Synthesis and Assessment of Novel Anti-chlamydial Benzylidene Acylhydrazides Derivatives

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 µM, better than 7.30 µM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 µM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

Download Full-text

TAMARIND EXTRACT INHIBITS CYTOCHROME P450 (CYP3A4 ISOZYME) - AN IN VITRO STUDY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.25767 ◽

2018 ◽

Vol 11 (7) ◽

pp. 333

Author(s):

Jagadish Rajkumaar R ◽

Anitha Roy ◽

Lakshmi T

Keyword(s):

Room Temperature ◽

Potassium Phosphate ◽

In Vitro Study ◽

Inhibitory Effect ◽

Dependent Manner ◽

Fruit Pulp ◽

Ic50 Value ◽

Dose Dependent ◽

Cytochrome P 450

Objective: The aim of the present study was to analyze the effect of the aqueous fruit pulp extract of Tamarindus indica L. (tamarind extract) on cytochrome P 450 isoform CYP3A4.Methods: Tamarind extract at different concentrations from 5 to 100 μg/ml was examined for its inhibitory property toward cytochrome P 450 isoform CYP3A4. The various concentrations of tamarind extract, potassium phosphate buffer, CYP450 reagent, and substrate 7-Benzyloxy-4- trifluoromethylcoumarin were added to a 96-well plate. The mixtures were preincubated for 20 min at room temperature. The reaction was started by a mixture of free constituted substrate and NADP+ and incubated at room temperature for 30–60 min. The reaction was stopped by Tris-HCl buffer, pH 10.5. The fluorescent intensities of the products were measured by PerkinElmer Enspire fluorescence reader using an excitation and emission wavelength of 405 nm and 460 nm, respectively. Inhibitory concentration (IC50) was calculated by plotting concentrations of tamarind extract against the corresponding percentage inhibition.Results: All the tested concentrations of extract except 5 μg/ml showed good inhibition against CYP3A4 in a dose-dependent manner. The IC50 value of tamarind for CYP3A4 inhibitory activity was found to be 27.89 μg/ml.Conclusion: T. indica aqueous fruit pulp extract exhibited an inhibitory effect on CYP34A, thereby indicating the possibilities of herb-drug interaction if these extracts are coadministered with the prescribed drugs that are metabolized by CYP3A4.

Download Full-text

INHIBITORY EFFECT OF ARTOCARPUS LOWII KING COMPOUNDS ON COX-2 AND 15-LO ACTIVITIES

Jurnal Teknologi ◽

10.11113/jt.v76.3652 ◽

2015 ◽

Vol 76 (1) ◽

Author(s):

Mohamad Norisham Mohamad Rosdi ◽

Hasnah Mohd Sirat ◽

Siti Awanis Abdullah ◽

Shajarahtunnur Jamil ◽

Ida Idayu Muhamad ◽

...

Keyword(s):

Inhibitory Effect ◽

Arachidonic Acid Metabolism ◽

Cyclooxygenase 2 ◽

Inflammatory Activity ◽

Dependent Manner ◽

Direct Inhibition ◽

Noticeable Effect ◽

Ic50 Value ◽

Anti Inflammatory ◽

Dose Dependent

Artocarpus lowii King is a rare species of plant in Moraceae family. In this study, the anti-inflammatory activity of cycloheterophyllin, isobavachalcone, 4-hydroxylonchocarpin and 2’,4’-dihydroxy-4-methoxy-3’-prenyldihydroxychalcone isolated from A. lowii King were investigated on classical enzymes in arachidonic acid metabolism pathways; cyclooxygenase and lipoxygenase. Isobavachalcone directly inhibited cyclooxygenase-2 enzyme in dose dependent manner, with IC50 value of 0.95 μM. No noticeable effect has been observed with the other tested compounds. In addition, none of the tested compounds displays a direct inhibition on 15-lipoxygenase when compared to the resveratrol as control with the IC50 value of 1.5 μM. Isobavachalcone showed inhibitory effect on cyclooxygenase-2. This study suggests that A. lowii King contains potential anti-inflammatory activity.

