On the search for potential anti-Trypanosoma cruzi drugs: Synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-beta-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC50/24 h values in the range of 10.9-101.5 mu M. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies. (C) 2012 Elsevier Masson SAS. All rights reserved.

Spectroscopic, Structural, and Conformational Properties of (Z)-4,4, 4-Trifluoro-3-(2-hydroxyethylamino)-1-(2-hydroxypheny1)-2-buten-1-one, C12H12F3NO3: A Trifluoromethyl-Substituted beta-Aminoenone

The ( Z)-4,4,4-trifluoro-3-(2-hydroxyethylamino)-1-(2-hydroxyphenyl)-2-buten-1-one (C12H12F3NO3) compound was thoroughly studied by IR, Raman, UV-visible, and C-13 and F-19 NMR spectroscopies. The solid-state molecular structure was determined by X-ray diffraction methods. It crystallizes in the P2(1)/c space group with a = 12.1420(4) angstrom, b = 7.8210(3) angstrom, c := 13.8970(5) angstrom, beta = 116.162(2)degrees, and Z = 4 molecules per unit cell. The molecule shows a nearly planar molecular skeleton, favored by intramolecular OH center dot center dot center dot 0 and NH center dot center dot center dot 0 bonds, which are arranged in the lattice as an OH center dot center dot center dot 0 bonded polymer coiled around crystallographic 2-fold screw-axes. The three postulated tautomers were evaluated using quantum chemical calculations. The lowest energy tautomer (I) calculated with density functional theory methods agrees with the observed crystal structure. The structural and conformational properties are discussed considering the effect of the intra- and intermolecular hydrogen bond interactions.

1,3-Azoles from ortho-naphthoquinones: Synthesis of aryl substituted imidazoles and oxazoles and their potent activity against Mycobacterium tuberculosis

Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 mu g/mL against susceptible and resistant strains of M. tuberculosis, Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes. (C) 2012 Elsevier Ltd. All rights reserved.

Conformational preferences for some 3-(4 '-substituted phenylsulfonyl)-1-methyl-2-piperidones through spectroscopic and theoretical studies

The analysis of the infrared (IR) carbonyl band of some 3-(4'-substituted phenylsulfonyl)-1-methyl-2-piperidones 1-5 bearing as substituents: OMe 1, Me 2, H 3, Cl 4 and NO2 5, supported by B3LY13/6-31G(d,p) calculations along with NBO analysis (for 1, 3 and 5) and X-ray diffraction (for 5), indicated the existence of three stable conformations i.e. quasi-axial (q-ax), syn-clinal (s-cl) and quasi-equatorial (q-eq). In the gas phase, the q-ax conformer is calculated as the most stable (ca. 88%) and the least polar, the s-cl conformer is less stable (ca. 12%) but more polar, and the q-eq conformer is the least stable (ca. 1%) and the most polar of the three conformers evaluated. The sum of the most important orbital interactions from NBO analysis and the trend of the electrostatic interactions accounts for the relative populations as well as for the v(CO) frequencies of the q-ax. s-cl and q-eq conformers calculated in the gas phase. The unique IR v(CO) band in CCl4 may be ascribed to the most stable q-ax conformer. The more intense (60%) high frequency doublet component in CHCl3 may be assigned to the summing up of the least stable q-eq and the less stable s-cl conformers, as their frequencies are almost coincident. The occurrence of only a single v(CO) band in both CH2Cl2 and CH3CN supports the fact that the v(CO) band of the two more polar conformers appear as a single band. Additional support to this rationalization is given by the single point PCM method, which showed a progressive increase of the q-eq + s-cl/q-ax population ratio going from the gas phase to CCl4, to CHCl3, to CH2Cl2 and to CN3CN. X-ray single crystal analysis of 5 indicates that this compound displays a quasi-axial geometry with respect to the [O=C-CH-S] moiety, and that the 2-piperidone ring assumes a slightly distorted half-chair conformation. In the crystal packing, molecules of 5 are arranged into supramolecular layers linked through C-H center dot center dot center dot O interactions along with it pi center dot center dot center dot pi interactions between adjacent benzene rings. (C) 2012 Elsevier B.V. All rights reserved.

Lipophilicity as a determinant of binding of procaine analogs to rat alpha(3)beta(4) nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structureactivity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the a3 beta 4 nAChR heterologously expressed in KXa3 beta 4R2 cells. Affinity values (log[1/IC50]) of these compounds for the a3 beta 4 nAChR were determined by their competition with [3H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structureactivity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity. (c) 2012 Wiley Periodicals, Inc.

Synthesis and characterization of the atropisomeric relationships of a substituted N-phenyl-bipyrazole derivative with anti-inflammatory properties

This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The 1H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs. Chirality 24:463470, 2012. (c) 2012 Wiley Periodicals, Inc.

Stereoselective synthesis of novel diels-alder adducts of p-substituted Methyl Thiocinnamates and Cyclopentadiene

This article describes the Diels-Alder reaction between methyl thiocinnamates, substituted at the para position by electron-donating and electron-withdrawing groups, with cyclopentadiene in the presence of catechol boron bromide (CBB) as a Lewis acid catalyst. The adduct configuration was confirmed by H-1 NMR coupling constants and single-crystal x-ray diffraction. Total endo stereoselectivity was observed in all reactions and was attributed to the effective secondary interaction between the boron atom and the incipient double bond in the norbonene resulting from the planar geometry of the catalyst. C-13 NMR chemical shifts of the coordinated dienophile carbonyl carbons with CBB compared to those of the non coordinated thiocinammates suggest a strong complexation with the catalyst.

Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)coumarin derivatives: Effect on inducible nitric oxide synthase

A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-alpha secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that it pi center dot center dot center dot pi interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored. (C) 2012 Elsevier Masson SAS. All rights reserved.