Pharmaceutical Analogues Research Articles

Design, synthesis, and study of 2-pyridone-based pharmaceutical analogues

2-pyridones are an important class of compounds among the N-heterocycles due to the abundant presence of their structural derivatives in many biologically active compounds. The synthesis of 2-pyridone derivatives (compounds 3A-3C) involves the condensation of aldehyde, malononitrile, and ethyl acetoacetate by a base-catalyzed reaction. Heterocyclic ring rearrangements were carried out using the simplest acid as a catalyst to produce hydroaromatic compounds, followed by dehydrogenation to yield the corresponding aromatic analogues. A sample of the crystals obtained from the synthesized compounds 3A-3C were studied to explore the types of hydrogen bonding and other intermolecular interactions involved in the supramolecular assemblies. Hirsheld surface analyses were also conducted to support the weak interactions and investigate their contributions within the supramolecular assemblies. In silico studies were also performed on the molecular recognition and ADMET properties of the compounds to reveal the most promising compounds for drug development.

Photoinduced Transition-Metal and External Photosensitizer Free Benzylic Fluorination of Unactivated Alkylarenes.

A green and efficient protocol for the direct monofluorination of unactivated alkylarenes under visible-light irradiation has been developed, without any extraneous transition-metal catalysts or photosensitizers. This method is compatible with a broad spectrum of functional groups, including carboxylic and alcoholic scaffolds, under mild reaction conditions. Gram-scale synthesis of a fluorine-containing pharmaceutical analogue was successfully executed, underscoring the strategy's reliability and practicality. Furthermore, mechanistic studies suggest that a single-electron transfer mechanism might be responsible for the generation of the benzylic radicals in initiation step.

Metal-Free Photoredox Catalyzed Sulfonylation of Phenylhydrazines with Thiols.

The sulfonylation method stands out as a simple and efficient approach for synthesizing sulfonamides. Despite the advancements in constructing the sulfonamide framework, the potential use of phenyl hydrazine as an amination source remains unexplored. Herein, we report a metal-free, environment-friendly photoredox-catalyzed sulfonylation of phenylhydrazines using thiols, employing MeCN:H2O as a green solvent and eosin Y as a photoredox catalyst. This strategy exhibits a broad substrate scope and good functional group compatibility, including hetero(aryl) as well as aliphatic phenylhydrazines. Finally, this protocol also demonstrated good application for the synthesis of pharmaceutical analogues.

One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation.

The coupling of carboxylic acids and amines to form amide linkages is the most commonly performed reaction in the pharmaceutical industry. Herein, we report a new strategy that merges these traditional amide coupling partners to generate sulfonamides, important amide bioisosteres. This method leverages copper ligand-to-metal charge transfer (LMCT) to convert aromatic acids to sulfonyl chlorides, followed by one-pot amination to form the corresponding sulfonamide. This process requires no prefunctionalization of the native acid or amine and extends to a diverse set of aryl, heteroaryl, and s-rich aliphatic substrates. Further, we extend this strategy to the synthesis of (hetero)aryl sulfonyl fluorides, which have found utility as "click" handles in chemical probes and programmable bifunctional reagents. Finally, we demonstrate the utility of these protocols in pharmaceutical analogue synthesis.

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes.

The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for parasubstituted arene rings, appearing in a number of lead pharmaceutical candidates. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often nonmodular sequences. While challenging, direct functionalization of the strong bridge BCP C-H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here, we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C-H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one-step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogues, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

