Mixed Mechanism Of Action Research Articles

Synthesis of Carbazole-Thiazole Dyes via One-Pot Tricomponent Reaction: Exploring Photophysical Properties, Tyrosinase Inhibition, and Molecular Docking.

Carbazole is an aromatic heterocyclic organic compound consisting of two fused benzene rings and a pyrrole ring and is a very valuable building structure for the design of many compounds for use in various fields of chemistry and medicine. This study presents three new carbazole-based thiazole derivatives that differ in the presence of a different halogen atom: chlorine, bromine, and fluorine. Experimental studies and quantum-chemical simulations show the effect of changing a halogen atom on the physicochemical, biological, and linear and nonlinear optical properties. We have also found that carbazoles C-Cl, C-Br, and C-F exhibit high tyrosinase inhibitory activity, with IC50 values in the range of 68-105 µM with mixed mechanism of action. Finally, molecular docking to the active site of Concanavalin A (ConA) and bioavailability for all compounds were evaluated.

Post-Partum Depression Lactating Rat Model for Evaluating Ketamine's Safety as a Pharmacotherapeutic Treatment: Roles in Cardiac and Urinary Function.

Depression is one of the world’s most common and mentally disabling illnesses. Post-partum depression is a subtype of depression that affects one in seven women worldwide. Successful pharmacological treatment must consider the consequences for both, since the mother–child bond is fundamental for the well-being of both mother and infant as well as the general development of the newborn. Changes in maternal physiology and/or behavior can significantly influence the development of breastfed infants. Ketamine has been extensively studied for use as an antidepressant due to its mixed mechanisms of action. Safety and efficacy studies in the cardiovascular and urinary systems of a lactating postpartum depression animal model are essential for contributing toward ketamine’s clinical use in the respective patient population. Thus, this project aimed to study the implications of postpartum maternal exposure to ketamine during lactation on the cardiovascular system of female rats submitted to the depression induction model by maternal separation. This model promotes depressive effects through stress caused by the interruption of mother–infant bond early in the offspring’s life. To achieve depression, each dam was separated from her offspring for 3 h per day, from post-natal day 2 (PND2) to PND12. Experimental groups received daily treatment with either 5, 10, or 20 mg/kg of ketamine intraperitoneally during the lactation period, from PND2 to PND21. Behavioral tests consisted of the maternal and aggressive maternal behavior tests, the olfactory preference test, and the forced swim test. A technique for the detection of catecholamines and indoleamines in the heart muscle was developed for the experimental model groups. The histopathological evaluation was performed on these animals’ cardiac muscles and urinary bladders. Our findings suggest that ketamine is safe for use in postpartum depression and does not induce cardiovascular and/or urinary systems toxicity.

Treatment of Diabetes and Osteoporosis-A Reciprocal Risk?

Diabetes mellitus is a metabolic and systematic disorder that requires individualized therapy. The disease leads to various consequences, resulting in the destruction of tissues and organs. The aforementioned outcomes also include bone mineral disorders, caused by medications as well as diet therapy and physical activity. Some drugs may have a beneficial effect on both bone mineral density and the risk of fractures. Nevertheless, the impact of other medications remains unknown. Focusing on pharmacotherapy in diabetes may prevent bone mineral disorders and influence both the treatment and quality of life in patients suffering from diabetes mellitus. On the other hand, anti-osteoporosis drugs, such as antiresorptive or anabolic drugs, as well as drugs with a mixed mechanism of action, may affect carbohydrate metabolism, particularly in patients with diabetes. Therefore, the treatment of diabetes as well as osteoporosis prevention are vital for this group of patients.

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity.

A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a–3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02–44.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59–9.86 μM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced.

Characterization of substituted piperazines able to reverse MDR in Escherichia coli strains overexpressing resistance-nodulation-cell division (RND) efflux pumps.

