The development of novel antimicrobial agents represents a timely research topic. Eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against Mycobacterium tuberculosis, M. avium and M. kansasii, eight bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and for the inhibition of mycobacterial isocitrate lyase. Some compounds were further screened against drug-resistant M. tuberculosis and for their cytotoxicity. Minimum inhibitory concentrations (MICs) for all mycobacterial strains were within 0.5-32 μmol/L, with 4-chloro-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-(trifluoromethyl)benzoate superiority. Gram-positive bacteria including MRSA were inhibited with MICs ³ 0.49 μmol/L, while Gram-negative ones were much less susceptible. Salicylanilide 4-(trifluoromethyl)benzoates showed significant antibacterial properties, for many strains being comparable to standard drugs (isoniazid, benzylpenicillin) with no cross-resistance. All esters showed mild inhibition of mycobacterial isocitrate lyase and four compounds were comparable to 3-nitropropionic acid without a direct correlation between in vitro MICs and enzyme inhibition.

Salicylate (SA, 2-hydroxybenzoate) is a phytohormone best known for its role as a critical mediator of local and systemic plant defense responses. In response to pathogens such as Pseudomonas syringae, SA is synthesized and activates widespread gene expression. In gh3.12/pbs3 mutants of Arabidopsis thaliana, induced total SA accumulation is significantly compromised as is SA-dependent gene expression and plant defense. AtGH3 subfamily I and II members have been shown to conjugate phytohormone acyl substrates to amino acids in vitro, with this role supported by in planta analyses. Here we sought to determine the in vitro biochemical activity and kinetic properties of GH3.12/avrPphB susceptible 3 (PBS3), a member of the uncharacterized AtGH3 subfamily III. Using a novel high throughput adenylation assay, we characterized the acyl substrate preference of PBS3. We found PBS3 favors 4-substituted benzoates such as 4-aminobenzoate and 4-hydroxybenzoate, with moderate activity on benzoate and no observed activity with 2-substituted benzoates. Similar to known GH3 enzymes, PBS3 catalyzes the conjugation of specific amino acids (e.g. Glu) to its preferred acyl substrates. Kinetic analyses indicate 4-aminobenzoate and 4-hydroxybenzoate are preferred acyl substrates as PBS3 exhibits both higher affinities (apparent K(m) = 153 and 459 microm, respectively) and higher catalytic efficiencies (k(cat)/K(m) = 0.0179 and 0.0444 microm(-1) min(-1), respectively) with these acyl substrates compared with benzoate (apparent K(m) = 867 microm, k(cat)/K(m) = 0.0046 microm(-1) min(-1)). Notably, SA specifically and reversibly inhibits PBS3 activity with an IC(50) of 15 microm. This suggests a general mechanism for the rapid, reversible regulation of GH3 activity and small molecule cross-talk. For PBS3, this may allow for coordination of flux through diverse chorismate-derived pathways.

Using DFT calculations at various theory levels, quantum-chemical simulations of decomposition paths were performed for a series of nitroalkyl benzoates. It was discovered, that these reactions proceed via polar, but one-step mechanism. It turned out that depending on the nature of the substituent in the ester molecule and on medium polarity, the studied reactions may take place via transition states with varied synchronicity—from E1-like structures, to E1cb-like structures. A purely ionic, two-stage mechanism was not identified in any of the cases.

The most potent catechin in green tea is (-)-epigallocatechin-3-gallate [(-)-EGCG], which, however, is unstable under physiological conditions. To discover more stable and more potent polyphenol proteasome inhibitors, we synthesized several novel fluoro-substituted (-)-EGCG analogs, named F-EGCG analogs, as well as their prodrug forms with all of -OH groups protected by acetate. We report that the prodrug form of one F-EGCG analog exhibited greater potency than the previously reported peracetate of (-)-EGCG to inhibit proteasomal activity, suppress cell proliferation, and induce apoptosis in human leukemia Jurkat T cells, demonstrating the potential of these compounds to be developed into novel anti-cancer and cancer-preventive agents.

