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Carnosine is a naturally occurring dipeptide that has been advocated by some authors as an interesting scaffold for the development of potential therapeutic agents in view of the positive outcomes of its supplementation in animal models of human diseases. Its mode of action seems to depend on the quenching of toxic electrophiles, such as 4–hydroxynonenal (HNE). However, carnosine’s bioavailability in humans is lower than that in other mammals. The main reason for such an unfavorable pharmacokinetic profile is the activity of the enzyme human serum carnosinase (E.C. 3.4.13.20), which rapidly hydrolyzes carnosine upon absorption. Therefore, some studies have focused on the design of carnosinase-resistant derivatives that retain binding activity toward toxic electrophiles. Nevertheless, the structural modification of the N-terminus amino group of carnosine has rarely been considered, possibly because of its key role in the electrophile scavenging mechanism. This was proven, since some carnosine N-terminus modification generated inactive compounds, despite some derivatives retaining oral bioavailability and gaining resistance to carnosinase hydrolysis. Herein, we therefore report a study aimed at exploring whether the amino group of carnosine can be conveniently modified to develop carnosinase-resistant derivatives retaining the dipeptide activity toward toxic electrophiles.

In medicinal chemistry, the precise configuration of molecules is a crucial determinant of their pharmacological properties. Hence, the introduction of a new chiral center during the synthetic pathway involves the assignment of configuration. Herein we assign, by means of molecular modeling 1H and 2D Nuclear Overhauser Effect NMR techniques, the configuration of the two diastereomers 2S-(1R-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine and 2S-(1S-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine, which are useful to synthetize analogs of the potent and highly selective dipeptidyl peptidase IV and carbonic anhydrase inhibitor recently published.

Carnosine is a naturally occurring dipeptide that has been advocated by some authors as an interesting scaffold for the development of potential therapeutic agents in view of the positive outcomes of its supplementation in animal models of human diseases. Its mode of action seems to depend on the quenching of toxic electrophiles, such as 4–hydroxynonenal (HNE). However, carnosine's bioavailability in humans is lower than that in other mammals. The main reason for such an unfavorable pharmacokinetic profile is the activity of the enzyme human serum carnosinase (E.C. 3.4.13.20), which rapidly hydrolyzes carnosine upon absorption. Therefore, some studies have focused on the design of carnosinase-resistant derivatives that retain binding activity toward toxic electrophiles. Nevertheless, the structural modification of the N-terminus amino group of carnosine has rarely been considered, possibly because of its key role in the electrophile scavenging mechanism. This was proven, since some carnosine N-terminus modification generated inactive compounds, despite some derivatives retaining oral bioavailability and gaining resistance to carnosinase hydrolysis. Herein, we therefore report a study aimed at exploring whether the amino group of carnosine can be conveniently modified to develop carnosinase-resistant derivatives retaining the dipeptide activity toward toxic electrophiles. [ABSTRACT FROM AUTHOR]

Human exposure to dicarbonyls occurs via ingestion (e.g., food), inhalation (e.g., electronic cigarettes) and dysregulation of endogenous metabolic pathways (e.g., glycolysis). Dicarbonyls are electrophiles able to induce carbonylation of endogenous substrate. They have been associated with the onset and progression of several human diseases. Several studies have advocated the use of dicarbonyl binders as food preservatives or as drugs aimed at mitigating carbonylation. This study presents the setup of an easy and cheap assay for the screening of selective and potent dicarbonyl binders. The method is based on the incubation of the candidate molecules with a molecular probe. The activity is then determined by measuring the residual concentration of the molecular probe over time by liquid chromatography (LC). However, the naturally occurring dicarbonyls (e.g., glyoxal, methylglyoxal) are not appealing as probes since they are hard to separate and detect using the most popular LC variants. Benzylglyoxal (BGO) was therefore synthesized and tested, proving to be a convenient probe that allows a direct quantification of residual dicarbonyls by reversed phase LC without derivatization. The method was qualified by assessing the binding ability of some molecules known as binders of natural occurring dicarbonyls, obtaining results consistent with literature.

Obesity and type 2 diabetes (T2DM) are major public health concerns associated with serious morbidity and increased mortality. Both obesity and T2DM are strongly associated with adiposopathy, a term that describes the pathophysiological changes of the adipose tissue. In this review, we have highlighted adipose tissue dysfunction as a major factor in the etiology of these conditions since it promotes chronic inflammation, dysregulated glucose homeostasis, and impaired adipogenesis, leading to the accumulation of ectopic fat and insulin resistance. This dysfunctional state can be effectively ameliorated by the loss of at least 15% of body weight, that is correlated with better glycemic control, decreased likelihood of cardiometabolic disease, and an improvement in overall quality of life. Weight loss can be achieved through lifestyle modifications (healthy diet, regular physical activity) and pharmacotherapy. In this review, we summarized different effective management strategies to address weight loss, such as bariatric surgery and several classes of drugs, namely metformin, GLP-1 receptor agonists, amylin analogs, and SGLT2 inhibitors. These drugs act by targeting various mechanisms involved in the pathophysiology of obesity and T2DM, and they have been shown to induce significant weight loss and improve glycemic control in obese individuals with T2DM.

