, prevents chronic ischemic renal injury in two-kidney, one-clip hypertensive rats.

Tempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.

New families of hetero-tri-spin 2p-3d-4f complexes: synthesis, crystal structures, and magnetic properties.

In this work we report the synthesis, crystal structures, and magnetic behavior of 2p-3d-4f heterospin systems containing the nitroxide radical 4-azido-2,2,6,6-tetramethylpiperidine-1-oxyl radical (N3tempo). These compounds were synthesized through a one-pot reaction by using [Cu(hfac)2], [Ln(hfac)3] (hfac = hexafluoroacetylacetonate, Ln = Dy(III), Tb(III) or Gd(III)), and the N3tempo radical. Depending on the stoichiometric ratio used, the synthesis leads to penta- or trimetallic compounds, with molecular formulas [Cu3Ln2(hfac)8(OH)4(N3tempo)] (Ln = Gd, Tb, Dy) and [CuLn2(hfac)8(N3tempo)2(H2O)2] (Ln = Gd, Dy). The magnetic properties of all compounds were investigated by direct current (dc) and alternating current (ac) measurements. The ac magnetic susceptibility measurements of Tb(III)- and Dy(III)-containing compounds of both families revealed slow relaxation of the magnetization, with magnetic quantum tunneling in zero field.

Exploring N-acylhydrazone derivatives against clinical resistant bacterial strains.

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.

Synthetic indole and melatonin derivatives exhibit antimalarial activity on the cell cycle of the human malaria parasite Plasmodium falciparum.

Discovering the mechanisms by which cell signaling controls the cell cycle of the human malaria parasite Plasmodium falciparum is fundamental to designing more effective antimalarials. To better understand the impacts of melatonin structure and function on the cell cycle of P. falciparum, we have synthesized two families of structurally-related melatonin compounds (7-11 and 12-16). All synthesized melatonin analogs were assayed in P. falciparum culture and their antimalarial activities were measured by flow cytometry. We have found that the chemical modification of the carboxamide group attached at C-3 position of the indole ring of melatonin (6) was crucial for the action of the indole-related compounds on the P. falciparum cell cycle. Among the melatonin derivatives, only the compounds 12, 13 and 14 were capable of inhibiting the P. falciparum growth in low micromolar IC50. These results open good perspectives for the development of new drugs with novel mechanisms of action.

Antivenom effects of 1,2,3-triazoles against Bothrops jararaca and Lachesis muta snakes.

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 of Bothrops jararaca and Lachesis muta. In vitro assays 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 effects in vivo as well. Mice treated with these compounds were fully protected from hemorrhagic lesions caused by such venoms. But, only the B. jararaca edema-inducing activity was neutralized by the triazoles. So the inhibitory effect of triazoles derivatives against some in vitro and in vivo biological 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.

Synthesis using microwave irradiation and antibacterial evaluation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-naphthoquinones.

This paper describes a novel series of N,O-acetals and N,S-acetals (7a-o) derived from 2-amino-1,4-naphthoquinones that were synthesized and evaluated as potential antimicrobial agents. These compounds were obtained in good yields using microwave irradiation, and several of them showed promising antibacterial profiles. Three of our biologically active 2-amino-1,4-naphthoquinone N,O-acetals and N,S-acetals tested against hospital bacterial strains were identified as potential lead compounds. Characterization of all compounds was performed using one-dimensional NMR techniques ((1)H, (13)C-APT), IR spectra, elemental analyses and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS).

Nitroxides attenuate carrageenan-induced inflammation in rat paws by reducing neutrophil infiltration and the resulting myeloperoxidase-mediated damage.

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) and other cyclic nitroxides have been shown to inhibit the chlorinating activity of myeloperoxidase (MPO) in vitro and in cells. To examine whether nitroxides inhibit MPO activity in vivo we selected acute carrageenan-induced inflammation on the rat paw as a model. Tempol and three more hydrophobic 4-substituted derivatives (4-azido, 4-benzenesulfonyl, and 4-(4-phenyl-1H-1,2,3-triazol-1-yl)) were synthesized, and their ability to inhibit the in vitro chlorinating activity of MPO and carrageenan-induced inflammation in rat paws was evaluated. All of the tested nitroxides inhibited the chlorinating activity of MPO in vitro with similar IC(50) values (between 1.5 and 1.8 µM). In vivo, the attenuation of carrageenan-induced inflammation showed some correlation with the lipophilicity of the nitroxide at early time points but the differences in the effects were small (<2-fold) compared with the differences in lipophilicity (>200-fold). No inhibition of MPO activity in vivo was evident because the levels of MPO activity in rat paws correlated with the levels of MPO protein. Likewise, paw edema, levels of nitrated and oxidized proteins, and levels of plasma exudation correlated with the levels of MPO protein in the paws of the animals that were untreated or treated with the nitroxides. The effects of the nitroxides in vivo were compared with those of 4-aminobenzoic hydrazide and of colchicine. Taken together, the results indicate that nitroxides attenuate carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting MPO-mediated damage. Accordingly, tempol was shown to inhibit rat neutrophil migration in vitro.

Synthesis and evaluation of D-gluconamides as green mineral scales.

A series of 13 D-gluconamides were synthesized in moderate to good yields and evaluated as green scale inhibitors. The crystal structures of two compounds were determined by X-ray crystallography. The compounds 6c and 6d showed a reasonable inhibition of BaSO(4) precipitation from aqueous solution (47% and 51%, respectively) that indicated the potential for these derivatives of δ-gluconolactone.

Synthesis, antitubercular activity, and SAR study of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides.

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-1H-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.

Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives.

In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 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-1,2,3-triazol-4'-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC(50) values of 1.30 and 1.26 µM, respectively, displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity indices are high. Under the assay conditions, they have better performance than does the reference compound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional NMR techniques ((1)H, (13)C-APT, COSY-(1)H×(1)H and HETCOR (1)J(CH)) and by elemental analysis.

Synthesis, biological, and theoretical evaluations of new 1,2,3-triazoles against the hemolytic profile of the Lachesis muta snake venom.

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-1H-[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 microM) with 1-(4'-chlorophenylsulfonylamino)-5-methyl-1H-[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.

Antiviral evaluation of N-amino-1,2,3-triazoles against Cantagalo virus replication in cell culture.

This paper describes the antiviral evaluation of new N-amino-1,2,3-triazole derivatives, 1-(substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters, 3 and 1-(4-substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazides, 4, on Cantagalo virus replication. 1-(4-Fluoro-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazide, 4e, exhibited a significant antiviral effect. Characterization of all compounds was confirmed by IR, (1)H and (13)C spectroscopies and elemental analysis. In addition, molecular structure of 4e was also reported.

Synthesis, antiplatelet and in silico evaluations of novel N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides.

This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a-j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a-j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.