anti-Helicobacter Pylori Agents Research Articles

Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms

Thirty protoberberine derivatives, of which twenty five were new, were synthesized and evaluated for their anti-Helicobacter pylori (HP) activities, taking 2,3,10-trimethoxy-9-p-methylbenzylaminoprotopalmatine chloride 1 as the lead. Among them, berberine (BBR) derivative 7c displayed the highest potency against six tested metronidazole (MTZ)-resistant strains and two tested MTZ-susceptible strains with the MIC values of 0.4–1.6 μg/mL with favorable druglike profiles including low toxicity and high stabilities in plasma and artificial gastric fluid. Mechanistic study revealed that 7c might target HP urease with IC50 value of 0.27 μg/mL against Jack bean urease. Furthermore, 7c might change the permeability of the bacterial membrane and direct interact with HP DNA, which also contribute to its bactericidal activity. Therefore, BBR derivatives constituted a new family of anti-HP candidates, with the advantage of good safety profile and multi-target mechanisms, and are worthy for further investigation.

Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms

Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms

Synthesis and Biological Evaluation of New Nitroimidazole Derivatives as Anti-Helicobacter pylori Agents Against Metronidazole-Resistant Strains

: Since several Helicobacter pylori strains have become resistant to metronidazole, new nitroimidazole derivatives based on metronidazole were designed and synthesized with different substituents on imidazole nitrogen. The activity of the synthesized compounds was evaluated against 20 clinically isolated metronidazole-resistant H. pylori strains. Some synthesized compounds were effective against those metronidazole-resistant H. pylori strains. Three compounds exhibited the most potent inhibitory activities (MIC50 = 8 µg/mL and MIC90 = 16 µg/mL).

Erlotinib-containing benzenesulfonamides as anti-Helicobacter pylori agents through carbonic anhydrase inhibition.

Aim: Development of dual-acting antibacterial agents containing Erlotinib, a recognized EGFR inhibitor used as ananticancer agent, with differently spaced benzenesulfonamide moieties known to bind and inhibit Helicobacter pylori carbonic anhydrase (HpCA) or the antiviral Zidovudine. Methods & materials: Through rational design, tenderivatives were obtained via a straightforward synthesis including a click chemistry reaction. Inhibitory activity against a panel of pathogenic carbonic anhydrases and antibacterial susceptibility of H. pylori ATCC 43504 were assessed. Docking studies on α-carbonic anhydraseenzymes and EGFR were conductedto gain insight intothe binding mode of these compounds. Results & conclusion: Some compounds proved to be strong inhibitors of HpCA and showed good anti-H. pylori activity. Computational studieson the targeted enzymes shed light on theinteraction hotspots.

Benzimidazole derivatives act as dual urease inhibitor and anti-helicobacter pylori agent; synthesis, bioactivity, and molecular docking study

A series of benzimidazole derivatives 8a–h were synthesized in acceptable yield and characterized by spectroscopic methods such as 1H-NMR, 13C-NMR, MS, and Elemental analysis. In the urease inhibitory assay, all 8a–h showed higher urease inhibition activity (IC50: 5.85–20.82 µM) in comparison to thiourea and hydroxyurea as standard (IC50: 22 and 100 µM respectively). 8g exhibited the best activity with the IC50 value of 5.85 µM. The docking study represented a possible mode of interaction between 8g and the active site. To investigate the cytotoxicity of the synthesized compounds, an MTT assay was performed on two different cell lines which showed 8a–h have IC50 values higher than 50 µM on both tested cell lines. 8a–h were checked for antibacterial activity and the best activity was found by 8d against Helicobacter pylori with an inhibition zone of 20 mm even stronger than gentamicin with an inhibition zone of 18 mm.

From Diospyros kaki L. (Persimmon) Phytochemical Profile and Health Impact to New Product Perspectives and Waste Valorization.