A series of twenty substituted 2-hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(alkoxycarbonyl)amino]benzoates were prepared and characterized. As similar compounds have been described as potential antimycobacterials, primary in vitro screening of the synthesized carbamates was also performed against two mycobacterial species. 2-Hydroxy-3-[2-(2,6-dimethoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, 2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride, and 2-hydroxy-3-[2-(2-methoxyphenoxy)ethylamino]-propyl 4-(butoxycarbonylamino)benzoate hydrochloride showed higher activity against M. avium subsp. paratuberculosis and M. intracellulare than the standards ciprofloxacin, isoniazid, or pyrazinamide. Cytotoxicity assay of effective compounds was performed using the human monocytic leukaemia THP-1 cell line. Compounds with predicted amphiphilic properties were also tested for their effects on the rate of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. All butyl derivatives significantly stimulated the rate of PET, indicating that the compounds can induce conformational changes in thylakoid membranes resulting in an increase of their permeability and so causing uncoupling of phosphorylation from electron transport.

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

Chemical modification of wood applying benzotriazolyl-activated carboxylic acids has proven to be a versatile method for the durable functionalization of its lignocellulosic biopolymers. Through this process, the material properties of wood can be influenced and specifically optimized. To check the scope and limitations of this modification method, various benzamide derivatives with electron-withdrawing (EWG) or electron-donating (EDG) functional groups in different positions of the aromatic ring were synthesized and applied for covalent modification of Scots pine (Pinus sylvestris L.) sapwood in this study. The bonded amounts of substances (up to 2.20 mmol) were compared with the reactivity constants of the Hammett equation, revealing a significant correlation between the modification efficiency and the theoretical reactivity constants of the corresponding aromatic substitution pattern. The successful covalent attachment of the respective substituted benzamides was proven by attenuated total reflection infrared (ATR-IR) spectroscopy, while the stability of the newly formed ester bond was proven in a standardized leaching test.

Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.

Two new coordination solids [Cu2(μ2-Bz)4(CH3OH)2][Cu2(η2-Bz)2(phen)2(H2O)2]·(NO3)2 (1) and [Cu(phen)(H2O)(Bz)(η2-Bz)] (2) (phen = 1,10-phenanthroline; Bz = benzoate) have been synthesized and characterized using elemental analysis, TGA, spectroscopic (IR, UV-vis-NIR and ESR) and single crystal X-ray diffraction techniques. Change of the solvent from methanol to DMF results in changes in the architectures that are triggered by a change from square pyramidal to octahedral coordination at the divalent metal centers for complexes 1 and 2 respectively. The structural topology of the complexes is established by the interplay of strong O-H⋯O and weak C-H⋯O, C-H⋯C, π-π stacking interactions. Unconventional parallel intramolecular and anti-parallel intermolecular contacts involving the chelate rings (CR) also stabilize the structures. The energetic analyses of the structures evidence that the parallel arrangement is energetically favoured which is likely due to the presence of the Cu⋯Cu cuprophilic interaction in 1 that is not established in 2. Compound 1 exhibits the highest antibacterial activity against Rhizobium leguminosarum among the tested cultures. In vitro cytotoxicity and apoptosis studies were carried out for compounds 1 and 2 on malignant Dalton's lymphoma cell line (DL). Both compounds showed a significant effect on the decrease in cell viability as compared to a control, while compound 2 induced remarkable cytotoxicity towards DL cells. Treatment also showed the appearance of membrane blebbing, chromatin condensation and fragmented nuclei which are typical characteristic features of apoptotic cell death. Furthermore, a docking study revealed that both compounds docked in the active sites of all the cancer target proteins under study. Moreover, SAR analysis revealed that oxygen and nitrogen atoms of compound 1 and the oxygen atoms of compound 2 are crucial for biological activities.

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton-Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10-100 μg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand-receptor complexes (-35.8--42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (-35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.

Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy ("Eltrombopag" OR "Benzoates" OR "Hydrazines") AND ("Idiopathic Thrombocytopenic Purpura" OR "immune thrombocytopenia" OR "Idiopathic Thrombocytopenic Purpuras" OR "Immune Thrombocytopenia" OR "Autoimmune Thrombocytopenia" OR "Werlhof"). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous (P = .27, I2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous (P = .001, I2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al (P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).

