Parabens are endocrine-disrupting chemicals present in a variety of pharmaceutical and personal care products. Due to their wide-spread use, significant amounts are also released into the aquatic ...domain of the environment. During water disinfection, parabens give rise to halogenated transformation products. As opposed to parabens, there is considerable lack of knowledge with regard to the endocrine-disrupting potential of their halogenated counterparts, which presents a challenge for regulatory decision making. We aimed to fill this knowledge gap by using the Endocrine Disruptome and VirtualToxLab™ to predict their endocrine-disrupting potential on the basis of calculated affinities for different nuclear receptors. The applied computational approach indicates a high probability of halogenated parabens binding to glucocorticoid, thyroid and aryl hydrocarbon receptors and suggests that disinfection is likely to form transformation products with more pronounced endocrine-disrupting activities than those of parent parabens. The obtained results not only highlight the need for additional in vitro/in vivo investigations of these chemicals as endocrine disruptors but also provide a means of guiding and prioritizing these future studies, in order to assess fully their hazard to human health.
•endocrine-disrupting potential of halogenated parabens was investigated in silico.•Halogenation can increase the endocrine-disrupting activity of parent parabens.•Monohalogenated benzyl parabens were identified as most potent endocrine disruptors.
The 2-aminothiazole functionality has long been established as a privileged structural feature and therefore frequently exploited in the process of drug discovery and development. It has been ...introduced into numerous compounds due to its capacity for targeting a wide range of therapeutic target proteins. On the other hand, the aminothiazole group has also been classified as a toxicophore susceptible to metabolic activation and the ensuing reactive metabolite formation, hence caution is warranted when used in drug design. This review is divided into three parts entailing: (i) the general characteristics of the aminothiazole group, (ii) the advantages of the aminothiazole group in medicinal chemistry, and (iii) the impact of the integrated aminothiazole group on compound safety profile.
•The advantages of the 2-aminothiazole group in medicinal chemistry were detailed.•2-aminothiazoles were studied as toxicophores that form reactive metabolites.•Chemical strategies that reduce the intrinsic hepatotoxicity were highlighted.
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•Novel bifunctional 1,2,4-oxadiazole derivatives were designed and synthesized.•Trichloromethyl functionality was displaced by various nucleophiles.•Compounds may act as building ...blocks for incorporation into larger bioactive molecules.
A straightforward route for preparing derivatives of ethyl 5-trichloromethyl-1,2,4-oxadiazole-3-carboxylate, in which the 5-trichloromethyl and/or the ester functionalities are displaced by various nucleophiles, has been designed. Mild reaction conditions were chosen to enable the formation of products, which constitute a new series of bifunctional 3,5-disubstituted 1,2,4-oxadiazole building blocks capable of being integrated into biologically relevant molecules.
Dysregulation of nucleotide-binding oligomerization domains 1 and 2 (NOD1 and NOD2) has been implicated in the pathology of various inflammatory disorders, rendering them and their downstream ...signaling proteins potential therapeutic targets. Selective inhibition of NOD1 and NOD2 signaling could be advantageous in treating many acute and chronic diseases; therefore, harnessing the full potential of NOD inhibitors is a key topic in medicinal chemistry. Although they are among the best studied NOD-like receptors (NLRs), the therapeutic potential of pharmacological modulation of NOD1 and NOD2 is largely unexplored. This review is focused on the scientific progress in the field of NOD inhibitors over the past decade, including the recently reported selective inhibitors of NOD1 and NOD2. In addition, the potential approaches to inhibition of NOD signaling as well as the advantages and disadvantages linked with inhibition of NOD signaling are discussed. Finally, the potential directions for drug discovery are also discussed.
Due to its endocrine-disrupting properties, bisphenol A (BPA) is being phased out from plastics, thermal paper and epoxy resins, and its replacements are being introduced into the market. Bisphenols ...are released into the environment, where they can undergo halogenation. Unlike BPA, the endocrine-disrupting potential of BPA analogues and their halogenated transformation products has not been extensively studied. The aim of this study was to evaluate the endocrine-disrupting potential of 18 BPA analogues and their halogenated derivatives by calculating affinities for 14 human nuclear receptors utilizing the Endocrine Disruptome and VirtualToxLab™ in silico tools.
Our simulations identified AR, ERs, and GR as the most favorable targets of bisphenols and their derivatives. Several BPA analogues displayed a higher predicted potential for endocrine disruption than BPA. Our models highlighted BPZ and BPPH as the most hazardous in terms of predicted endocrine activities. Halogenation, in general, was predicted to increase the binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ. Notably, mono- or 2,2′-di-halogenated bisphenols exhibited the highest potential for endocrine disruption. In vitro corroboration of the obtained results should be the next milestone in evaluating the safety of BPA substitutes and their halogenated transformation products.
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•Endocrine-disrupting potential of BPA, BPA analogues, and their halogenated derivatives was investigated in silico.•BPPH, BPTMC and BPZ were identified as the most potent endocrine disruptors.•Halogenation increases predicted binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ•Mono- or 2,2′-dihalogenated bisphenols exhibited the highest predicted endocrine disrupting potential.