Fibroblast growth factor 21 and dietary macronutrient intake in female mice

Fibroblast growth factor- 21 (FGF21) is a metabolic stress hormone that is released from the liver in response to various nutritional challenges. Because of its notable effects to improve metabolic health, including body fat loss, glucose control, and hepatosteatosis, several pharmaceutical analogs of FGF21 are in development for the treatment of metabolic disease. In addition, a small but developing literature clearly demonstrates that FGF21 also controls feeding behavior. Pharmacological administration of FGF21 reduces the consumption of simple sugars and other sweet tastants, and it increases the consumption of dietary proteins in males, suggesting another potential mechanism by which FGF21-treatment could improve metabolic health— by promoting healthy eating. Despite that sex is a key biological variable influencing feeding behavior and macronutrient selection, the current literature to date primarily on males. In this study, we investigated the effect of FGF21 on sucrose intake and macronutrient selection in female mice. Similar to our previous findings in male mice, we report that FGF21 administration decreases the consumption of sucrose solution by females, and that this is offset by increased chow intake. Also in agreement with our previous findings in males, we report that FGF21 increases the consumption of dietary protein by female mice, and this is offset by either reduced carbohydrate or by reduced fat intake. Lastly, we find that the effect of FGF21 to direct macronutrient intake in females depends on its actions in neurons. Overall, our data support a role for FGF21 to direct macronutrient intake in a similar manner in female and male mice.

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of theabsorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Italian Public Health Expenditure for Vitamin D is still high: New Outlook to Saving From a Consumption Analysis in the Liguria Region

PurposeItalian expenditure for vitamin D greatly increased in the last few years, reaching €314 million ($376.8 million) in 2019. In Italy, the main cause of the increase in public spending for vitamin D is the marketing of high-cost medicines. At national and regional levels, some interventions have been performed to reduce expenditure, but spending has continued to increase. The aim of this work is to propose a new saving strategy determined by an analysis of a significant sample of the market. MethodsData on the use of vitamin D formulations, including data for the different active substances that represent its pharmaceutical analogue and composition of groups of equivalence, were extrapolated from the Italian Medicines Agency transparency lists and from the Farmadati database. Data on pharmaceutical expenditure were obtained from the Data Warehouse of Liguria Region; the composition of this expenditure was analyzed in detail, focusing on the characteristics of the pharmaceutical preparations and their cost (price per defined daily dose). FindingsVitamin D expenditure paralleled that of cholecalciferol, the most used active ingredient, which in Liguria increased from €643,352 ($772,022.4) in 2010 to €8,006,574 ($9,607,888.8) in 2019 (increase of 1144%). Spending focused on high-cost formulations, exceeding 90% of total cholecalciferol cost in 2019. We simulated a possible optimization of the expense for cholecalciferol by applying a revised price to all the cholecalciferol consumptions in high-cost products because these formulations do not have an added therapeutic value, finding that the saving would be at least 60%. National data on the detailed expenditure composition for vitamin D are not available, but we found a strong resemblance between total cholecalciferol expenditure time series in Italy and the Liguria Region. ImplicationsThe expense of cholecalciferol and consequently the expense of vitamin D could be optimized by modifying the reimbursement of high-cost formulations. At a national level, savings should be proportional to that estimated for the Liguria Region. On the basis of the 2019 data, Italian savings with respect to total cholecalciferol expenditure should be €170.65 million ($204.78 million); per capita cholecalciferol expenditure would shift from €4.66 ($5.59) to €1.84 ($2.21).

Lewis Basic Salt-Promoted Organosilane Coupling Reactions with Aromatic Electrophiles.

Lewis basic salts promote benzyltrimethylsilane coupling with (hetero)aryl nitriles, sulfones, and chlorides as a new route to 1,1-diarylalkanes. This method combines the substrate modularity and selectivity characteristic of cross-coupling with the practicality of a base-promoted protocol. In addition, a Lewis base strategy enables a complementary scope to existing methods, employs stable and easily prepared organosilanes, and achieves selective arylation in the presence of acidic functional groups. The utility of this method is demonstrated by the synthesis of pharmaceutical analogues and its use in multicomponent reactions.

Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer

Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.

Chemical Reactivity Theory and Empirical Bioactivity Scores as Computational Peptidology Alternative Tools for the Study of Two Anticancer Peptides of Marine Origin.

