Synergistic effect of phenylpropanoids and flavonoids with antibiotics against Gram-positive and Gram-negative bacterial strains.

CONTEXT: The increase in bacterial resistance to currently available medications, which increases mortality rates, treatment costs is a global problem, and highlights the need for novel classes of antibacterial agents or new molecules that interact synergistically with antimicrobials. OBJECTIVE: The current work explores the potential synergistic effects of certain natural phenylpropanoids and flavonoids on ciprofloxacin (CIP), ampicillin (AMP), gentamicin (GEN), and tetracycline (TET). MATERIALS AND METHODS: The adjuvant role of cinnamic acid, p-coumaric acid, caffeic acid, ferulic acid, ferulic acid methyl ester, sinapic acid, apigenin, and luteolin was evaluated by determining the MIC (minimal inhibitory concentration) values of antibiotics in the presence of subinhibitory concentrations (200, 100, and/or 50 µM) of the compounds in Gram-positive and Gram-negative bacterial strains using a 2-fold broth microdilution method. The 96-well plates were incubated at 37 °C for 18 h, and dimethyl sulfoxide was used as a solvent control. RESULTS: The combination of luteolin with CIP, reduced the MIC values of the antibiotic from 0.625 to 0.3125 µM and to 0.078 µM in 100 and 200 µM concentration, respectively, in sensitive Staphylococcus aureus. Sinapic acid decreased the MIC value of CIP from 0.625 to 0.3125 µM in S. aureus, from 1.56 to 0.78 µM in Klebsiella pneumoniae, and the MIC of GEN from 0.39 to 0.095 µM in Pseudomonas aeruginosa strains. DISCUSSION AND CONCLUSIONS: These findings are useful in delaying the development of resistance, as the required antibacterial effect can be achieved with the use of lower concentrations of antibiotics.

Phytochemical Investigation of Carex praecox Schreb. and ACE-Inhibitory Activity of Oligomer Stilbenes of the Plant.

Phenolic compounds are the main special metabolites of Cyperaceae species from phytochemical, pharmacological, and chemotaxonomical points of view. The present study focused on the isolation, structure determination, and pharmacological investigation of constituents from Carex praecox. Twenty-six compounds, including lignans, stilbenes, flavonoids, megastigmanes, chromenes, and phenylpropanoids, were identified from the methanol extract of the plant. Five of these compounds, namely, carexines A-E, are previously undescribed natural products. All compounds were isolated for the first time from C. praecox. The ACE-inhibitory activity of seven stilbenoid compounds was tested, and (-)-hopeaphenol proved to be the most active (IC50 7.7 ± 0.9 µM). The enzyme-kinetic studies revealed a mixed-type inhibition; therefore, domain-specific studies were also conducted. The in silico docking of (-)-hopeaphenol to the ACE affirmed some favorable interactions. In addition, the antiproliferative and antibacterial effects of some compounds were also evaluated.

Antitumor Activity of Symmetrical Selenoesters in Doxorubicin Resistant Breast Cancer.

BACKGROUND/AIM: Previously, selenocompounds (Se-compounds) and in particular selenoesters have shown promising anticancer activities. Since molecular symmetry can enhance the anticancer activity, nine symmetrical selenoesters (Se-esters) have been designed as novel, potentially active anticancer agents against doxorubicin resistant breast cancer cells. MATERIALS AND METHODS: To assess the biological effects of the symmetrical Se-esters, the antiproliferative activity was determined on sensitive MCF-7 and doxorubicin resistant KCR breast cancer cell lines. The interaction of the derivatives with doxorubicin was evaluated by checkerboard combination assay on KCR cells. Furthermore, apoptosis induction and ATPase activity in the presence of Se-esters were also determined on KCR cells. RESULTS: The symmetrical derivatives showed a noteworthy antiproliferative activity, with two of them showing IC50 values in submicromolar concentration on MCF-7 cells. In addition, some derivatives showed selectivity towards the resistant KCR cells. The combination of most of them with doxorubicin resulted in synergistic interaction, and all Se-esters could induce early and late apoptosis in KCR cells. Finally, the compounds affected the ATPase activity of ABCB1 (P-gp). CONCLUSION: The symmetrical Se-esters showed potent anticancer activity, according to in vitro tests. Further research needs to be performed to obtain similar derivatives with a better activity and selectivity, and to ascertain the potential application of these Se-containing compounds using in vivo systems.