Download Full-text

Inhibitory Activity of Pyrroloisoxazolidine Derivatives against Chlamydia trachomatis

BioMed Research International ◽

10.1155/2021/8889247 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Min Ni ◽

Shunxin Xu ◽

Ziyi Liu ◽

Yin Xue ◽

Wenxia Xie ◽

...

Keyword(s):

Chlamydia Trachomatis ◽

Inhibitory Activity ◽

Dependent Manner ◽

Human Pathogens ◽

High Concentration ◽

Obligate Intracellular ◽

Reticulate Body ◽

Ic50 Values ◽

Dose Dependent

The obligate intracellular bacterium Chlamydia trachomatis is a group of worldwide human pathogens that can lead to serious reproductive problems. The frequent clinical treatment failure promoted the development of novel antichlamydial agents. Here, we firstly reported a group of pyrroloisoxazolidine-inhibited C. trachomatis in a dose-dependent manner in vitro. Among them, compounds 1 and 2 exhibited the strongest inhibitory activity with IC50 values from 7.25 to 9.73 μM. The compounds disturbed the whole intracellular life cycle of C. trachomatis, mainly targeting the middle reticulate body proliferation stages. Besides, the compounds partially inhibited the chlamydial infection by reducing elementary body infectivity at high concentration. Our findings suggest the potential of pyrroloisoxazolidine derivatives as promising lead molecules for the development of antichlamydial agents.

Download Full-text

EVALUATION OF THE CYTOCHROME P450 INHIBITORY EFFECT OF THYME OLEORESIN FROM THYMUS VULGARIS L. - AN IN VITRO STUDY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i9.26759 ◽

2018 ◽

Vol 11 (9) ◽

pp. 149

Author(s):

Adeline Persia R ◽

Anitha Roy ◽

Lakshmi T

Keyword(s):

Cytochrome P450 ◽

Potassium Phosphate ◽

In Vitro Study ◽

Inhibitory Effect ◽

Thymus Vulgaris ◽

Dependent Manner ◽

Inhibitory Effects ◽

Ic50 Value ◽

Dose Dependent

Objective: The objective of this study was to evaluate the effect of thyme oleoresin on cytochrome P450 (CYP3A4) enzyme.Materials and Methods: The different concentrations of thyme (5–100 μg/ml) were examined for its inhibitory property toward cytochrome P450 isoform (CYP3A4). Thyme, potassium phosphate buffer, CYP450 reagent, and substrate 7-Benzyloxy-4-trifluoromethylcoumarin were added to a 96-well plate. The mixtures were preincubated for 20 min at room temperature. The fluorescent intensities of the products were measured by PerkinElmer Enspire fluorescence reader using an excitation and emission wavelength of 405 nm and 460 nm, respectively. Values are expressed as mean ± standard error mean (n=3). IC50 was calculated by plotting concentrations of thyme against the corresponding percent inhibition.Results: All the tested concentrations of thyme showed inhibitory effect against CYP3A4 in a dose-dependent manner. At 5 μg/ml, it showed a percentage inhibition of 1.82±0.61, whereas 100 μg/ml showed 66.05±0.16. The IC50 value of thyme for CYP3A4 inhibitory activity was found to be 39.14 μg/ml.Conclusion: This study proves that the inhibitory effect of thyme oleoresin on cytochrome P450. The inhibitory effects of thyme indicate the possibilities of herb-drug interaction if this extract is coadministered with prescribed drugs that are metabolized by CYP3A4.

Download Full-text

Targeting BMI-1 with PLGA–PEG nanoparticle-containing PTC209 modulates the behavior of human glioblastoma stem cells and cancer cells

Cancer Nanotechnology ◽

10.1186/s12645-021-00078-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Elham Poonaki ◽

Fatemeh Ariakia ◽

Mohammad Jalili-Nik ◽

Mehdi Shafiee Ardestani ◽

Gholamhossein Tondro ◽

...

