Some Structure-activity Relationships Research Articles

In Vitro Structure–Activity Relationships Between Dammarane-Type Saponins Isolated From Panax notoginseng and Their Anti-inflammatory Properties

Objectives: Total saponin extracts from the roots of Panax notoginseng have been proven to have anti-inflammatory properties. Dammarane-type saponins isolated from the roots of P notoginseng have been shown to be active inhibitors of nitric oxide (NO) and tumor necrosis factor-α (TNF-α). To clarify the structural requirements for inhibition, some structure–activity relationships (SARs) were determined. Methods: RAW264.7 macrophages were maintained in vitro under standard cell culture conditions. The release of NO and TNF-α from these cells was induced by lipopolysaccharides (LPS) and was measured. The primary SAR inhibitory activity of LPS-induced NO and TNF-α and production in RAW264.7 macrophage cells were evaluated by cytotoxicity assays. Results: SAR studies of dammarane-type saponins revealed that the glycosides substituent at C-3, C-6, and C-20 were important features for the NO and TNF-α production in RAW264.7 cells induced LPS. Moreover, the 5(6)-double bond and the OH group at C-7 improved the TNF-α inhibitory activity. In the case of ginsenoside Rh2, the C-20 configuration was needed for potent TNF-α inhibition. Conclusions: These results provide an approach for understanding the structural requirements of dammarane-type saponins isolated from P notoginseng for optimum anti-inflammatory properties of these compounds.

Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones

Polyphenols consumption has been associated with a lower risk of cardiovascular diseases (CVDs) notably through nitric oxide (NO)- and estrogen receptor α (ERα)-dependent pathways. Among polyphenolic compounds, chalcones have been suggested to prevent endothelial dysfunction and hypertension. However, the involvement of both the NO and the ERα pathways for the beneficial vascular effects of chalcones has never been demonstrated. In this study, we aimed to identify chalcones with high vasorelaxation potential and to characterize the signaling pathways in relation to ERα signaling and NO involvement. The evaluation of vasorelaxation potential was performed by myography on wild-type (WT) and ERα knock-out (ERα-KO) mice aorta in the presence or in absence of the eNOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). Among the set of chalcones that were synthesized, four (3, 8, 13 and 15) exhibited a strong vasorelaxant effect (more than 80% vasorelaxation) while five compounds (6, 10, 11, 16, 17) have shown a 60% relief of the pre-contraction and four compounds (12, 14, 18, 20) led to a lower vasorelaxation. We were able to demonstrate that the vasorelaxant effect of two highly active chalcones was either ERα-dependent and NO-independent or ERα-independent and NO-dependent. Thus some structure-activity relationships (SAR) were discussed for an optimized vasorelaxant effect.

Photoelectron spectra and biological activity of cinnamic acid derivatives revisited

The electronic structures of several derivatives of cinnamic acid have been studied by UV photoelectron spectroscopy (UPS) and Green's function quantum chemical calculations. The spectra reveal the presence of dimers in the gas phase for p-coumaric and ferulic acids. The electronic structure analysis has been related to the biological properties of these compounds through the analysis of some structure-activity relationships (SAR).

Synthesis, anti-HIV activity and molecular modeling study of 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives

Abstract A series of novel 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a–l were synthesized by a simple method with the aim of developing novel HIV non-nucleoside reverse transcriptase inhibitors. All the synthesized compounds were structurally confirmed by spectral analyses. The structure of 6a was unambiguously verified by X-ray structure determination. The synthesized compounds were evaluated for their anti-HIV activity and four analogs displayed moderate inhibitory activity with EC50 values ranging from 10.10 to 12.40 μg mL–1. Molecular docking of 6g with HIV-1 reverse transcriptase was studied to rationalize some structure-activity relationships (SARs).