Persimmon (Diospyros kaki L.) fruit’s phytochemical profile includes carotenoids, proanthocyanidins, and gallic acid among other phenolic compounds and vitamins. A huge antioxidant potential is present given this richness in antioxidant compounds. These bioactive compounds impact on health benefits. The intersection of nutrition and sustainability, the key idea behind the EAT-Lancet Commission, which could improve human health and decrease the global impact of food-related health conditions such as cancer, heart disease, diabetes, and obesity, bring the discussion regarding persimmon beyond the health effects from its consumption, but also on the valorization of a very perishable food that spoils quickly. A broad option of edible products with better storage stability or solutions that apply persimmon and its byproducts in the reinvention of old products or even creating new products, or with new and better packaging for the preservation of food products with postharvest technologies to preserve and extend the shelf-life of persimmon food products. Facing a global food crisis and the climate emergency, new and better day-to-day solutions are needed right now. Therefore, the use of persimmon waste has also been discussed as a good solution to produce biofuel, eco-friendly alternative reductants for fabric dyes, green plant growth regulator, biodegradable and edible films for vegetable packaging, antimicrobial activity against foodborne methicillin-resistant Staphylococcus aureus found in retail pork, anti-Helicobacter pylori agents from pedicel extracts, and persimmon pectin-based emulsifiers to prevent lipid peroxidation, among other solutions presented in the revised literature. It has become clear that the uses for persimmon go far beyond the kitchen table and the health impact consumption demonstrated over the years. The desired sustainable transition is already in progress, however, mechanistic studies and clinical trials are essential and scaling-up is fundamental to the future.

Armeniaspirol A: a novel anti-Helicobacter pylori agent.

SummaryAntibiotic resistance in Helicobacter pylori has been growing worldwide with current treatment regimens. Development of new compounds for treatment of H. pylori infections is urgently required to achieve a successful eradication therapy in the future. Armeniaspirols, a novel class of natural products isolated from Streptomyces armeniacus, have been previously identified as antibacterial agents against Gram‐positive pathogens. In this study, we found that armeniaspirol A (ARM1) exhibited potent antibacterial activity against H. pylori, including multidrug‐resistant strains, with MIC range values of 4–16 μg ml‐1. The underlying mechanism of action of ARM1 against H. pylori involved the disruption of bacterial cell membranes. Also, ARM1 inhibited biofilm formation, eliminated preformed biofilms and killed biofilm‐encased H. pylori in a dose‐dependent manner. In a mouse model of multidrug‐resistant H. pylori infection, dual therapy with ARM1 and omeprazole showed efficient in vivo killing efficacy comparable to the standard triple therapy, and induced negligible toxicity against normal tissues. Moreover, at acidic pH 2.5, ARM1 exhibited a much more potent anti‐H. pylori activity than metronidazole. Thus, these findings demonstrated that ARM1 is a novel potent anti‐H. pylori agent, which can be developed as a promising drug lead for treatment of H. pylori infections.

Plectranthus barbatus Andrews as anti-Helicobacter pylori agent with activity against adenocarcinoma gastric cells

Helicobacter pylori colonizes half of the World population and has been associated with gastric diseases including gastric cancer. In this scenario, Plectranthus barbatus is a wide-used medicinal plant in Brazil in the treatment of gastric injuries, however, no scientific report describe it against H. pylori. The aim of this study was to evaluate the ethyl acetate fraction (EAF) chemical profile from P. barbatus and its anti-H. pylori, immunomodulatory, antioxidant and cytotoxic activities. The substances identified by (-)-ESI-FT-ICR MS were plectrin, hydrolyzed abieatane, barbatusin, 3β-hydroxy-3-deoxibarbatusin, cyclobutatusin, luteolin, rosmarinic acid and coleoside B. The anti-H. pylori results presented a minimum inhibitory concentration (MIC) of 256 μg/mL and minimum bactericidal concentration (MBC) of 1024 μg/mL. Scanning electron microscopy evidenced H. pylori morphological changes in its surface induced by EAF. Molecular docking studies were conducted to investigate the binding mode of the proposed compounds at H. pylori Penicillin-Binding Protein active site. Antioxidant activities presented IC50 ranging from 26.64 ± 0.62–69.96 ± 1.25 μg/mL and the immunomodulatory activity was significant to IL-6 and NO with 28 % and 35 % of inhibition at 25 μg/mL. EAF showed significant cytotoxic activity with CI50 of 33.89 ± 0.32 μg/mL on gastric adenocarcinoma cells. These results indicate the potential of P. barbatus as candidate for H. pylori eradication and H. pylori induced related gastric disease prevention.