The cis-dihydroxylation of arenes by Rieske dearomatizing dioxygenases (RDDs) represents a powerful tool for the production of chiral precursors in organic synthesis. Here, the substrate specificity of the RDD benzoate dioxygenase (BZDO) in Ralstonia eutropha B9 whole cells was explored using quantitative 1H nuclear magnetic resonance spectroscopy (q1H-NMR). The specific activity, specific carbon uptake, and regioselectivity of the dihydroxylation reaction were evaluated in resting cell cultures for a panel of 17 monosubstituted benzoates. Two new substrates of this dioxygenase system were identified (2-methyl- and 3-methoxybenzoic acid) and the corresponding cis-diol metabolites were characterized. Higher activities were observed for benzoates with smaller substituents, predominantly at the 3-position. Elevated activities were also observed in substrates bearing greater partial charge at the C-2 position of the benzoate ring. The regioselectivity of the reaction was directly measured using q1H-NMR and found to have positive correlation with increasing substituent size. These results widen the pool of cis-diol metabolites available for synthetic applications and offer a window into the substrate traits that govern specificity for BZDO.

Tartrazine (Yellow 5 or E102) is a synthetic food dye able to modify perception and behavior, causing agitation, confusion, rhinitis and can produce hyperactivity syndrome in children when is combined with benzoates. Additionally, it can trigger oxidative stress which consequently generates metabolic disorders. Therefore, the study was designed to evaluate the harmful effects of the food additive tartrazine and to observe beneficial properties of blackthorn fruits (Prunus spinosa) on the blood and organs of albino Wistar rats.

Esters of weak acids have shown improved antimycobacterial activity over the corresponding free acids and nitro benzoates in particular have previously shown to have a very intriguing activity. To expand the potential of nitro-derivatives of benzoic acid as antimycobacterial drugs and explore the effects of various structural features on the activity of these compounds, we have obtained a library of 64 derivatives containing esters and thioesters of benzoates and studied their activity against M. tuberculosis, the stability of the compounds, their activation by mycobacterial enzymes and the potential cytotoxicity against human monocytic THP-1 cell line. Our results showed that the most active compounds are those with an aromatic nitro substitution, with the 3,5-dinitro esters series being the most active. Also, the greater antitubercular activity for the nitro derivatives was shown to be unrelated to their pKa values or hydrolysis rates. Given the conventional relationship between nitro-containing substances and toxicity, one might anticipate that the great antimicrobial activity of nitro compounds would be associated with high toxicity; yet, we have not found such a relationship. The nitrobenzoate scaffold, particularly the 3,5-dinitrobenzoate scaffold, merits further investigation, because it has the potential to generate future antimycobacterial agents with improved activity.

Flax (Linum usitatissimum) is a crop plant valued for its oil and fiber. Unfortunately, large losses in cultivation of this plant are caused by fungal infections, with Fusarium oxysporum being one of its most dangerous pathogens. Among the plant's defense strategies, changes in the expression of genes of the shikimate/phenylpropanoid/benzoate pathway and thus in phenolic contents occur. Among the benzoates, salicylic acid, and its methylated form methyl salicylate play an important role in regulating plants' response to stress conditions. Upon treatment of flax plants with the fungus we found that methyl salicylate content increased (4.8-fold of the control) and the expression profiles of the analyzed genes suggest that it is produced most likely from cinnamic acid, through the β-oxidative route. At the same time activation of some genes involved in lignin and flavonoid biosynthesis was observed. We suggest that increased methyl salicylate biosynthesis during flax response to F. oxysporum infection may be associated with phenylpropanoid pathway activation.

A series of piperidinium-based herbicidal ionic liquids (HILs) were synthesized and investigated. The designed HILs, obtained with high yields, consisted of cation 1-alkyl-1-methylpiperidinium with surface activity and a commercially available herbicidal anion: (3,6-dichloro-2-methoxy)benzoates (dicamba). The above-mentioned compounds were characterized in terms of surface activity and phytotoxicity. Preliminary results were obtained at higher wettability for all HILs when compared to the wettability of commercial Dicash, with HIL having 18 atoms in the carbon chain being the best effectiveness in wetting surfaces (weeds and crop leaves), whereby a drop of HILs with short alkyl chains (C8-C10) could not slide down a leaf. Our findings present that wettability or mobility of HILs drops varied depending on the plant species. Moreover, in this study, by zeta potential and atomic force microscopy measurements, we provide conclusive evidence to demonstrate that alkyl chain elongation plays a significant role in the evolution of surface properties of HILs.