Synthesis of new potential anticancer agents based on 4-thiazolidinone and oleanane scaffolds

The synthesis and evaluation of the anticancer activity of new acylated oximes derivatives of oleanolic acid with 4-thiazolidinone-3(5)-carboxylic acid moieties were described. Newly synthesized compounds were elucidated on the basis of elemental analyses and spectral data (IR, 1H, and 13C NMR). Anticancer activity of the tested compounds has been evaluated in vitro at National Cancer Institute (NCI) in which some structure activity relationships (SARs) were discussed. Among the tested compounds, 3-[(2,4-thiazolidinedione-5-ylidene)-carboxyimino]olean-12-en-28-oic acid methyl ester (IVm) was superior to other related compounds with mean values of pGI50 = 5.51/5.57, pTGI = 5.09/5.13, and pLC50 = 4.62/4.64, low toxicity and moderate activity level in vivo hollow fiber assay.

Ferrocenyl chalcones versus organic chalcones: A comparative study of their nematocidal activity

A series of 30 organic chlacones and 33 ferrocenyl (Fc) chalcones were synthesized and characterized by melting point, elemental analysis, spectroscopy (1H NMR and FTIR) and, in two cases, by X-ray crystallography. The biological activity of each compound (10−4M in DMSO) against the model nematode Caenorhabditis elegans was examined in terms of % mortality (percent nematodes that died) and % fecundity (percent nematodes that reproduced) and compared to that obtained for the control medium (1% DMSO) over a 14-day period. Detailed conformational analyses for two Fc-chalcones (studied also by X-ray crystallography) were performed via molecular modeling studies. In general, the organic chalcones were found to be less polar than their Fc analogs. Some structure–activity relationships (SARs) were determined: (a) The nematocidal activities of the organic chalcones in this series were found to be much greater than those of their ferrocenyl analogs. (b) The position of the carbonyl group played a central role in the biological activity of both classes of chalcones studied. (c) For both classes of chalcones, lipophilicity of a compound seemed to play a significant role in its nematocidal activity. (d) The planarity of a ferrocenyl-chlacone seems to play a role in its activity.

Efficient synthesis of 6-(hetero)arylthieno[3,2- b]pyridines by Suzuki–Miyaura coupling. Evaluation of growth inhibition on human tumor cell lines, SARs and effects on the cell cycle

A wide variety of new bi(hetero)aryl derivatives of the thieno[3,2- b]pyridine skeleton was obtained in high to excellent yields (65–91%) by Suzuki–Miyaura cross-coupling of the methyl 3-amino-6-bromothieno[3,2- b]pyridine-2-carboxylate, recently reported by us, with aryl or heteroaryl pinacolboranes or potassium trifluoroborates. The coupling products obtained were evaluated for their growth inhibitory effect on three human tumor cell lines, representing different tumor models, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma) and NCI-H460 (non-small cell lung cancer). Some of the compounds showed an interesting activity against the tested cell lines, with GI 50 values in the μM range, and it was possible to establish some structure–activity relationships (SARs). Several compounds presented GI 50 values below 15 μM, particularly a bithiophene and an o-aniline thienopyridine derivative. The first presented selectivity for MCF-7 and NCI-H460 cell lines, with very low GI 50 values (0.7–1.0 μM), while the latter was active against the three cell lines tested in this study, also presenting very low GI 50 values (2.5–4.2 μM). The effect of these two compounds on cell cycle progression was analyzed in the NCI-H460 cell line. Results showed that both compounds interfered with the normal cell cycle distribution.

Antifungal activity of synthetic di(hetero)arylamines based on the benzo[ b]thiophene moiety

The antifungal activity of several di(hetero)arylamine derivatives of the benzo[ b]thiophene system was evaluated against clinically relevant Candida, Aspergillus, and dermatophyte species by a broth macrodilution test based on CLSI (formerly NCCLS) guidelines. The most active compound showed a broad spectrum of activity (against all tested fungal strains, including fluconazole-resistant fungi), with particularly low MICs for dermatophytes. Results from the inhibition of the dimorphic transition in Candida albicans and flow cytometry studies further confirmed their biological activity. With this study it was possible to establish some structure–activity relationships (SARs). The hydroxy groups proved to be essential for the activity in the aryl derivatives. Furthermore, the spectrum of activity in the pyridine derivatives was broadened by the absence of the ester group on position 2 of the benzo[ b]thiophene system.