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•PGE2 receptor subtypes EP1–4 are valuable drug targets.•Structural features for subtype-selective activity of EP1–4 receptor modulators are presented.•Binding affinities, functional ...activities and selectivities of presented EP modulators are provided.•Recent findings of the clinical value of EP receptor modulators are discussed.
Prostaglandin E2 is a potent endogenous molecule that binds to four different G-protein-coupled receptors: EP1–4. Each of these receptors is a valuable drug target, with distinct tissue localisation and signalling pathways. We review the structural features of EP modulators required for subtype-selective activity, as well as the structural requirements for improved pharmacokinetic parameters. Novel EP receptor subtype selective agonists and antagonists appear to be valuable drug candidates in the therapy of many pathophysiological states, including ulcerative colitis, glaucoma, bone healing, B cell lymphoma, neurological diseases, among others, which have been studied in vitro, in vivo and in early phase clinical trials.
The structural requirements for novel highly potent and selective agonists and antagonists of prostaglandin EP1 to EP4 receptors and their therapeutic potential are presented in this original review.
The dipeptide d-Glu-
o-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The
-diaminopimelic ...acid (
-DAP) moiety is known to be very stringent in terms of the allowed structural modifications which still retain the NOD1 activity. The aim of our study was to further explore the chemical space around the
-DAP portion and provide a deeper understanding of the structural features required for NOD1 agonism. In order to achieve the rigidization of the terminal amine functionality of
-DAP, isoxazoline and pyridine heterocycles were introduced into its side-chain. Further, we incorporated the obtained
-DAP mimetics into the structure of iE-DAP. Collectively, nine innovative iE-DAP derivatives additionally equipped with lauroyl or didodecyl moieties at the α-amino group of d-Glu have been prepared and examined for their NOD1 activating capacity. Overall, the results obtained indicate that constraining the terminal amino group of
-DAP abrogates the compounds' ability to activate NOD1, since only compound
retained noteworthy NOD1 agonistic activity, and underpin the stringent nature of this amino acid with regard to the allowed structural modifications.
Dietary supplements “fat burners”, freely available on the market, are intended to promote weight loss and reduce fat accumulation, either via stimulation of lipolysis or by inhibition of ...lipogenesis. Proponents claim that fat burners can increase fat metabolism, although their usefulness remains controversial. Fat burners are usually claimed to be of natural origin and viewed as being inherently safe. This review focuses on the most common ingredients of natural origin usually found in the fat burners, their molecular mechanisms of action and the toxicological profiles of these compounds in order to gain an insight into their safety.
•Fat burners are commonly claimed to be of natural origin and therefore often viewed as inherently safe.•Mechanisms of action of fat burner ingredients have been reviewed.•Toxicological profiles of fat burner ingredients have been thoroughly examined.•Potentially dangerous interactions between fat burner ingredients have been pointed out.
A straightforward route for preparing 1,2,4-oxadiazole mimetics of Ala-Glu/iGln is presented. Display omitted
Heterocyclic Ala-Glu/i-Gln mimetics, in which one or both carboxylic acid functionalities ...are bioisosterically replaced by a 1,2,4-oxadiazole ring system, are designed and synthesized. A straightforward route for preparing orthogonally protected 1,2,4-oxadiazole-bearing dipeptide building blocks is presented. These compounds constitute a new series of non-natural dipeptides, capable of being integrated into biologically relevant peptides. The synthesis starts from d-glutamic acid, and mild reaction conditions are chosen to allow the formation of products.
The everyday use of household and personal care products (HPCPs) generates an enormous amount of chemicals, of which several groups warrant additional attention, including: (i) parabens, which are ...widely used as preservatives; (ii) bisphenols, which are used in the manufacture of plastics; (iii) UV filters, which are essential components of many cosmetic products; and (iv) alkylphenol ethoxylates, which are used extensively as non-ionic surfactants. These chemicals are released continuously into the environment, thus contaminating soil, water, plants and animals. Wastewater treatment and water disinfection procedures can convert these chemicals into halogenated transformation products, which end up in the environment and pose a potential threat to humans and wildlife. Indeed, while certain parent HPCP ingredients have been confirmed as endocrine disruptors, less is known about the endocrine activities of their halogenated derivatives. The aim of this review is first to examine the sources and occurrence of halogenated transformation products in the environment, and second to compare their endocrine-disrupting properties to those of their parent compounds (i.e., parabens, bisphenols, UV filters, alkylphenol ethoxylates). Albeit previous reports have focused individually on selected classes of such substances, none have considered the problem of their halogenated transformation products. This review therefore summarizes the available research on these halogenated compounds, highlights the potential exposure pathways, and underlines the existing knowledge gaps within their toxicological profiles.
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•Halogenated transformation products are found in the environment and in human tissues.•Halogenated derivatives disrupt different hormonal pathways than parent compounds.•Halogenation in general decreases estrogen and androgen receptor activation.•Introduction of halogens increases activation of thyroid and aryl hydrocarbon receptors.
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