Trichomonicidal activity of a new anthraquinone isolated from the roots of Morinda panamensis Seem.

Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis, is the most common nonviral sexually transmitted infection worldwide. Although drug treatment is available, unpleasant side effects and increased resistance to the nitroimidazole family have been documented. Hence, there is a need for the identification of new and safe therapeutic agents against T. vaginalis. Antimicrobial activity of anthraquinone compounds has been reported by a number of authors. The genus Morinda is well known for the diversity of anthraquinones with numerous biological activities. A new anthraquinone, lucidin-ω-isopropyl ether, was isolated from the roots of Morinda panamensis Seem. The structure of the compound was determined by 1 H and 13 C Nuclear Magnetic Resonance (NMR) analyses, in addition to comparison with literature reports. Using in vitro susceptibility assay, the half inhibitory concentration (IC50 ) of lucidin-ω-isopropyl ether for T. vaginalis (1.32 µg/mL) was found similar to that of metronidazole concentration tested (6 µM = 1.03 µg/mL). In addition, this anthraquinone was capable of inhibiting the parasite's ability to kill HeLa cells and decreased proteolytic activity of the proteinase TvMP50 from T. vaginalis. This was associated with the decreased expression of the mp50 gene. These results demonstrate the trichomonicidal potential by lucidin-ω-isopropyl ether. Further action-mode studies are necessary to elucidate the antiparasitic mechanism of this new anthraquinone to develop a more potent antitrichomonal agent.

Biosynthesis of Grandione: An Example of Tandem Hetero Diels-Alder/Retro-Claisen Rearrangement Reaction?

Mechanistic theoretical studies about the feasibility of the traditional proposed mechanism of formation for icetexane diterpene dimer grandione were assessed using density functional method at the M06-2X/6-31G(d,p) level of theory. Bulk water solvent effects were taken into account implicitly using the polarizable continuum model (SCI-PCM). The results were compared with the selectivity found in the biomimetic synthesis performed by experimental research groups. The relative free energy calculation shows that the one-step H-DA formation mechanism nominated in the literature is not a viable mechanism. We found that an alternative competing Tandem pathway is consistent with the experimental trends. Thus, our results suggested that the compound grandione is formed via a H-DA/retro-Claisen rearrangement and not by the traditional H-DA mechanism proposed early in the experimental studies. The H-DA initial step produce a biecyclic adduct followed by a domino retro-Claisen rearrangement that releases the energy strain of the bicyclic intermediary. Steric issues and hyperconjugation interactions are the mainly factors driving the reaction nature and the selectivity in the formation reaction. Finally, the enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

Biogenesis of Triterpene Dimers from Orthoquinones Related to Quinonemethides: Theoretical Study on the Reaction Mechanism.

The biogenetic origin of triterpene dimers from the Celastraceae family has been proposed as assisted hetero-Diels-Alder reaction (HDA). In this work, computational calculation of HDA between natural quinonemethides (tingenone and isopristimerol) and hypothetical orthoquinones has been performed at the M06-2X/6-31G(d) level of theory. We have located all the HDA transition states supporting the biogenetic route via HDA cycloadditions. We found that all reactions take place through a concerted inverse electron demand and asynchronous mechanism. The enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

Bis(2-amino-4-phenyl-1,3-thia-zol-3-ium) tetra-chlorido-palladate(II).

The title compound, (C9H9N2S)2[PdCl4], consists of two monoprotonated 2-amino-4-phenyl-1,3-thia-zole molecules and one tetra-chlorido-palladate anion. The organic molecules exhibit a dihedral angle between the main rings planes of 31.82 (9)°. In the anion, the Pd(II) atom is located on a crystallographic centre of symmetry with a square-planar geometry. In the crystal, the anions and cations are connected through bifurcated N-H⋯Cl hydrogen bonds, and these inter-actions lead to hydrogen-bonded tapes of cations and anions along [100].

Molecular orbital and topological electron density study of n → π* interactions: amides and thioamides cases.

The n → π* interactions were studied in amides and thioamides systems models, through the analysis of the electron density topology along with the Natural Bonding Orbital (NBO) approach. The effect of the dispersion terms was assessed using different DFT functionals. The NBO, independent gradient model (IGM), and the analysis of the reduced density gradient outcomes show that dispersion forces play a significant role in the strength of n → π* interactions. The IGM results indicate that δg height values for n → π* interactions do not extend beyond 0.025. All the methods used in this work predict that n → π* interaction between pairs of thioamides is stronger than those between amides. However, the electron density topology-based methods were not able to replicate the trends in the relative force of this interaction found in the experimental and NBO results.

Lupeol acetate isolated from Chrysophyllum cainito L. fruit as a template for the synthesis of N-alkyl-arylsulfonamide derivatives and their synergistic effects with metronidazole against Trichomonas vaginalis.