Indonesian Euphorbiaceae: Ethnobotanical Survey, In Vitro Antibacterial, Antitumour Screening and Phytochemical Analysis of Euphorbia atoto.

Indonesia is among the countries with the most significant biodiversity globally. Jamu, the traditional medicine of Indonesia, predominantly uses herbal materials and is an integral component of the Indonesian healthcare system. The present study reviewed the ethnobotanical data of seven Indonesian Euphorbiaceae species, namely Euphorbia atoto, E. hypericifolia, Homalanthus giganteus, Macaranga tanarius, Mallotus mollissimus, M. rufidulus, and Shirakiopsis indica, based on the RISTOJA database and other literature sources. An antimicrobial screening of the plant extracts was performed in 15 microorganisms using the disk diffusion and broth microdilution methods, and the antiproliferative effects were examined in drug-sensitive Colo 205 and resistant Colo 320 cells by the MTT assay. The antimicrobial testing showed a high potency of M. tanarius, H. giganteus, M. rufidulus, S. indica, and E. atoto extracts (MIC = 12.5-500 µg/mL) against different bacteria. In the antitumour screening, remarkable activities (IC50 0.23-2.60 µg/mL) were demonstrated for the extracts of H. giganteus, M. rufidulus, S. indica, and E. atoto against Colo 205 cells. The n-hexane extract of E. atoto, with an IC50 value of 0.24 ± 0.06 µg/mL (Colo 205), was subjected to multistep chromatographic separation, and 24-methylene-cycloartan-3ß-ol, jolkinolide E, tetra-tert-butyl-diphenyl ether, α-tocopherol, and ß-sitosterol were isolated.

Reversal of Multidrug Resistance by Symmetrical Selenoesters in Colon Adenocarcinoma Cells.

Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the ABCB1 protein. The combined effect of the compounds with doxorubicin was demonstrated with a checkerboard assay. The ABCB1 inhibitory and the apoptosis-inducing effects of the derivatives were measured with flow cytometry. Whole transcriptome sequencing was carried out on Illumina platform upon the treatment of resistant cells with the most potent derivatives. One ketone and three methyl ester selenoesters showed synergistic or weak synergistic interaction with doxorubicin, respectively. Ketone selenoesters were the most potent ABCB1 inhibitors and apoptosis inducers. Nitrile selenoesters could induce moderate early and late apoptotic processes that could be explained by their ABCB1 modulating properties. The transcriptome analysis revealed that symmetrical selenoesters may influence the redox state of the cells and interfere with metastasis formation. It can be assumed that these symmetrical selenocompounds possess toxic, DNA-damaging effects due to the presence of two selenium atoms in the molecule, which may be augmented by the presence of symmetrical groups.

5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells.

Multidrug resistance (MDR) is considered one of the major mechanisms responsible for the failure of numerous anticancer and antiviral chemotherapies. Various strategies to overcome the MDR phenomenon have been developed, and one of the most attractive research directions is focused on the inhibition of MDR transporters, membrane proteins that extrude cytotoxic drugs from living cells. Here, we report the results of our studies on a series newly synthesized of 5-arylidenerhodanines and their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. In the series, compounds possessing a triphenylamine moiety and the carboxyl group in their structure were of particular interest. These amphiphilic compounds showed over 17-fold stronger efflux pump inhibitory effects than verapamil. The cytotoxic and antiproliferative effects of target rhodanines on T-lymphoma cells were also investigated. A putative binding mode for 11, one of the most potent P-gp inhibitors tested here, was predicted by molecular docking studies and discussed with regard to the binding mode of verapamil.

Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma.

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 µM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 µM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC50: 16.73 µM) as well as concerning the antiproliferative effect (IC50: 5.35 µM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness.

Discovery of a novel class of small-molecule antibacterial agents against Staphylococcus aureus.

Background: With constantly increasing resistance against the known antibiotics, the search for novel antibacterial compounds is a challenge. The number of synthetic antibacterial agents is limited. Materials & methods: We discovered novel small-molecule antibacterial agents that are accessible via a simple two-step procedure. The evaluation against Staphylococcus aureus showed antibacterial effects depending on the substituent positioning at the residues of the molecular scaffold. Additionally, we investigated the potential of the compounds to increase the antibacterial activity of tetracycline. Results: The most effective antibacterial compounds possessed a 3-methoxy function at an aromatic residue. In combination with tetracycline, we found a strong effect for a few compounds in boosting the antibacterial activity, so the first promising lead compounds with dual activities could be identified.