Keyword(s):

Drug Loading ◽

Polycomb Group ◽

Dependent Manner ◽

Migration Ability ◽

Jnk Signaling ◽

Human Glioblastoma ◽

Core Member ◽

Ic50 Values ◽

Human Gbm ◽

Dose Dependent

AbstractDespite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.

Download Full-text

In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03309-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qun Zhang ◽

Zengqiang Qu ◽

Yanqing Zhou ◽

Jin Zhou ◽

Junwei Yang ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Liver Microsomes ◽

In Vitro Study ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Drug Drug Interaction ◽

Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

Download Full-text

Immunomodulatory activities of whey fractions in efferent prefemoral lymph of sheep

Journal of Dairy Research ◽

10.1017/s0022029900031757 ◽

1996 ◽

Vol 63 (2) ◽

pp. 257-267 ◽

Cited By ~ 12

Author(s):

Chun W. Wong ◽

Geoffrey O. Regester ◽

Geoffrey L. Francis ◽

Dennis L. Watson

Keyword(s):

Immune Responses ◽

Bovine Milk ◽

Inhibitory Effect ◽

Dependent Manner ◽

Milk Whey ◽

Significant Difference ◽

Lymphocyte Phenotypes ◽

Dose Dependent

SummaryStudies on the immunomodulatory activities of ruminant milk and colostral whey fractions were undertaken. By comparing with boiled colostral whey in a preliminary experiment, a putative heat-labile immunostimulatory factor for antibody responses was found to be present in ovine colostral whey. Studies were then undertaken in sheep in which the efferent prefemoral lymphatic ducts were cannulated bilaterally, and immune responses in the node were measured following subcutaneous injection in the flank fold of whey protein preparations of various purities. A significant sustained decline of efferent lymphocyte output was observed following injection with autologous crude milk whey or colostral whey preparations, but no changes were observed in interferon-gamma levels in lymph plasma. Two bovine milk whey fractions (lactoperoxidase and lactoferrin) of high purity were compared in bilaterally cannulated sheep. A transient decline over the first 6 h was seen in the efferent lymphocyte output and lymph flow rate after injection of both fractions. A significant difference was seen between the two fractions in interferongamma levels in lymph at 6 h after injection. However, no significant changes in the proportion of the various efferent lymphocyte phenotypes were seen following either treatment. Whereas both fractions showed a significant inhibitory effect in a dose-dependent manner on the proliferative response of T lymphocytes, but not B lymphocytes, to mitogenic stimulation in vitro, no similar changes were seen following in vivo stimulation with these two fractions.

Download Full-text

Reversible arrest of Artemia development by cadmium

Canadian Journal of Zoology ◽

10.1139/z86-246 ◽

1986 ◽

Vol 64 (8) ◽

pp. 1633-1641 ◽

Cited By ~ 30

Author(s):

Parvaneh Rafiee ◽

Christopher O. Matthews ◽

Joseph C. Bagshaw ◽

Thomas H. MacRae

Keyword(s):