Synthesis and antioxidant activity evaluation of new 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[ b]thiophenes obtained by Buchwald–Hartwig C–N cross-coupling

New 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[ b]thiophenes were prepared by palladium-catalyzed Buchwald–Hartwig cross-coupling of 7-bromo or 7-amino-2,3-dimethylbenzo[ b]thiophenes, previously prepared by us, with substituted (4-methoxy or 3,4-dimethoxy) anilines and 3-aminopyridine or with substituted (3-methoxy or 4-cyano) bromobenzenes and 2-bromopyridine, respectively, using Pd(OAc) 2, rac-BINAP or Xantphos as ligands, and Cs 2CO 3 as base. Their antioxidant properties were evaluated by several methods: reducing power, scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, inhibition of erythrocyte hemolysis and inhibition of lipid peroxidation using the β-carotene linoleate system. EC 50 values for all the methods were determined and it was possible to establish some structure–activity relationships (SARs) based on the presence and position of different substituents on the phenyl ring (1 or 2 OMe and C N), on the presence of a pyridine ring and on the position of its nitrogen atom relative to the N–H bond.

Synthesis and antimicrobial activity studies of ortho-chlorodiarylamines and heteroaromatic tetracyclic systems in the benzo[ b]thiophene series

ortho-Chlorodiarylamines in the 2,3,7-trimethylbenzo[ b]thiophene series were prepared in high yields (70–85%) by C–N palladium-catalyzed cross-coupling using P( t-Bu) 3 as ligand and NaO t-Bu as base. A palladium-assisted C–C intramolecular cyclization of the coupling products gave thienocarbazoles and the dechlorinated diarylamines. Studies of antimicrobial activity of the compounds obtained, against representative species of bacteria ( Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus and Bacillus subtilis) and fungi ( Candida albicans), were performed. We have also included in the biological assays some pyridine derivatives previously prepared by us, and it was possible to establish some structure–activity relationships (SARs).

Evaluation of the antioxidant properties of diarylamines in the benzo[ b]thiophene series by free radical scavenging activity and reducing power

The antioxidant properties of substituted diarylamines in the benzo[ b]thiophene series were evaluated by their reducing power and free radical scavenging activity. The results were compared with those of standards: acid ascorbic for the first method and BHA and BHT for the second. For both methods it was possible to establish some structure–activity relationships (SARs) based on the position of the arylamination on the benzo[ b]thiophene moiety, the presence of different substituents on the phenyl ring (F, 1 or 2 OMe) and on the thiophene ring (H, CO 2Et, CO 2H).

5-Amino-2-carbonylthiophene derivatives for use as p38 MAPK inhibitors in the treatment of inflammatory diseases

This recent patent application from Astex (WO2004089929) describes p38 inhibitors containing uncyclised amides or ureas. Other urea and amide inhibitors of p38 are in the prior art. The present invention is based on the substitution pattern on a thiophene scaffold to which the amides and ureas are attached. An earlier patent application from Astex (WO2004004720) describes p38 inhibitors in which the generic structures do not require amides or ureas. However, the earlier patent application provides some structure–activity relationships (SARs) in which the most potent analogues are amides or ureas. Common structural features are apparent for the likely potent acyclic amide and ureas in the two Astex patent applications. These features may also connect the functionality in the Astex compounds to similar structures in competitor acyclic amide and urea p38 inhibitors. Crystallography data on two series of competitor acyclic urea and amide analogues have been reported.

Polyamidoamine (Yet Not PAMAM) dendrimers as bioinspired materials for drug delivery: structure-activity relationships by molecular simulations.

In this paper, we report the results obtained from a comprehensive characterization of newly synthesized dendrimeric molecules in a solvated environment, by computer-aided simulations. The evidences allowed us to formulate some structure-activity relationships (SARs) between the experimentally verified cytotoxicity/noncytotoxicity of these compounds and some molecular features such as, for instance, radius of gyration, molecular shape, and dimensions. In particular, all noncytotoxic dendrimers were characterized by a more dense and globular shape and by a smoother surface pattern, as quantified by their fractal dimension D.