The Relationship between Antibiotic Susceptibility and pH in the Case of Uropathogenic Bacteria.

Urinary tract infections (UTIs) are common bacterial infections caused mainly by enteric bacteria. Numerous virulence factors assist bacteria in the colonization of the bladder. Bacterial efflux pumps also contribute to bacterial communication and to biofilm formation. In this study, the phenotypic and genetic antibiotic resistance of clinical UTI pathogens such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were determined by disk diffusion method and polymerase chain reaction (PCR). Following this, different classes of antibiotics were evaluated for their antibacterial activity at pH 5, 6, 7 and 8 by a microdilution method. Gentamicin (GEN) was the most potent antibacterial agent against E. coli strains. The effect of GEN on the relative expression of marR and sdiA genes was evaluated by quantitative PCR. The slightly acidic pH (pH 6) and GEN treatment induced the upregulation of marR antibiotic resistance and sdiA QS activator genes in both E. coli strains. Consequently, bacteria had become more susceptible to GEN. It can be concluded that antibiotic activity is pH dependent and so the artificial manipulation of urinary pH can contribute to a more effective therapy of multidrug resistant bacterial infections.

Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers.

Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (K1-K8, also known as oxoselenoesters) and seven cyano-containing selenoesters (N1-N7, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay. As key results, all the compounds showed cytotoxicity against cancer cells at low micromolar concentrations, with cyanoselenoesters being strongly selective. All of the oxoselenoesters, except K4, were potent ABCB1 inhibitors, and two of them, namely K5 and K6, enhanced the activity of doxorubicin in a synergistic manner. The majority of these ketone derivatives modulated the ATPase activity, showed wound healing activity, and induced apoptosis, with K3 being the most potent, with a potency close to that of the reference compound. To summarize, these novel derivatives have promising multi-target activity, and are worthy to be studied more in-depth in future works to gain a greater understanding of their potential applications against cancer.

Triterpenes and Phenolic Compounds from the Fungus Fuscoporia torulosa: Isolation, Structure Determination and Biological Activity.

Investigation of the methanol extract of the poroid fungus Fuscoporia torulosa resulted in the isolation of a novel triterpene, fuscoporic acid (1), together with inoscavin A and its previously undescribed Z isomer (2 and 3), 3,4-dihydroxy-benzaldehide (4), osmundacetone (5), senexdiolic acid (6), natalic acid (7), and ergosta-7,22-diene-3-one (8). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analyses, as well as molecular modeling studies. Compounds 1, 6-8 were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines. Compound 8 was effective against Colo 205 (IC50 11.65 ± 1.67 µM), Colo 320 (IC50 8.43 ± 1.1 µM) and MRC-5 (IC50 7.92 ± 1.42 µM) cell lines. Potentially synergistic relationship was investigated between 8 and doxorubicin, which revealed a synergism between the examined compounds with a combination index (CI) at the 50% growth inhibition dose (ED50) of 0.521 ± 0.15. Several compounds (1 and 6-8) were tested for P-glycoprotein modulatory effect in Colo 320 resistant cancer cells, but none of the compounds proved to be effective in this assay. Fungal metabolites 2-5 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) and DPPH assays. Compounds 4 and 5 were found to have a considerable antioxidant effect with EC50 0.25 ± 0.01 (DPPH) and 12.20 ± 0.92 mmol TE/g (ORAC). The current article provides valuable information on both the chemical and pharmacological profiles of Fuscoporia torulosa, paving the way for future studies with this species.

Juncaceae Species as Promising Sources of Phenanthrenes: Antiproliferative Compounds from Juncus maritimus Lam.