Solvent-free Mechano-chemical Synthesis of New Omeprazole Derived Metal Complexes: Characterization, Urease Inhibitory Kinetics and Selective Anti-Helicobacter pylori Activity

Background: Metal-based antimicrobial agents have recently been identified as an alternate therapy for the treatment of infectious diseases. This investigation relates to one-pot solventfree preparation of some new transition metal complexes of omeprazole (OMP), followed by their characterization and in vitro applications as anti-Helicobacter pylori agents and urease inhibitors. Methods: The complexes were characterized by elemental analyzer, IR, Powder X-Ray diffraction, 1H-NMR,13C-NMR and mass spectrometric and thermal methods, which elucidated that the complexes have the general formula [ML] X where M ═ Zn, Ni, Cu and X═ CH3COO– and [ML] X. H2O, where M ═ Co, X═ CH3COO–. The complexes exhibited antibacterial activity against selected strains of Gram +ve and Gram –ve bacteria including Staphylococcus aureus (ATCC 29213), S. epidermidis (ATCC 12228), Escherichia coli (ATCC 12435), Proteus vulgaris (NCTC 4175), Pseudomonas aeruginosa (ATCC 49189) and fifteen local isolates and two reference strains of H. pylori. Zinc omeprazole (Zn-OMP), cobalt omeprazole (Co-OMP) and copper omeprazole (Cu- OMP), all exhibited potent and selective anti-H. pylori activity in the range of 1.0-16 µgmL-1, 8.0- 64 µgmL-1and 32-128 µgmL-1, respectively. Results: However, all of the complexes showed mild anti-bacterial activity against rest of the tested strains. Amoxicillin (break points of 1≤) was used as a reference standard. Zn-OMP was found to be equally effective against the antibiotic-resistant and antibiotic-susceptible strains of H. pylori, whereas Co-OMP and Cu-OMP exhibited mixed trends. Urease inhibition was evaluated by using the urease isolated from H. pylori reference. Zn-OMP was found to be the most potent urease inhibitor followed by Cu-OMP and then Co-OMP. Lineweaver-Burk plots were used to determine Michaelis Menten constant for elucidating the mechanism of inhibition. Conclusion: The results of the present work revealed that the devised mechano-chemical method can be explored as an environment-friendly route for the synthesis of metal based anti- H. plyori drugs. Keywords: Solvent-free synthesis, omeprazole, metal complexes, spectroscopic analyses, TGA, Anti-H. pylori activity, urease inhibition, lineweaver-burk plots.

Probiotics as Anti-Helicobacter pylori Agent: State of the Art

Probiotics as Anti-Helicobacter pylori Agent: State of the Art

Oxyprenylated ferulic acid derivatives in Italian citrus liqueurs

Fiorito S., Epifano F., Taddeo V.A., Genovese S. (2015): Oxyprenylated ferulic acid derivatives in Italian citrus liqueurs. Czech J. Food Sci., 33: 237–241. 4'-Geranyloxyferulic and boropinic acid have been recently found as phytochemicals exerting promising pharmaco logical effects as cancer chemopreventive, anti-inflammatory, neuroprotective, and antiHelicobacter pylori agents. An RP HPLC-UV/Vis method for the qualitative and quantitative analysis of these oxyprenylated derivatives in hand made citrus-based typical Italian liqueurs like limoncello, arancello, and mandarinetto was successfully performed. Concentration values showed a great variation between the different liquors, limoncello, from Abruzzo region, being the richest one both in 4’-geranyloxyferulic acid (1.68 ± 0.03 µg/ml of liquor) and boropinic acid (0.16 ± 0.01 µg/ml). Only in two cases boropinic acid was not detected.

Analysis of biologically active oxyprenylated ferulic acid derivatives in Citrus fruits.

4'-Geranyloxyferulic (GOFA) and boropinic acid have been discovered during the last decade as interesting phytochemicals having valuable pharmacological effects as cancer chemopreventive, anti-inflammatory, neuroprotective, and anti-Helicobacter pylori agents. A reverse-phase HPLC-UV/Vis method for the separation and quantification of the title oxyprenylated ferulic acid derivatives in extracts obtained from peels of nine edible Citrus and Fortunella fruits was successfully applied. Concentration values showed a great variation between the different species, being orange (C. sinensis) the fruit richest in GOFA (0.141 ± 0.011 mg/g of exocarp fresh weight) and kumquat (Fortunella japonica) the one in which boropinic acid was recorded as the most abundant phytochemical (0.206 ± 0.002 mg/g of exocarp fresh weight). Both secondary metabolites were not detected only in three species. The set-up methodology showed limits of quantification (LOQ) values, that were able to selectively quantify both GOFA and boropinic acid. Results described herein depict a potential chemopreventive dietary feeding role for the Rutaceae spp. under investigation.

