Pharmacologically Active Compounds Research Articles

Cryptocarya genus: Phytochemistry, Traditional Uses, and Pharmacological Properties

Abstract: Medicinal plants are claimed to be a safer and more powerful treatment option for many ailments. Plants of the genus Cryptocarya, which biosynthesize numerous bioactive compounds, majorly flavonoids, pyrones, alkaloids, coumarins, and terpenoids, have demonstrated a variety of health benefits, including antimalarial, cytotoxic, antimicrobial, antituberculosis, and anti-inflammation properties. Due to the significant applications in traditional medicine of several communities and secondary metabolites already isolated, this study presents the ethnopharmacological, phytochemical and therapeutic potential of species of the genus Cryptocaria. A total of 177 new bioactive compounds with diverse chemical structures have been reported from the genus. The data set revealed that the genus Cryptocarya is a source of cytotoxic substances, which have the potential to be used in the treatment of diseases resulting from cellular mutations. Further phytochemical and biological assessments may lead to the development of new pharmacologically active compounds.

Oxygen Vacancy-Mediated CuWO4/CuBi2O4 Samples with Efficient Charge Transfer for Enhanced Catalytic Activity toward Photodegradation of Pharmacologically Active Compounds.

Photocatalytic degradation is a promising method for controlling the increasing contamination of the water environment due to pharmacologically active compounds (PHACs). Herein, oxygen vacancy (OV)-modulated Z-scheme CuWO4/CuBi2O4 hybrid systems were fabricated via thermal treatment by loading of CuWO4 nanoparticles with OVs on CuBi2O4 surfaces. The synthesized CuWO4/CuBi2O4 hybrid samples exhibited an enhanced photodegradation ability to remove PHACs under visible-light irradiation. More importantly, an optimized sample (10 wt % CuWO4/CuBi2O4) exhibited superior catalytic activity and excellent recycling stability for PHAC photodegradation. In addition, possible degradation paths for PHAC removal over the CuWO4/CuBi2O4 hybrid systems were proposed. The enhanced photocatalytic performance could be attributed to the efficient separation and transfer of photoformed charge pairs via the Z-scheme mechanism. This Z-scheme mechanism was systematically analyzed using trapping experiments of active species, ultraviolet photoelectron spectroscopy, electron spin resonance, and the photodepositions of noble metals. The findings of this study can pave the way for developing highly efficient Z-scheme photocatalytic systems for PHAC photodegradation.

Synthesis of N,N-diethylaminopropylurea and Monosubstituted Urea Derivatives from Primary Amines and Potassium Cyanate

Abstract: Urea derivatives are an important class of pharmacologically-active compounds due to their ability to form hydrogen bonds with biological targets. Several synthetic pathways have been developed to access urea derivatives, such as the metal-free and metal-catalysed carbonylation reactions of amines and the Curtius, Hofmann, and Tiemann rearrangement reactions. This study aimed to synthesize urea derivatives from primary amines. The urea derivatives were synthesized from primary amines and potassium cyanate in 1M HCl aqueous solution under ambient conditions and were isolated, followed by characterization using FTIR, DSC, and NMR (1H and 13C). A new urea derivative, N, N-diethylaminopropylurea (6), together with N-phenylurea (1), para-tolylurea (2), orthomethoxyphenylurea (3), para-methoxyphenylurea (4), N-benzylurea (5), and N-butylurea (7), was successfully synthesized under acidic conditions. This work presents the synthesis and characterization data of a newly-reported urea derivative, N, N-diethylaminopropylurea (6), and extends the substrate scope to basic side chains in the synthesis of urea derivatives from primary amines and potassium cyanate in water.

Optimization and scale up of the enzymatic hydrolysis of Californian red worm protein (Eiseniafoetida)