Juncaceae family represents an abundant source of phenanthrenes. In continuation of our work aiming at the isolation of biologically active compounds from Juncaceae species, Juncus maritimus Lam. was subjected to phytochemical and pharmacological investigations. The isolation process was carried out by using combined extraction and chromatographic methods. The structures of the obtained chemical compounds were elucidated by spectroscopic analysis, including HRESIMS, 1D (1H, 13C-JMOD), and 2D (1H-1H-COSY, HSQC, HMBC, NOESY) NMR spectra. Four new [maritins A-D (1-4)] and seven known phenanthrenes (5-11) were isolated from the plant, of which two (4 and 11) are phenanthrene dimers composed of effusol monomers. Maritin C (3) has an unusual 4,5-ethanophenanthrene skeleton most likely produced by biosynthetic incorporation of a vinyl group into a cyclohexadiene ring. Compounds 1-11 were tested for their antiproliferative activity on seven human tumor cell lines (HeLa, HTM-26, T-47D, A2780, A2780cis, MCF-7, KCR) and one normal cell line (MRC-5) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The dimeric phenanthrenes showed strong antiproliferative activity against T-47D cells with IC50 values of 9.1 and 6.2 µM, respectively.

An insight into the structure of 5-spiro aromatic derivatives of imidazolidine-2,4-dione, a new group of very potent inhibitors of tumor multidrug resistance in T-lymphoma cells.

A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6-22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6-16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6-16), occurred the most potent P-gp inhibitors in the MDR T-lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action.

Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells.

Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric alkaloids isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation of the indole nitrogen. Twenty-six new derivatives (3-28) were prepared by reaction with different aliphatic and aromatic halides, whose structures were elucidated mainly by NMR, including 2D NMR experiments. Their MDR reversal ability was evaluated through a functional assay, using as models resistant human colon adenocarcinoma and human ABCB1-gene transfected L5178Y mouse lymphoma cells, overexpressing P-glycoprotein (P-gp), by flow cytometry. A considerable increase of activity was found for most of the derivatives, being the strongest P-gp inhibitors those sharing N-phenethyl moieties, displaying outstanding inhibitory activity, associated with weak cytotoxicity. Chemosensitivity assays were also performed in a model of combination chemotherapy in the same cell lines, by studying the in vitro interactions between the compounds and the antineoplastic drug doxorubicin. Most of the compounds have shown strong synergistic interactions with doxorubicin, highlighting their potential as MDR reversers. QSAR models were also explored for insights on drug-receptor interaction, and it was found that lipophilicity and bulkiness features were associated with inhibitory activity, although linear correlations were not observed.

Antiproliferative Phenanthrenes from Juncus tenuis: Isolation and Diversity-Oriented Semisynthetic Modification.

The occurrence of phenanthrenes is limited in nature, with such compounds identified only in some plant families. Phenanthrenes were described to have a wide range of pharmacological activities, and numerous research programs have targeted semisynthetic derivatives of the phenanthrene skeleton. The aims of this study were the phytochemical investigation of Juncus tenuis, focusing on the isolation of phenanthrenes, and the preparation of semisynthetic derivatives of the isolated compounds. From the methanolic extract of J. tenuis, three phenanthrenes (juncusol, effusol, and 2,7-dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene) were isolated. Juncusol and effusol were transformed by hypervalent iodine(III) reagent, using a diversity-oriented approach. Four racemic semisynthetic compounds possessing an alkyl-substituted p-quinol ring (1-4) were produced. Isolation and purification of the compounds were carried out by different chromatographic techniques, and their structures were elucidated by means of 1D and 2D NMR, and HRMS spectroscopic methods. The isolated secondary metabolites and their semisynthetic analogues were tested on seven human tumor cell lines (A2780, A2780cis, KCR, MCF-7, HeLa, HTB-26, and T47D) and on one normal cell line (MRC-5), using the MTT assay. The effusol derivative 3, substituted with two methoxy groups, showed promising antiproliferative activity on MCF-7, T47D, and A2780 cell lines with IC50 values of 5.8, 7.0, and 8.6 µM, respectively.

Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues.

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1-3) or a bioisosteric analogue core (compounds 4-6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

Ketone- and Cyano-Selenoesters to Overcome Efflux Pump, Quorum-Sensing, and Biofilm-Mediated Resistance.