Normal Development ◽

Developmental Process ◽

Inhibitory Effect ◽

Microtubule Assembly ◽

Abnormal Development ◽

Dependent Manner ◽

Physiological Changes ◽

Molecular Aspects ◽

Reduced Rate ◽

Dose Dependent

Under normal conditions, an encysted Artemia embryo undergoes a developmental process that culminates in the gradual, uninterrupted emergence of the prenauplius from the cyst. The hatching membrane surrounding the emerged organism is then ruptured, usually beginning at the posterior end, and a motile nauplius is released. We have observed this process microscopically in the presence and absence of cadmium and report that cadmium disrupts Artemia development in a dose–dependent manner. At 0.1 μM, cadmium slows emergence but nauplii eventually resume rellatively normal development. Emergence and hatching are either delayed considerably or almost entirely prevented at 1 μM cadmium. Cadmium at 10 μM, completely arrests emergence but development continues at a reduced rate, eventually resulting in hatching of some organisms without need for complete emergence. If organisms exposed to 10 μM cadmium are washed, abnormally shaped emerged forms are released and many of these eventually hatch, although in an unusual manner. Cadmium at 10 μM causes complete, rapid precipitation of purified Artemia tubulin at 0 °C but cadmium at the lower concentrations tested has no apparent inhibitory effect on microtubule assembly. Although we do not know the actual cadmium–induced physiological changes that result in abnormal development of Artemia, our results indicate that we can now examine the interdependence of morphological and molecular aspects of Artemia development in a way not previously possible.

Download Full-text

Role Of Cyclic Amp In The Inhibition Of Human Platelet Functions By Quercetin, A Flav0N0Id That Potentiates PGI2 Effect

10.1055/s-0038-1652487 ◽

1981 ◽

Author(s):

J P Cazenave ◽

A Beretz ◽

A Stierlé ◽

R Anton

Keyword(s):

Maximum Level ◽

Inhibitory Effect ◽

Dependent Manner ◽

Pde Inhibitors ◽

Pde Inhibition ◽

Induced Aggregation ◽

Camp Levels ◽

Dose Dependent

Injury to the endothelium (END) and subsequent platelet (PLAT)interactions with the subEND are important steps in thrombosis and atherosclerosis. Thus,drugs that protect the END from injury and also inhibit PLAT function are of interest. It has been shown that some flavonoids(FLA), a group of compounds found in plants, prevent END desquamation in vivo, inhibit cyclic nucleotide phosphodiesterases(PDE)and inhibit PLAT function. We have studied the structure-activity relationships of 13 purified FLA on aggregation and secretion of 14c-5HT of prelabeled washed human PLAT induced by ADP, collagen(COLL) and thrombin(THR). All the FLA were inhibitors of the 3 agents tested. Quercetin(Q), was the second best after fisetin. It inhibited secretion and aggregation with I50 of 330µM against 0.1 U/ML.THR, 102µM against 5µM ADP and 40 µM against COLL. This inhibitory effect is in the range of that of other PDE inhibitors like dipyridamole or 3-isobutyl-l- methylxanthine. The aggregation induced by ADP, COLL and THR is at least mediated by 3 mechanisms that can be inhibited by increasing cAMP levels. We next investigated if Q, which is a PDE inhibitor of bovine aortic microsomes,raises PLAT cAMP levels. cAMP was measured by a protein-binding method. ADP- induced aggregation(5µM) was inhibited by PGI2 (0.1 and 0.5 nM) . Inhibition was further potentiated(l.7 and 3.3 times) by lOµM Q, which alone has no effect on aggregation. The basal level of cAMP(2.2 pmol/108PLAT) was not modified by Q (50 to 500µM). Using these concentrations of Q,the rise in cAMP caused by PGI2(0.1 and 0.5nM) was potentiated in a dose dependent manner. Q potentiated the effect of PGI2 on the maximum level of cAMP and retarded its breakdown. Thus Q and possibly other FLA could inhibit the interaction of PLAT with the components of the vessel wall by preventing END damage and by inhibiting PLAT function through a rise in cAMP secondary to PDE inhibition and potentiation of the effect of vascular PGI2 on PLAT adenylate cyclase.

Download Full-text

In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03397-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Na Liu ◽

Ping Chen ◽

Xiaojun Du ◽

Junxia Sun ◽

Shasha Han

Keyword(s):

Human Liver ◽

Competitive Inhibition ◽

Liver Microsomes ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Inhibition Model ◽

Dose Dependent

Abstract Background Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin. Methods The effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 μM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver–Burk plots to characterize the specific inhibition model and kinetic parameters. Results Obtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 μM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 μM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 μM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 μM− 1 and the Kinact value of 0.0515 min− 1. Conclusions The in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.

Download Full-text