Although the best-known use of the different species of earthworm is the production of organic fertilizer, they can also be considered a rich source of biologically and pharmacologically-active compounds, for use in the treatment of various diseases. In recent decades, with the development of biochemical technologies, research on the pharmaceutical effects of compounds extracted from different species of earthworms has begun. Enzymatic hydrolysis is the most common and widely used technique for producing bioactive hydrolysates, because it uses moderate operating conditions, with a certain specificity for the substrate. In the present study, the objective was to optimize and scale up the enzymatic hydrolysis of Eisenia foetida protein to obtain peptides with biological activity. The substrate characterization was carried out according to AOAC, a response surface design was performed for the optimization of the enzymatic hydrolysis and then the scaling was performed by means of dimensional analysis. The results show that the major component of the paste is protein, 65% of which is albumin, and the absence of pathogenic microorganisms was also found. Regarding optimization, it was found that the optimal hydrolysis conditions are achieved with pH = 8.5; temperature = 45 °C; amount of substrate = 125 g and volume of enzyme = 1245μL. For the scaling, 4 dimensionless pi-numbers were calculated which describe the process with no statistically significant differences between the model and the prototype; it can be concluded that the enzymatic hydrolysate of Eisenia foetida presents high values of antioxidant activity evaluated by different methodologies.

Metabolomic analysis reveals the impact of ketoprofen on carbon and nitrogen metabolism in rice (Oryza sativa L.) seedling leaves.

Pharmacologically active compounds (PACs) are becoming common pollutants in the natural environment, posing potential risks to crop quality; however, the toxic effects and metabolic changes that they cause in agricultural plants remain unclear. Here, we investigated the effects of ketoprofen on respiration rate, ATP synthesis, carbon and nitrogen metabolism, and metabolomics in rice seedling leaves. The results showed that ketoprofen treatment adversely affected the respiration rate, ATP content, H+-ATPase activity and induced changes in the contents of carbon assimilation products (soluble sugar, reducing sugar, sucrose, and starch) and the activities of key enzymes in carbon metabolism (sucrose synthase (SS), sucrose phosphate synthase (SPS), and sucrose invertase (InV)). The contents of nitrate, ammonium, and free amino acids, and the activities of key enzymes involved in nitrogen metabolism (nitrate reductase (NR), nitrite reductase (NiR), glutamine synthetase (GS), glutamate synthase (GOGAT), and glutamate dehydrogenase (GDH)) were also affected in a concentration-dependent manner. Metabolomics analysis showed that ketoprofen disturbed the type and content of metabolites (amino acids, carbohydrates, and secondary metabolites) to varying degrees and perturbed key metabolic pathways (substance synthesis and energy metabolism), ultimately resulting in the reduction of rice seedling biomass. This study provides important information and a useful reference for the accurate assessment of the environmental risks of PACs.

Synthesis and Structural Characterization of Pyridine-2,6-dicarboxamide and Furan-2,5-dicarboxamide Derivatives.

Derivatives based on pyridine-2-6- and furan-2,5-dicarboxamide scaffolds reveal numerous chemical properties and biological activities. This fact makes them an exciting research topic in supramolecular and coordination chemistry and in discovering new pharmacologically-active compounds. This work aimed to obtain a series of symmetrical pyridine-2-6- and furan-2,5-dicarboxamides through a condensation reaction of the appropriate acyl chlorides and aromatic amides. Successful syntheses were confirmed with NMR spectroscopy. We solved their crystal structures for seven compounds; two pyridine and five furan derivatives. Based on our crystallographic studies, we were able to indicate supramolecular features of the crystals under investigation. Additionally, Hirshfeld surface analysis allowed us to calculate a distribution of intermolecular contacts in the dicarboxamide crystals.

The Protective Function and Modification of Secondary Metabolite Accumulation in Response to Light Stress in Dracocephalum forrestii Shoots.

The aim of this work was to determine the effect of stress conditions caused by different light sources, i.e., blue LED (λ = 430 nm), red LED (λ = 670 nm), blue and red LED (70%:30%) and white LED (430–670 nm) on the growth and morphology of cultivated in vitro Dracocephalum forrestii shoot culture. It also examines the effects on bioactive phenolic compound production and photosynthetic pigment content, as well as on antioxidant enzyme activity (CAT, SOD, POD) and antioxidant properties. The most beneficial proliferation effect was observed under white LEDs (7.1 ± 2.1 shoots per explant). The white and blue lights stimulated the highest fresh weight gain, while red light induced the highest dry weight gain. The total phenolic acid content ranged from 13.824 ± 1.181 to 20.018 ± 801 mg g DW−1 depending on light conditions. The highest content of rosmarinic acid was found in the control shoots (cultivated under fluorescent lamps), followed by culture grown under red light. All LED treatments, especially red and blue, increased salvianolic acid B content, and blue increased apigenin p-coumarylrhamnoside biosynthesis. The greatest ferric reduction activity was observed in shoots cultivated under red light, followed by blue; this is associated with the presence of the highest total phenol content, especially phenolic acids. Similarly, the highest DPPH radical scavenging potential was observed under red light followed by blue. This study proves that LEDs have emerged as significant support for directed in vitro propagation, taking advantage of specific stress responses on various light spectra. This study also showed how stress induced by different LED light spectra increases in Dracocephalum forrestii the synthesis of pharmacologically-active compounds. Hence, light stress may turn out to be a simpler alternative to metabolic engineering for improving the production of secondary metabolites of therapeutic value.