HPLC analysis of 4′-geranyloxyferulic and boropinic acids in grapefruits of different geographical origin

4′-Geranyloxyferulic [3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid] (GOFA) and boropinic acid have been discovered as valuable phytochemicals exerting notable pharmacological effects as cancer chemopreventive and anti-Helicobacter pylori agents, respectively. A reverse-phase HPLC-UV/Vis method for their separation and quantification was successfully applied to evaluate the presence of these natural products in extracts obtained from the pulp and the exocarp of white grapefruits of different geographical origin. The recorded concentration values showed a great variation between the different sources, being the species richest in both secondary metabolites the one from South America. The set-up methodology showed LOQ values able to selectively quantify both GOFA and boropinic acid. Results described herein depict a potential chemopreventive dietary feeding role for grapefruits.

Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5-(5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylo ri agents

Background and the purpose of the studyHelicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test.MethodsThe title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole.Results and discussionThe results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5-nitrothiophen counterpart.ConclusionThe most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4-thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 μg/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori.

Vitamin-C as anti-Helicobacter pylori agent: More prophylactic than curative- Critical review

Potential of nonantibiotic therapies for treatment of Helicobacter pylori-related acid peptic disease remains underexplored. Several clinical studies have shown that higher prevalence of H. pylori infection is associated with low Vitamin C (Vit C) level in serum and gastric juice. However, there is no consensus regarding the usefulness of Vit C supplementation in the management of H. pylori infection. Surveying the existing literature we conclude that high concentration of Vit C in gastric juice might inactivate H. pylori urease, the key enzyme for the pathogen's survival and colonization into acidic stomach. Once infection established, urease is not very important for its survival. The role of Vit-C as anti-H. pylori agent in peptic ulcer diseases appears to be preventive rather than curative. Rather than supplementing high dose of Vit C along with conventional triple therapy, it is preferable to complete the conventional therapy and thereafter start Vit C supplementation for extended period which would prevent reinfection in susceptible individuals, provided the patients are not achlorhydric. Further studies are required to prove the role of Vit C in susceptible population.

Total Synthesis of an Anti‐Helicobacter pylori Agent, Actinopyrone A

Actinopyrone A, an anti-Helicobacter pylori agent, was synthesized in nine steps from a silyl dienol ether. A vinylogous anti-aldol was stereoselectively synthesized by our developed remote stereoinduction methodology; coupling of this with a sulfone and a phosphonate species led to the construction of a vinylpyrone compound. This was submitted to reductive de-conjugation to give actinopyrone A. The absolute stereochemistry of actinopyrone A was determined to have the configuration 14R,15R.

(2′′S,5′′R,7′′S)-2-[2′-(2′′-Methyl-1′′,6′′-dioxaspiro[4.5]dec-7′′-yl)ethylsulfonyl]-1,3-benzothiazole

The crystal structure of the title compound, C18H23NO4S2, has been investigated in order to establish the relative stereochemistry at the spiro ring junction and the absolute stereochemistry of the mol­ecule. The title compound is a key inter­mediate for the synthesis of the spiro­acetal-containing anti-Helicobacter pylori agent, spiro­laxine methyl ether, for which the absolute stereochemistry has not previously been reported.

A Novel Multicompartment Dissolution Apparatus for Evaluation of Floating Dosage Form Containing Poorly Soluble Weakly Basic Drug