The emergence of drug-resistant pathogens leads to a gradual decline in the efficacy of many antibacterial agents, which poses a serious problem for proper therapy. Multidrug resistance (MDR) mechanisms allow resistant bacteria to have limited uptake of drugs, modification of their target molecules, drug inactivation, or release of the drug into the extracellular space by efflux pumps (EPs). In previous studies, selenoesters have proved to be promising derivatives with a noteworthy antimicrobial activity. On the basis of these results, two series of novel selenoesters were synthesized to achieve more potent antibacterial activity on Gram-positive and Gram-negative bacteria. Fifteen selenoesters (eight ketone-selenoesters and seven cyano-selenoesters) were investigated with regards to their efflux pump-inhibiting, anti-quorum-sensing (QS), and anti-biofilm effects in vitro. According to the results of the antibacterial activity, the ketone-selenoesters proved to be more potent antibacterial compounds than the cyano-selenoesters. With regard to efflux pump inhibition, one cyano-selenoester on methicillin-resistant S. aureus and one ketone-selenoester on Salmonella Typhimurium were potent inhibitors. The biofilm inhibitory capacity and the ability of the derivatives to disrupt mature biofilms were noteworthy in all the experimental systems applied. Regarding QS inhibition, four ketone-selenoesters and three cyano-selenoesters exerted a noteworthy effect on Vibrio campbellii strains.

Nitrogen-containing naringenin derivatives for reversing multidrug resistance in cancer.

Naringenin (1), isolated from Euphorbia pedroi, was previously derivatized yielding compounds 2-13. In this study, aiming at expanding the pool of analogues of the flavanone core towards better multidrug resistance (MDR) reversal agents, alkylation reactions and chemical modification of the carbonyl moiety was performed (15-39). Compounds structures were assigned mainly by 1D and 2D NMR experiments. Compounds 1-39 were assessed as MDR reversers, in human ABCB1-transfected mouse T-lymphoma cells, overexpressing P-glycoprotein (P-gp). The results revealed that O-methylation at C-7, together with the introduction of nitrogen atoms and aromatic moieties at C-4 or C-4', significantly improved the activity, being compounds 27 and 37 the strongest P-gp modulators and much more active than verapamil. In combination assays, synergistic interactions of selected compounds with doxorubicin substantiated the results. While molecular docking suggested that flavanone derivatives act as competitive modulators, molecular dynamics showed that dimethylation promotes binding to a modulator-binding site. Moreover, flavanones may also interact with a vicinal ATP-binding site in both nucleotide-binding domains, hypothesizing an allosteric mode of action.

Benzoxazole-Based Metal Complexes to Reverse Multidrug Resistance in Bacteria.

Bacteria often show resistance against antibiotics due to various mechanisms such as the expression of efflux pumps, biofilm formation, or bacterial quorum sensing (QS) controls. For successful therapy, the discovery of alternative agents is crucial. The objective of this study was to evaluate the efflux pump, anti-biofilm, and QS inhibiting, as well as antibacterial effects of 2-trifluoroacetonylbenzoxazole ligands (1-3) and their metal complexes (4-12) in bacteria. The ligand 2 and its Zn(II) complex 5, and furthermore the Cu(II) complex 7 of ligand 1, exerted remarkable antibacterial activity on the Staphylococcus aureus 272123 (MRSA) strain. In the minimum inhibitory concentration (MIC) reduction assay the ligand 3, the Zn(II) complex 5 of ligand 2, and the Cu(II), Ni(II), Mg(II), Fe(III) complexes (7, 8, 9, 12) of ligand 1 enhanced the antibacterial activity of ciprofloxacin in MRSA. An increased ethidium bromide accumulation was detected for ligand 3 in MRSA while the Fe(III) complex 12 of ligand 1 decreased the biofilm formation of the reference S. aureus ATCC 25923 strain. The Zn(II) and Ag(II) complexes (3 and 4) of ligand 1 and ligand 3 inhibited the QS. Based on our results, the ligands and their metal complexes could be potential alternative drugs in the treatment of infectious diseases.

N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins.

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment, the ability of novel histamine H3 receptor ligands to reverse the cancer MDR was evaluated, using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. The most active compounds displayed significant cytotoxic and antiproliferative effects as well as a very potent MDR efflux pump inhibitory action, 3-5-fold stronger than that of reference inhibitor verapamil. Although these compounds possess weak antagonistic properties against histamine H3 receptors, they are valuable pharmacological tools in the search for novel anticancer molecules. Furthermore, for the most active compounds, an insight into mechanisms of action using either, the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp, was performed.