The Rapidly Changing Composition of the Global Street Drug Supply and its Effects on High-risk Groups for COVID-19

Background: Globally, an alarming number of pharmaceutically active compounds are now routinely added to the street drugs of abuse, cocaine and heroin. In some cases, seventeen (17) or more potentially toxic compounds are found in a single street purchased bag or block of cocaine or heroin. Pharmacologically active compounds, impurities, or breakdown products from drug manufacturing and industrial chemicals (collectively referred to as toxic adulterants) are now found in street drugs. They include, but are not limited to: antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, antiinflammatorys, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, veterinary medications, bronchodilators, expectorants, sedatives, muscle relaxers, natural/synthetic hallucinogens, decongestants, new psychoactive substances (NPS), industrial compounds, fungicides, and impurities in the manufacturing process. All can be found within a single street purchase of heroin or cocaine. Routine clinical or workplace drug testing will not detect all these toxic adulterants. Only specialty forensic tests, specifically ordered, will detect them. The synergistic effect on the human body of such an unprecedented combination of pharmacologically active compounds is unknown and potentially deadly. This is especially seen in daily substance users who are exposed to these combinations multiple times a day over an extended period of time. Individuals with substance use disorders (SUDs) have several co-occurring health problems that make them more susceptible to COVID-19, including compromised immune, pulmonary, cardiovascular, and respiratory systems. These problems are high-risk factors for the acquisition of COVID-19 infection and more serious complications from the virus, including hospitalization and death. Objective: The study aims to bring to the attention of public health officials, addiction medicine specialists, treatment officials, therapists, and the general public the alarming increase of dangerous toxic adulterants being added to street drugs and their potentially lethal synergistic effects. Also, it aims to provide insights into how these new formulations can have serious pathophysiological effects on individuals with Substance Abuse Disorders (SUDs) during the COVID-19 pandemic. Methods: The literature on street drug cutting agents, toxic adulterants, NPS, manufacturing byproducts, and other industrial compounds will be reviewed. Also, a review of the literature of pathophysiological effects, especially on SUD patients, in light of the COVID-19 pandemic will be presented. This is combined with international and USA studies that were carried out by the Colombo Plan that identified these new combinations of toxic adulterants in street drugs, using state-of-the-art field and forensic laboratory detection technologies. Results: The majority of street drugs, in some cases more than ninety-five percent, now have multiple toxic adulterants. It is rare that a street purchase of cocaine or heroin does not contain multiple toxic adulterants, cutting agents, NPS, manufacturing byproducts, or industrial chemicals. Conclusion: This dangerous new composition in world street drug supply is unprecedented and may be the undetected cause of many psychostimulant and opioid overdose deaths, as many toxic adulterants are not routinely tested in post-mortem or street drug seizure cases. In addition, several of these toxic adulterants create a catastrophic drop in white blood cells, causing neutropenia and making the substance users susceptible to a wide range of opportunistic infections, including COVID-19. This profound change in the world street drug supply has catastrophic implications for individuals with SUDs and our health care system, especially in the era of the COVID-19 pandemic.

Indole Alkaloids with Potential Anticancer Activity.

Indole alkaloids, which are abundant in nature, are a significant source of pharmacologically active compounds. Indole alkaloids have the potential to exert anticancer activity via various antiproliferative mechanisms, and some of them, such as Vinblastine and Vincristinem, have already used in clinics or under clinical evaluations for the treatment of cancers. Therefore, indole alkaloids occupy an important position in the discovery of novel anticancer agents. This review emphasizes the recent development of indole alkaloids as potential anticancer agents, their structure-activity relationship, and mechanisms of action covering the articles published from 2015 to 2020.