Introduction Oral controlled release (CR) dosage forms generally have a transit time of 1–3 hours in the stomach,3–5 hours in the intestine and 4–11 hours in the colon(1). However,some drugs require more retention time in the stomach for better results. Gastro-retentive drug delivery is superior for drugs such as (a) drugs having a narrow absorption window,(b) drugs having their local effect in stomach (for example,antacids and anti helicobacter pylori agents), (c) drugs having pH-dependent stability, (d) drugs having low solubility at intestinal pH,and (e) drugs having colonic degradation (2,3). Approaches to achieve higher gastric residence time include (a) low density systems that float on gastric fluid, (b) bioadhesive systems that adhere to mucosal surface of stomach,(c) expandable systems that increase in size by swelling or unfolding to retard passage through the pylorus, (d) high density systems that sink in the lower curvature of the stomach,(e) magnetically controlled systems that operate by incorporation of magnetite oxide or coated magnets (4–6). Weakly basic drugs have lower pKa values and remain in ionized form at stomach pH having higher solubility,and in un-ionized form at intestinal pH having lower solubility (7). According to pH partition theory (14),drug is absorbed in un-ionized form,thus weakly basic drug absorbs from the intestine. When weakly basic drug is incorporated in a conventional CR dosage form,only a fraction of the drug is dissolved due to lesser solubility at its absorption site,such as the intestine. Incorporation of weakly basic drug into a gastro-retentive dosage form is beneficial over a conventional CR dosage form so that released drug continuously reaches its absorption site such as the intestine (8). Cinnarizine is a weak base (pKa 1.95,7.5) having higher solubility at lower pH (0.29 mg/mL in 0.1 N HCl) and lower solubility at higher pH (0.002 mg/mL in phosphate buffer pH 7.2),and thus is selected as the model drug for the floating dosage form (9,10). In vitro dissolution testing is generally carried out for quality control purposes and to establish an in vivo in vitro correlation. The currently used in vitro dissolution method for the floating dosage form is conducted at a constant pH 1.2 to mimic the stomach environment. The general prediction is that when drug is dissolved in vitro, it is considered that the drug is also absorbed in vivo. However, in vivo,the drug is exposed to varying dissolution environments in the gastrointestinal (GI) tract. Particularly,the pH in the GI tract Abstract Incorporation of a weakly basic drug into a gastro-retentive dosage form yields better biomedical benefits compared to incorporation into a conventional controlled release dosage form. Poorly soluble weakly basic drugs may precipitate upon entry into the small intestine,and this can affect absorption. To study drug release from floating dosage forms and simultaneously examine the effect of pH change on poorly soluble weakly basic drugs,a novel multicompartment dissolution system was developed by modifying beakers. The system consists of three serially placed compartments providing gastric, intestinal, and absorption compartment to mimic the in vivo dissolution and absorption in the gastrointestinal tract. A dosage form remained buoyant in the gastric compartment,released drug was allowed to transfer to the intestinal compartment,and soluble drug in the intestinal compartment was allowed to transfer to the absorption compartment through a filter. Dissolution profiles of 75 mg cinnarizine in conventional and floating tablets were studied. The results of conventional tablet showed that although cinnarizine was completely dissolved in the gastric compartment,approximately 50% of cinnarizine was precipitated in the intestinal compartment. A floating cinnarizine tablet showed complete release within 24 hours with nearly zero order release rate,and no precipitation observed in the intestinal compartment,giving 100% of cinnarizine transferred into the absorption compartment. The floating controlled release of poorly soluble weakly basic drug may give considerable biomedical benefits over conventional tablet formulation,which was demonstrated by the proposed novel multicompartment system. Variability of volume in the gastric and intestinal compartments was studied by making further modification in the apparatus. The proposed system may give good in vivo in vitro correlation,as attempts can be made to mimic in vivo conditions such as gastric volume,gastric secretion,gastric emptying to the intestine,and intestinal absorption.

Synthesis of a spiroacetal intermediate for the synthesis of the anti-Helicobacter pylori agent CJ-12, 954

A method has been established for the synthesis of the 5,5-spiroacetal moiety of the anti- Helicobacter pylori agents CJ-12,954 1 and CJ-13,014 2 in racemic form and as a mixture of stereoisomers. Retrosynthetically the key spiroacetal 9 is derived from the acyclic protected dihydroxyketone precursor 10 or 11 which in turn are available from enynone 25 or 26. Enynones 25 and 26 were prepared via addition of the acetylide derived from acetylenes 13 or 14 to aldehyde 12 followed by oxidation of the resultant alcohols 23 and 24 respectively. Acetylenes 13 and 14 in turn were available via (2,3)-sigmatropic rearrangement of allyl propargyl ether 16. Extension of this reaction in an asymmetric sense by use of a chiral base would have provided acetylene 14 in enantioenriched form, however, efforts towards this end were disappointing. Enynones 25 and 26 were converted to keto epoxides 10 and 11 respectively by treatment with meta-chloroperbenzoic acid followed by hydrogenation of the acetylene. Attempts to effect deprotection and cyclization of bis-silyl ethers 10 and 11 to spiroacetal 9 were complicated by the presence of the epoxide. In an alternative approach enynone 26 was converted to methyl acetal 29 upon treatment with camphorsulfonic acid in methanol. Subsequent epoxidation of the terminal alkene 29 afforded epoxide 30 which then underwent smooth hydrogenation and cyclization in situ to the desired spiroacetal 9.

ChemInform Abstract: Anti-Helicobacter pylori Agents. Part 4. 2-(Substituted guanidino)-4-phenylthiazoles and Some Structurally Rigid Derivatives.

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