In medicinal chemistry, the precise configuration of molecules is a crucial determinant of their pharmacological properties. Hence, the introduction of a new chiral center during the synthetic pathway involves the assignment of configuration. Herein we assign, by means of molecular modeling 1H and 2D Nuclear Overhauser Effect NMR techniques, the configuration of the two diastereomers 2S-(1R-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine and 2S-(1S-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine, which are useful to synthetize analogs of the potent and highly selective dipeptidyl peptidase IV and carbonic anhydrase inhibitor recently published. [ABSTRACT FROM AUTHOR]

Over the years secondary metabolites have been considered as lead molecules both in their natural form and as templates for medicinal chemistry. Some secondary metabolites such as polyphenols and flavan-3-ols exert beneficial effects after a modification by the microbiota. Synthetic precursors of some of these modified compounds, in turn, carried a γ-alkylidenebutenolide moiety which characterizes a large class of bioactive natural products endowed with a wide range of biological activities. For these reasons stereoselective preparation of γ-alkylidenebutenolide continues to be an important issue for organic chemists. Our objective is to synthetize the novel compound (Z)-5-(3′,4′-bis(benzyloxy)benzylidene)furan-2(5H)-one in a stereocontrolled-one-pot reaction. The product was obtained in good yield. Furthermore, the theoretical investigation of the transition states suggests a new procedure to achieve Z-isomer of β-unsubstituted γ-alkylidenebutenolide.

Cyclo(His-Pro) (CHP) is a cyclic dipeptide which is endowed with favorable pharmacokinetic properties combined with a variety of biological activities. CHP is found in a number of protein-rich foods and dietary supplements. While being stable at physiological pH, CHP can open yielding two symmetric dipeptides (His-Pro, Pro-His), the formation of which might be particularly relevant from dietary CHP due to the gastric acidic environment. The antioxidant and protective CHP properties were repeatedly reported although the non-enzymatic mechanisms were scantly investigated. The CHP detoxifying activity towards α,β unsaturated carbonyls was never investigated in detail, although its open dipeptides might be effective as already observed for histidine containing dipeptides. Hence, this study investigated the scavenging properties of TRH, CHP and its open derivatives towards 4-hydroxy-2-nonenal. The obtained results revealed that Pro-His possesses a marked activity and is more reactive than l-carnosine. As investigated by DFT calculations, the enhanced reactivity can be ascribed to the greater electrophilicity of the involved iminium intermediate. These findings emphasize that the primary amine (as seen in l-carnosine) can be replaced by secondary amines with beneficial effects on the quenching mechanisms. Serum stability of the tested peptides was also evaluated, showing that Pro-His is characterized by a greater stability than l-carnosine. Docking simulations suggested that its hydrolysis can be catalyzed by serum carnosinase. Altogether, the reported results evidence that the antioxidant CHP properties can be also due to the detoxifying activity of its open dipeptides, which might be thus responsible for the beneficial effects induced by CHP containing food.

Candida spp. are pathobionts, as they can switch from commensals to pathogens, responsible for a variety of pathological processes. Adhesion to surfaces, morphological switch and biofilm-forming ability are the recognized virulence factors promoting yeast virulence. Sessile lifestyle also favors fungal persistence and antifungal tolerance. In this study, we investigated, in vitro, the efficacy of two urinary cranberry metabolites, 5-(3′,4′-dihydroxy phenyl)-γ-valerolactone (VAL) and 4-hydroxybenzoic acid (4-HBA), in inhibiting C. albicans adhesion and biofilm formation. Both the reference strain SC5314 and clinical isolates were used. We evaluated biomass reduction, by confocal microscopy and crystal violet assay, and the possible mechanisms mediating their inhibitory effects. Both VAL and 4-HBA were able to interfere with the yeast adhesion, by modulating the expression of key genes, HWP1 and ALS3. A significant dose-dependent reduction in biofilm biomass and metabolic activity was also recorded. Our data showed that the two cranberry metabolites VAL and 4-HBA could pave the way for drug development, for targeting the very early phases of biofilm formation and for preventing genitourinary Candida infections.

From viruses to bacteria, our lives are filled with exposure to germs. In built environments, exposure to infectious microorganisms and their byproducts is clearly linked to human health. In the last year, public health emergency surrounding the COVID-19 pandemic stressed the importance of having good biosafety measures and practices. To prevent infection from spreading and to maintain the barrier, disinfection and hygiene habits are crucial, especially when the microorganism can persist and survive on surfaces. Contaminated surfaces are called fomites and on them, microorganisms can survive even for months. As a consequence, fomites serve as a second reservoir and transfer pathogens between hosts. The knowledge of microorganisms, type of surface, and antimicrobial agent is fundamental to develop the best approach to sanitize fomites and to obtain good disinfection levels. Hence, this review has the purpose to briefly describe the organisms, the kind of risk associated with them, and the main classes of antimicrobials for surfaces, to help choose the right approach to prevent exposure to pathogens.

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90–95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.

Over the years secondary metabolites have been considered as lead molecules both in their natural form and as templates for medicinal chemistry. Some secondary metabolites such as polyphenols and flavan-3-ols exert beneficial effects after a modification by the microbiota. Synthetic precursors of some of these modified compounds, in turn, carried a γ-alkylidenebutenolide moiety which characterizes a large class of bioactive natural products endowed with a wide range of biological activities. For these reasons stereoselective preparation of γ-alkylidenebutenolide continues to be an important issue for organic chemists. Our objective is to synthetize the novel compound (Z)-5-(3′,4′-bis(benzyloxy)benzylidene)furan-2(5H)-one in a stereocontrolled-one-pot reaction. The product was obtained in good yield. Furthermore, the theoretical investigation of the transition states suggests a new procedure to achieve Z-isomer of β-unsubstituted γ-alkylidenebutenolide. [ABSTRACT FROM AUTHOR]