Environmental risk assessment of pharmaceuticals at a seasonal holiday destination in the largest freshwater shallow lake in Central Europe

The presence of pharmacologically active compounds (PhACs) in surface waters poses an environmental risk of chronic exposure to nontarget organisms, which is a well-established and serious concern worldwide. Our aim was to determine the temporal changes in ecological risk quotient (RQ) based on the concentrations of 42 PhACs from six sampling sites on seven sampling dates in the water of a freshwater lake in Central Europe preferentially visited by tourists. Our hypothesis was that the environmental risk increases during the summer holiday season due to the influence of tourists. Different experimental toxicological threshold concentrations and seasonal measured environmental concentrations of 16 PhACs were applied to ecological risk assessment. RQs of 4 dominant PhACs (diclofenac, estrone [E1], estradiol [E2], and caffeine) indicated high ecological risk (RQ > 1) for freshwater ecosystems. Additionally, our results confirmed the assumptions that the high tourist season had a significant impact on the calculated RQ; however, these results are mainly due to the concentration and temporal change of particular PhACs, including diclofenac (5.3-419.4 ng/L), E1 (0.1-5.5 ng/L), and E2 (0.1-19.6 ng/L). The seasonal dependent highest RQs changed as follows: 9.80 (June 2017; E2), 1.23 (August 2017; E1), 0.43 (November 2017; E1), 0.51 (April 2018; E1), 5.58 (June 2018, diclofenac), 39.50 (August 2018; diclofenac), and 30.60 (October 2018; diclofenac).

Co-cultivation of the marine sponge Halichondria panicea and its associated microorganisms

Marine sponges host bacterial symbionts with biotechnological potential, yet isolation of true sponge symbionts remains difficult due to their host dependency. Moreover, attempts to grow sponges for their pharmacologically-active compounds outside of their habitat often results in a shift of their microbial community. In this study we evaluate suitable sponge cultivation methods that allow maintenance of both the marine sponge Halichondria panicea and its associated bacteria in an ex situ environment. In addition, we present a method for co-cultivation of sponge explants and microbes separated by a membrane in a multi-chamber device. Tests on ex situ cultivation of H. panicea under different controlled conditions showed that only high water exchange rates in the aquarium enabled maintenance of its dominant symbiont “Candidatus Halichondribacter symbioticus” at a high relative abundance in the sponge body, a prerequisite for co-cultivation. The bacterial enrichment retrieved from co-cultivation contained bacteria from nine different classes in addition to sequences corresponding to “Ca. H. symbioticus”. This represents an increase of the cultivable bacterial classes from H. panicea compared to standard isolation techniques on solid media plates. The current study provides insights into sponge-microbe maintenance under ex situ conditions and proposes a new method for the isolation of sponge-associated bacteria.

Spatiotemporal variations of pharmacologically active compounds in surface waters of a summer holiday destination

The release of pharmacologically active compounds (PhACs) into aquatic ecosystems poses an environmental risk resulting in a chronic exposure of non-target organisms. A great variety of PhACs, of generally low concentrations, and the complicated sample preparation, makes circumstantial the accurate detection and quantification. Additionally, there is little information published about the spatiotemporal variation of the PhAC load in a larger catchment area utilised for touristic purposes. In addition to the natural biotic and abiotic changes, the seasonal variation of tourism also has a dramatic impact on water quality and the natural ecosystem in larger catchment areas. Therefore, our aim was to develop a reliable solid-phase extraction (SPE)-supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) method for simultaneous multi-residue analysis of drugs to reveal the spatiotemporal changes in the PhAC contaminations in the waters of an important touristic region, the catchment area of the largest shallow lake in Central Europe, Lake Balaton (Hungary). The environmental application of the developed method revealed 69 out of the traced 134 chemical compounds, including 15 PhACs, which were detected from natural waters for the first time. Wastewater treatment plant (WWTP) loads have a major role in the PhAC contamination of the studied area; at the same time, the mass tourism-induced PhAC contamination was also detectable. Furthermore, the impact of tourism was indicated by elevated concentrations of recreational substances (e.g., caffeine and illicit drugs) in the touristic season affecting the water quality of this important summer holiday destination.

Naphthol-derived Betti bases as potential SLC6A14 blockers

Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na+- and Cl-- dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.