MDR in bacteria is threatening to public health. Overexpression of efflux pumps is an important cause of MDR. The co-administration of antimicrobial drugs and efflux pump inhibitors (EPIs) is a promising approach to address the problem of MDR. To identify new putative EPIs and to characterize their mechanisms of action. The effects of four selected piperazine derivatives on resistance-nodulation-cell division (RND) pumps was evaluated in Escherichia coli strains overexpressing or not expressing RND pumps by assays aimed at evaluating antibiotic potentiation, membrane functionality, ethidium bromide accumulation and AcrB expression. The cytotoxicity of selected piperazines towards primary cultures of human dermal fibroblasts was also investigated. Four molecules enhanced levofloxacin activity against strains overexpressing RND efflux pumps (AcrAB-TolC and AcrEF-TolC), but not against RND pump-deficient strains. They had little effects on membrane potential. Molecule 4 decreased, whereas the other three increased, membrane permeability compared with untreated control cells. The four molecules showed differences in the specificity of interaction with RND efflux pumps, by inactivating the transport of one or more antibiotics, and in the levels of ethidium bromide accumulation and of acrB expression inhibition. Piperazine derivatives are good candidates as inhibitors of RND efflux pumps. They decreased the activity of RND pumps by mixed mechanisms of action. Small structural differences among the molecules can be critical in defining their behaviour.

Effect of the dichloro-substitution on antiproliferative activity of phthalimide-thiazole derivatives. Rational design, synthesis, elastase, caspase 3/7, and EGFR tyrosine kinase activity and molecular modeling study

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC50 values in the range of 5.56–16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC50 values in the range of 6.69–10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC50 values about 32 μM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC50. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.

Pharmacologic Prevention of Myocardial Ischemia-Reperfusion Injury in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Establishing efficient perfusion into the myocardium is the main purpose in patients with acute coronary syndrome, but the process of reperfusion is not without risk and can damage the myocardium paradoxically. Unfortunately, there is no effective treatment for reperfusion injury, and efforts to find an efficient preventive approach are still ongoing. In the past 3 decades, there have been many successful animal studies on how to prevent reperfusion injury; nonetheless, translation to the clinical setting has almost always proven disappointing. In this article, we review clinical studies on the prevention of reperfusion injury in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention in a pharmacologic-based approach. We categorize all the agents that are evaluated for the prevention of myocardial reperfusion injury based on their mechanisms of action into 5 groups: drugs that can reduce oxidative stress, drugs that can affect cellular metabolism, rheological agents that target microvascular obstruction, anti-inflammatory agents, and agents with mixed mechanisms of action. Then, review all the clinical studies of these agents in the setting of primary percutaneous coronary intervention. Finally, we will discuss the possible reasons for the failure in translation of studies into practice and propose potential solutions to overcome this problem.

The Long Magenstrasse in the Treatment of Super Obese Patients (Results over 5 Years after Surgery)

Background: The considerable increase in Obesity and especially the increase in super obese patients (Body Mass Index—BMI ≥ 50 Kg/m2) who require surgery lead doctors to search for surgery techniques which give good results in terms of a consistent and stable weight loss associated with low morbidity and good quality of life. The Long Magenstrasse (LM) intervention, born from combining two properly modified surgical procedures (Selective Vagotomy with pyloric divulsion and Mangestrasse & Mill by Johnston) seems to have these characteristics according to our experience after operating on 660 patients. Methods: From October 2003 to October 2008 we treated 186 patients with LM. One hundred and sixty-two patients were regularly present to the annual follow-up, but 24 patients didn’t turn up, therefore, they were contacted by phone. On average, surgery lasted approximately 80 minutes (range: 50 - 90 minutes). Thirty patients were super obese with an average BMI of 57.4 Kg/m2; 156 patients were grade II and III obese with an average BMI of 40.7 Kg/m2. Results: The average BMI of the 30 super obese patients decreased from 57.4 Kg/m2 to 35.9 Kg/m2 one year after surgery, to 35.6, 5 years after surgery and it has remained stable until now. In the 156 patients suffering from II and III grade obesity, the average BMI decreased from 40.7 Kg/m2 to 27.8 Kg/m2 one year after surgery and it has remained stable until now. Out of all super obese diabetic patients, only one has partially maintained his/her therapy. Patients have reported a decreased appetite since the very first days of post-operative period with an early sense of satiety which is unchanged until today. Conclusions: A consistent and stable weight loss over 5 years after surgery even in Super Obese patients, a decrease in appetite with an early sense of satiety, a re-equilibrium of the metabolic syndrome in particular of Diabetes Mellitus, allow to classify LM among those surgical treatments with a mixed mechanism of action: both restrictive and functional, in particular, entero-hormonal and gastric neurosecretory.