Pentacyclic triterpenes are found in a great variety of natural products and constitute an organic template for the development of new derivative compounds with therapeutic applications. In the present work, lupeol acetate isolated from Chrysophyllum cainito L. fruit was used as a template for the synthesis of novel N-alkyl-arylsulfonamide derivatives, and their synergistic effects with metronidazole against strains of Trichomonas vaginalis were tested. A library of 18 derivatives was synthesized. Ten compounds exhibited an IC50 < 100 µM against a metronidazole-sensitive strain of T. vaginalis. Only seven of these compounds (12, 15, 18-22) also showed activity against metronidazole-resistant strains. The compounds 20 (N-cyclohexyl-p-chlorobenzenesulfonamidolupeol acetate) and 22 (N-cyclohexyl-p-nitrobenzenesulfonamidolupeol acetate) exhibited a similar IC50 against both susceptible and resistant T. vaginalis strains and enhanced the efficacy of metronidazole in a partial and total synergistic way, respectively. These data provided evidence of the trichomonicidal effect of N-alkyl-arylsulfonamide derivatives of lupeol acetate, representing highly promising novel antiparasitic agents.

Microwave-enhanced synthesis of 26-amino-22-oxocholestanes and their cytotoxic activity.

The synthesis of a series of 26-amino-22-oxocholestanes derived from diosgenin was accomplished via the substitution of an iodine atom at C-26 by primary and secondary amines. The reactions were conducted in refluxing acetonitrile and through microwave-assisted heating. The latter shows significant improvements in terms of reaction times going from hours to a few minutes or even seconds for completion. Only one of the selected amines, 4-aminourazole, did not yield the substitution product and the imine formation pathway was investigated instead, achieving the 26-iminourazole-22-oxocholestane. All the final products have been characterized and the cytotoxic activity of three of them has been evaluated in SiHa, MCF-7 and MDA tumor cell lines by the sulforhodamine B assay.

Cytotoxic and antiproliferative activity of thiazole derivatives of Ochraceolide A.

A series of 15 novel 1,3-thiazole amide derivatives of the pentacyclic triterpene Ochraceolide A (1) was synthesized, characterized, and evaluated in vitro against three human cancer cell lines (MCF-7, MDA-MB-231 and SiHa) and a normal cell line (Vero). Synthetic derivatives were obtained by acylation of the 2-aminothiazole triterpene 2, previously reported. Remarkably, the 5-nitrofuramide derivative (2o) showed better cytotoxic and antiproliferative activity than compound 2 and the other derivatives against the three cancer cell lines with CC50 and IC50 values of 1.6-12.7 µM. Furthermore, butyramide derivative (2c) was approximately 25 times more selective than 2, as well as 3.4 times more selective than Docetaxel, against SiHa cells in the cytotoxic assay, while the phenyl amide derivatives were inactive against the three cancer cell lines.

The origin of the regiospecificity of acrolein dimerization.

Acrolein dimerization is a intriguing case since the reaction does not occur to form the electronically preferred regioisomeric adduct. Various explanations have been suggested to rationalize this experimental regioselectivity, however, none of these arguments had been convincing enough. In this work, the hetero Diels-Alder acrolein dimerization was theoretically investigated using DFT and MP2 methods. The influence of nucleophilic/electrophilic interactions and non-covalent interactions (NCI) in the regiospecificity of the reaction were analyzed. Our results show that the NCI at the transition state are the key factor controlling the regiospecificity in this reaction. Besides, we found that the choice of calculation method can have an effect on the prediction of the mechanism in the reaction, as all DFT methods forecast a one-step hetero Diels-Alder acrolein dimerization, while MP2 predicts a stepwise description for the lower energy reaction channel.

Crystal structure and Hirshfeld surface analysis of N-(5-iodo-4-phenyl-thia-zol-2-yl)acetamide.

Two crystallographically independent mol-ecules (A and B) are present in the asymmetric unit of the title compound, C11H9IN2OS, which differ mainly in the dihedral angle between the phenyl and thia-zole rings [38.94 (16) and 32.12 (15)°, respectively]. In the crystal, the mol-ecules form ⋯A⋯B⋯A⋯B⋯ chains along the [001] and [010] directions through moderate N-H⋯O hydrogen bonds and C-H⋯π inter-actions, respectively. The overall three-dimensional network is formed by I⋯I and I⋯S inter-actions. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯C/C⋯H (26.2%), H⋯H (20.9%), H⋯I/I⋯H (19.4%) and H⋯O/O⋯H (6.8%) inter-actions.

21beta-Hydroxy-oleanane-type triterpenes from Hippocratea excelsa.

Stem bark of Hippocratea excelsa afforded six pentacyclic triterpenes, five oleanane and one ursane types. They were identified as 11beta,21beta-dihydroxy-olean-12-ene-3-one (2), 3alpha,11alpha,21beta-trihydroxy-olean-12-ene (3), 3alpha,21beta-dihydroxy-11alpha-methoxy-olean-12-ene (4), 3alpha,21beta-dihydroxy-olean-9(11),12-diene (5), 3alpha,21beta-dihydroxy-olean-12-ene (6) and 3alpha,21beta-dihydroxy-11alpha-methoxy-urs-12-ene, isolated as its diacetate derivative (7), as well as 3alpha,21beta-dihydroxy-olean-12-ene (1) previously isolated from the root bark. The known alpha- and beta-amyrin, oleanoic and ursolic acids, trans-polyisoprene, and the ubiquitous beta-sitosterol were also isolated. Structures were elucidated on the basis of spectroscopic analyses, including homo- and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC and HMBC) and comparison with literature data. The antigiardial activity of compounds 2-5 was not significant.