Protective effect of Juglans regia L. against ultraviolet B radiation induced inflammatory responses in human epidermal keratinocytes

BackgroundJuglans regia L. has a history of traditional medicinal use for the treatment of various maladies and have been documented with significant antioxidant and antiinflammatory properties. Although all parts of the plant are medicinally important, but male the flower of the plant has not been yet investigated against the photo-damage. PurposeThe present study, we sought to determine the photoprotective effect of the male flower of J. regia L. against ultraviolet-B radiation-induced inflammatory responses in human skin cells. MethodsThe profile of pharmacological active compounds present in the male flower of J. regia was analyzed by GC–MS. Then, the antioxidant property of methanolic extract of J. regia (MEJR) was analyzed by in vitro free radical scavenging assays. Further, we analyzed the sun protection factor of this extract by spectrophotometry. Moreover, we investigated the photoprotective effect of MEJR against UVB induced inflammatory signaling in human epidermal cells. Human skin epidermal keratinocytes (HaCaT) were pretreated with the MEJR (80 µg/ml), 30 min prior to UVB-irradiation at a dose of 20 mJ/cm2 and were investigated for lipid peroxidation, enzymatic antioxidants activity, apoptosis and inflammatory markers expression level. ResultsThe GC–MS results showed the presence of good amount of pharmacologically active compounds in the MEJR. We observed that the MEJR possess significant free radical scavenging activity and it was comparable with standard antioxidants. Further, the MEJR exhibits 8.8 sun-protection-factor (SPF) value. Pretreatment with MEJR, 30 min prior to UVB-irradiation, prevented ROS generation, lipid peroxidation and restored the activity of antioxidant status in HaCaT cells. Moreover, MEJR pretreatment significantly prevented UVB activated inflammatory markers like TNF-α, IL-1, IL-6, NF-κB, COX-2 in HaCaT. ConclusionThe present findings suggest that MEJR exhibit photoprotective effects and hence it may be useful for the treatment of inflammation related responses. The pharmacological mechanism of MEJR partly associated with its UV absorbance, modulation of inflammatory signaling as well as due to its free radical scavenging capability.

Compromised External Validity: Federally Produced Cannabis Does Not Reflect Legal Markets

As the most widely used illicit drug worldwide, and as a source of numerous under-studied pharmacologically-active compounds, a precise understanding of variability in psychological and physiological effects of Cannabis varieties is essential. The National Institute on Drug Abuse (NIDA) is designated as the sole legal producer of Cannabis for use in US research studies. We sought to compare the chemical profiles of Cannabis varieties that are available to consumers in states that have state-legalized use versus what is available to researchers interested in studying the plant and its effects. Our results demonstrate that the federally-produced Cannabis has significantly less variety and lower concentrations of cannabinoids than are observed in state-legal U.S. dispensaries. Most dramatically, NIDA’s varieties contain only 27% of the THC levels and as much as 11–23 times the Cannabinol (CBN) content compared to what is available in the state-legal markets. Research restricted to using the current range of federally-produced Cannabis thus may yield limited insights into the chemical, biological and pharmacological properties, and medical potential of material that is available in the state markets. Investigation is urgently needed on the full diversity of Cannabis chemotypes known to be available to the public.

Erylusamides: Novel Atypical Glycolipids from Erylus cf. deficiens.

Among marine organisms, sponges are the richest sources of pharmacologically-active compounds. Stemming from a previous lead discovery program that gathered a comprehensive library of organic extracts of marine sponges from the off-shore region of Portugal, crude extracts of Erylus cf. deficiens collected in the Gorringe Bank (Atlantic Ocean) were tested in the innovative high throughput screening (HTS) assay for inhibitors of indoleamine 2,3-dioxygenase (IDO) and showed activity. Bioassay guided fractionation of the dichloromethane extract led to the isolation of four new glycolipids, named erylusamide A–D. The structures of the isolated compounds were established by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and chemical derivatization. The metabolites shared a pentasaccharide moiety constituted by unusual highly acetylated d-glucose moieties as well as d-xylose and d-galactose. The aglycones were unprecedented long chain dihydroxyketo amides. Erylusamides A, B and D differ in the length of the hydrocarbon chain, while erylusamide C is a structural isomer of erylusamide B.