A novel series of N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinolines (14-33) containing triazole moiety were designed and synthesized through rational cycloadditions using the modified Pictet-Spengler reaction and the Click chemistry. Antiproliferative activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) revealed that many substituted triazole analogs of benzoates (20, 29) and benzaldehydes (30, 32) exhibited anticancer activity against all of the tested cancer cell lines in which the ester analog 20 was shown to be the most potent compound against HuCCA-1 (IC50 = 0.63 μM) and A549 (IC50 = 0.57 μM) cell lines. Triazoles bearing phenyl (15, 24), tolyl (26, 27), acetophenone (19), benzoate (20, 29), benzaldehyde (21, 30) and naphthalenyl (25) substituents showed stronger anticancer activity against HepG2 cells than that of the etoposide. Interestingly, the p-tolyl analog (27) displayed the most potent inhibitory activity (IC50 = 0.56 μM) against HepG2 cells without affecting normal cells. Of the investigated tetrahydroisoquinoline-triazoles, the promising compounds 20 and 27 were selected for molecular docking against AKR1C3, which was identified to be a plausible target site.

Interactions of tributyltin (TBTA) and triphenyltin (TPhTA) 2-[4 (dimethylamino)phenylazo]benzoates, showing promising cytostatic activity against tumor cells, with erythrocytes and with erythrocyte membranes and model lipid membranes have been investigated. The effect of TBTA and TPhTA on the erythrocyte and its model membrane was investigated by the microscopic and spectroscopic methods. Interaction of tin complexes with the membrane was determined on the basis of hemolytic activity, changes induced in the shape of erythrocytes, as well as physicochemical parameters of the membrane, such as fluidity. The studies showed that the compounds in higher concentration induce hemolysis; however, TBTA is more toxic than TPhTA. Both TBTA and TPhTA induce morphological alterations in red blood cells-from discocytes to spherocytes and from discocytes to echinocytes. The results suggest that investigated complexes interact with the erythrocyte membrane, change its properties, and probably locate themselves in the hydrophilic part of the membrane, which agrees with conclusions drawn from investigation of erythrocyte membranes and model lipid membranes with the help of fluorescence and infrared spectroscopy.

Amaranthus hybridus is one of the main weed species in Córdoba, Argentina. Until recently, this weed was effectively controlled with recurrent use of glyphosate. However, a population exhibiting multiple resistance (MR2) to glyphosate and imazamox appeared in a glyphosate resistant (GR) soybean field, with levels of resistance up to 93 and 38-fold higher to glyphosate and imazamox, respectively compared to the susceptible (S) population. In addition to imidazolinones, MR2 plants showed high resistance levels to sulfonylamino-carbonyl (thio) benzoates and moderate resistance to sulfonylureas and triazolopyrimidines. Multiple amino acid substitutions were found in both target genes, acetolactate synthase (ALS) and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), responsible for conferring high herbicides resistance levels in this A. hybridus population. In the case of EPSPS, the triple amino acid substitution TAP-IVS was found. In addition, MR2 plants also showed increased EPSPS gene expression compared to susceptible plants. A Ser653Asn substitution was found in the ALS sequence of MR2, explaining the pattern of cross-resistance to the ALS-inhibitor herbicide families found at the ALS enzyme activity level. No other mutations were found in other conserved domains of the ALS gene. This is the first report worldwide of the target site resistance mechanisms to glyphosate and ALS inhibitors in multiple herbicide resistance Amaranthus hybridus.

Roots, stems, leaves, and flowers of Longdan (Gentiana rigescens Franch. ex Hemsl) were collected from six geographic origins of Yunnan Province (n = 240) to implement the quality assessment based on contents of gentiopicroside, loganic acid, sweroside and swertiamarin and chemical profile using HPLC-DAD and FTIR method combined with principal component analysis (PCA). The content of gentiopicroside (major iridoid glycoside) was the highest in G. rigescens, regardless of tissue and geographic origin. The level of swertiamarin was the lowest, even unable to be detected in samples from Kunming and Qujing. Significant correlations (p < 0.05) between gentiopicroside, loganic acid, sweroside, and swertiamarin were found at inter- or intra-tissues, which were highly depended on geographic origins, indicating the influence of environmental conditions on the conversion and transport of secondary metabolites in G. rigescens. Furthermore, samples were reasonably classified as three clusters along large producing areas where have similar climate conditions, characterized by carbohydrates, phenols, benzoates, terpenoids, aliphatic alcohols, aromatic hydrocarbons, and so forth. The present work provided global information on the chemical profile and contents of major iridoid glycosides in G. rigescens originated from six different origins, which is helpful for controlling quality of herbal medicines systematically.