Double-phase hydrogel for buccal delivery of tramadol

Context: Treatment of chronic pain is complicated by the evidence that abuse of prescription opioids is rising; therefore, in many cases, chronic pain remains undertreated. Tramadol is an atypical central analgesic with a mixed mechanism of action offering many advantages over conventional opioids. Objective: We exploited the nonopioid action of tramadol, by bypassing the first-pass effect, as well as multiparticulate drug delivery. Our aim was to identify optimal formulation parameters for designing polyvinyl alcohol (PVA), single and mixed dual cross-linked tramadol microspheres-loaded hydrogel with adequate bioadhesion and providing controlled drug release for buccal delivery. Methods: Microspheres characterization was done by scanning electron microscopy and infrared spectroscopy. Other investigations comprised the evaluation of yield, drug content, particle size, rheology, swelling, mucoadhesion, release, and permeation studies through biological membranes all together with testing the antinociceptive activity and its attenuation by the antagonist naloxone HCl. Results and conclusion: PVA-alginate microspheres (F3)-loaded carbopol hydrogel attained: the highest mucoadhesion time (1436.67 min ± 5.77) and mucin adsorption capacity, shear thinning thixotropic properties with adequate yield value and hysteresis area, best drug release (RE = 84.20 ± 2.07%) and permeation efficiency (PE = 65.30 ± 7.02%). Dissolution and permeation profiles were compared using similarity factor; F3-loaded carbogel had the lowest value. During in vivo study, the nonsignificant difference between the AUC of the groups receiving F3-loaded carbogel buccally with (group 5) and without (group 4) administration of naloxone, and between group 4 and the oral group, showed that the buccal route may arguably provide an alternative safer route of tramadol administration.

Pharmacological properties and SAR of new 1,4-disubstituted piperazine derivatives with hypnotic-sedative activity.

Preparation, pharmacological properties and structure-activity relationships of new pyrimidyl-piperazine derivatives, exhibiting sedative and hypnotic activity in mice, are reported. The hypnotic activity of the compounds was comparable with that of zopiclone (the known hypnotic-sedative agent), their interaction with ethanol, however, being much lower. The obtained results suggested that zopiclone and pyrimidylpiperazines 2, 4 and 5 exerted their pharmacological activity through a different mechanism - zopiclone through the interaction with benzodiazepine receptors and compounds 2, 4 and 5 through an unidentified molecular target. The pharmacological properties of compound 3 could be the result of a mixed mechanism of action, combining the properties of zopiclone and those of compounds 2, 4 and 5. A common feature of zopiclone and compounds 2 and 3 was that, after their systemic administration, independently of mechanism of action, together with the hypnotic effect a reduction of the 5-HT turnover in the mouse brain was observed. Minimum structural requirements for the hypnotic activity were formulated. Structural considerations have shown that removing the alpha-carbonyl group did not influence the drug's ability to inhibit the locomotor activity. However, it did influence its ability to disturb motor coordination or abolish the righting reflex within non-lethal doses.

Discovery of a new anilino-3 H-pyrrolo[3,2- f]quinoline derivative as potential anti-cancer agent

The newly synthesized 1-[4-(3 H-pyrrolo[3,2- f]quinolin-9-ylamino)-phenyl]-ethanone hydrochloride showed high antiproliferative activity by mixed mechanisms of action. The compound acts by forming an intercalative complex with DNA and inhibiting DNA topoisomerase II (topo II) and by blocking the cell cycle in G 2/M phase. Probable cell death by apoptosis is also suggested by flow cytometry analysis.