Enantioselective simultaneous analysis of selected pharmaceuticals in environmental samples by ultrahigh performance supercritical fluid based chromatography tandem mass spectrometry

In order to assess the true impact of each single enantiomer of pharmacologically active compounds (PACs) in the environment, highly efficient, fast and sensitive analytical methods are needed. For the first time this paper focuses on the use of ultrahigh performance supercritical fluid based chromatography coupled to a triple quadrupole mass spectrometer to develop multi-residue enantioselective methods for chiral PACs in environmental matrices. This technique exploits the advantages of supercritical fluid chromatography, ultrahigh performance liquid chromatography and mass spectrometry. Two coated modified 2.5 μm-polysaccharide-based chiral stationary phases were investigated: an amylose tris-3,5-dimethylphenylcarbamate column and a cellulose tris-3-chloro-4-methylphenylcarbamate column. The effect of different chromatographic variables on chiral recognition is highlighted. This novel approach resulted in the baseline resolution of 13 enantiomers PACs (aminorex, carprofen, chloramphenicol, 3-N-dechloroethylifosfamide, flurbiprofen, 2-hydroxyibuprofen, ifosfamide, imazalil, naproxen, ofloxacin, omeprazole, praziquantel and tetramisole) and partial resolution of 2 enantiomers PACs (ibuprofen and indoprofen) under fast-gradient conditions (<10 min analysis time).The overall performance of the methods was satisfactory. The applicability of the methods was tested on influent and effluent wastewater samples. To the best of our knowledge, this is the first feasibility study on the simultaneous separation of chemically diverse chiral PACs in environmental matrices using ultrahigh performance supercritical fluid based chromatography coupled with tandem mass spectrometry.

Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells.

A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS.

Optimization of the synthesis of N-alkyl and N,N-dialkyl thioureas from waste water containing ammonium thiocyanate

The optimized methods for N-alkyl and N,N-dialkyl substituted thioureas synthesis starting from ammonium thiocyanates, waste water constituent from the production of tetramethylthiuram monosulfide (TMTS), and alkyl amine, are presented in this work. Therefore, thioureas synthesis was developed in two ways: Method I - reaction of the thiocyanate and alkylamine in the presence of hydrochloric acid; Method II - reaction of the thiocyanate with benzoyl chloride following by amine addition in the first step, and base hydrolysis in the second step. The structure of the synthesized compounds was confirmed by IR, 1H and 13C NMR and MS instrumental methods, and purity was determined by high-performance liquid chromatography method. It is shown that the proposed methods offer a high degree of conversion and purity of product, absence of by-products and technological applicability at industrial scale. Considering importance of the tetramethylthiuram disulfide (TMTD) and TMTS as vulcanization accelerators as well as thiourea as the pharmacologically active compounds, it can be said that application of the optimized methods of thiourea synthesis will provide significant improvement in sustainable development and implementation of eco-friendly production technology. The described, environmentally benign process of thioureas synthesis, represent a suitable option to existing methods.

IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities

The variety of chemically diverse pharmacologically-active compounds administered to patients is large and seemingly forever growing, and, with every new drug released and administered, there is always the potential of an allergic reaction. The most commonly occurring allergic responses to drugs are the type I, or immediate hypersensitivity reactions mediated by IgE antibodies. These reactions may affect a single organ, such as the nasopharynx (allergic rhinitis), eyes (conjunctivitis), mucosa of mouth/throat/tongue (angioedema), bronchopulmonary tissue (asthma), gastrointestinal tract (gastroenteritis) and skin (urticaria, eczema), or multiple organs (anaphylaxis), causing symptoms ranging from minor itching and inflammation to death. It seems that almost every drug is capable of causing an immediate reaction and it is unusual to find a drug that has not provoked an anaphylactic response in at least one patient. These facts alone indicate the extraordinary breadth of recognition of IgE antibodies for drugs ranging from relatively simple structures, for example, aspirin, to complex molecules, such as the macrolide antibiotics composed of a large macrocyclic ring with attached deoxy sugars. This wide recognition profile is borne out at the molecular level by results of quantitative immunochemical studies where hapten inhibition investigations have identified structural determinants complementary to IgE antibodies in the sera of allergic subjects. Allergenic determinants have been identified on a variety of drugs including neuromuscular blockers, penicillins, cephalosporins, opioids, thiopentone, sulfonamides, trimethoprim, quinolones, chlorhexidine and the non-steroidal anti-inflammatory drug aspirin. It is already clear that IgE can distinguish fine structural differences on a wide variety of molecules, determinants may be at least as small as an amino group or encompass the whole molecule, and individual drugs may demonstrate allergenic heterogeneity.