Structure–toxicity relationships for selected halogenated aliphatic chemicals

Toxicity to the ciliate Tetrahymena pyriformis (log (IGC 50 −1)) for 39 halogen-substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log (IGC 50 −1) along with the hydrophobic term, log K ow (1-octanol/water partition coefficient) and the electrophilic parameter, E lumo (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure–activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohols. The relationship for the haloalkanes [log (IGC 50 −1)=0.92 (log K ow)−2.58; n=4, r 2=0.993, s=0.063, f=276, Pr> f=0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log (IGC 50 −1)=0.63(log K ow)−1.18; n=19, r 2=0.860, s=0.274, f=104, Pr> f=0.0001] was observed for the haloalcohols. No hydrophobicity-dependent model ( r 2=0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log (IGC 50 −1)=−1.245( E lumo)+0.73; n=15, r 2=0.588, s=0.764, F=18.6, Pr> f=0.0009] was developed for the halonitriles. Additional analysis designed to examine surface-response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log (IGC 50 −1)=0.60(log K ow)−0.747( E lumo)−0.37; n=34, r 2=0.915, s=0.297, F=162, Pr> F=0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure–toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character.

Endocrine and adrenergic pharmacological intervention in diseases of the prostate.

The physiology of the male urogenital apparatus and reproductive function is critically dependent on a healthy prostate. Since growth and function of the prostate are governed by androgens, endocrine interventions with the synthesis, uptake, or metabolism of these hormones are major pharmacological/therapeutic strategies in prostate diseases, e.g. cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Pharmacological interference with androgen metabolism is associated with inevitable adverse effects. Therefore, it is important that such treatment be exercised with caution and weighed against its potential effects on the symptoms and outcome of the disease. α-Adrenergic blockade is an alternative treatment in BPH since α1-adrenoceptors are localized in the prostate stromal structures and considered to mediate an increased infravesical obstruction. Cancer of the prostate (CaP) is the most common cancer in the western male population with the highest incidence in Nordic countries (115/100 000) and in the USA, particularly in black Americans [1]. The incidence increases with age. About 30 to 35% of Swedish men at the age of 50 years have microscopic adenocarcinoma whereas the corresponding figure is more than 50% at the age of 80 years [2]. It has been estimated that about 7% of Swedish men will develop clinical CaP before the age of 75 years [2]. The other major disease of the prostate is BPH which is a histopathological diagnosis leading to benign prostatic enlargement and finally to bladder outlet obstruction. For the sake of simplicity, the clinical syndrome will be referred to as BPH in the following review. BPH is symptomatic in more than 40% of the ageing male population [3]. Shown in Table 1 are some prevalence numbers for CaP and BPH. Table 1 Prevalence of diseases of the prostate in relation to age. Given this situation, it is not surprising that diseases of the prostate have attracted considerable interest from the scientific community and the public. Compared with men from western societies, oriental men like the Japanese have a low incidence of CaP [4]. The higher incidence in oriental men living in the US compared with men in their native countries indicates that environmental as well as genetic factors influence the prevalence of this disease in the population. For BPH, development of effective pharmacological intervention therapies as well as new physical treatment modalities have challenged the classical surgical approaches to cure the disease. Even though the efficacy of drugs may be limited compared to surgical and physical means of treatment, they are often preferred because of the much lower complication risks [5]. A comparison of pharmacological and non-pharmacological treatments in terms of efficacy and complication risks is depicted in Figure 1. Figure 1 Efficacy of treatment methods for BPH in relation to risk of complications. Arbitrary dimensions on Y- and X-axes. TUMT=transurethral microwave treatment; TUNA=transurethral needle ablation; TUIP=transurethral incision of the prostate; TURP=transurethral ... The scope of this article is to describe the current possibilities and ideas for pharmacological intervention strategies, and to discuss their limitations and basis for further development of more advanced treatment programs.

Endocrine and adrenergic pharmacological intervention in diseasesof the prostate

Endocrine and adrenergic pharmacological intervention in diseasesof the prostate