This work presents an account of the reactivity behavior of the anticancer marine drugs, Soblidotin and Tasidotin, based on the calculation of the global and local descriptors resulting from Chemical Reactivity Theory (CRT), also known as Conceptual DFT, for their consideration as a useful complement to approximations based on Molecular Docking. The information on the global and local reactivity descriptors of the Soblidotin and Tasidotin molecules, obtained through our proposed methodology, may be used for the design of new pharmaceutical analogs by relying on the chemical interactions between these peptides and their protein-type biological receptors. It can be concluded that the CRT approximation to the global and local chemical reactivity, based on the descriptors, can provide interesting information for the consideration of both molecules as potential therapeutic drugs. This is complemented by a study on Advanced Glycation Endproduct (AGE) inhibition, by comparison with the usual molecular systems considered for the task, as a re-purposing study. Finally, the bioactivity scores for Soblidotin and Tasidotin are predicted through an empirical procedure, based on comparison with molecular structures with well-known pharmacological properties.

Characterization of the iron core in Ferrifol®, a pharmaceutical analogue of ferritin, using Mössbauer spectroscopy and magnetization measurements

Mössbauer spectra of Ferrifol® measured at 295, 220, 140 and 90 K demonstrated non-Lorentzian two-peak spectra which were better fitted using a superposition of 5 quadrupole doublets with different quadrupole splitting but similar isomer shift and equal line width. Unusual line broadening was observed in the Mössbauer spectra of Ferrifol® measured in this temperature range. This is consistent with the unusual line broadening already observed earlier in the Mössbauer spectra (295–90 K) of ferritin and its pharmaceutical analogues Ferrum Lek and Maltofer® (Oshtrakh M.I. et al., Spectrochim. Acta, Part A: Mol. Biomol. Spectrosc., 2017, 172, 14–24, DOI: 10.1016/j.saa.2016.06.034). The Mössbauer spectrum of Ferrifol® at 60 K demonstrated a slow decrease of magnetic relaxation in the iron core. Magnetization measurements revealed mainly paramagnetic state of the Ferrifol® iron core and apparently blocking temperature around 33 K.

Late-Stage Functionalization of Arylacetic Acids by Photoredox-Catalyzed Decarboxylative Carbon-Heteroatom Bond Formation.

The rapid transformation of pharmaceuticals and agrochemicals enables access to unexplored chemical space and thus has accelerated the discovery of novel bioactive molecules. Because arylacetic acids are regarded as key structures in bioactive compounds, new transformations of these structures could contribute to drug/agrochemical discovery and chemical biology. This work reports carbon-nitrogen and carbon-oxygen bond formation through the photoredox-catalyzed decarboxylation of arylacetic acids. The reaction shows good functional group compatibility without pre-activation of the nitrogen- or oxygen-based coupling partners. Under similar reaction conditions, carbon-chlorine bond formation was also feasible. This efficient derivatization of arylacetic acids makes it possible to synthesize pharmaceutical analogues and bioconjugates of pharmaceuticals and natural products.

Identification and Detection of Undeclared Herbal Slimming Adulterants

The Food and Drug Administration (FDA) is advising consumers to stop using multiple weight-loss products that contain the undeclared drug ingredients e.g. sibutramine, which was removed from the market in 2010 for safety reasons and may present significant risks for those with coronary artery disease and other heart issues. Sibutramine and similar undeclared ingredients in herbal medicines are a real challenge for the public health and safety. In recent years, the need for quality assurance tools to ensure the identity, purity, and quality of botanical material has risen dramatically. HPTLC has emerged as a versatile, high throughput, and cost-effective technology, that is uniquely suited to meet these requirements. Most separation techniques do not allow parallel analysis of numerous samples at the same time and they often face problems in separating complex mixtures of substances. However, visual evaluation of HPTLC plates allows for convenient comparison of many samples side by side, where similarities and differences can clearly be seen. The quality of raw materials is rapidly and easily determined by HPTLC. For the identification of herbal drugs and other naturally derived materials standardized HPTLC is the method of choice and recommended by pharmacopoeias worldwide, furthermore adulterated samples are reliably identified. The main objective of the present study is to check pharmaceutical analogue adulteration of nonprescription and prescription slimming products in the laboratory using chromatographic techniques and to discuss its side effects in the interest of consumers and public health safety. Since intentional adulteration of “natural herbalmedicines” with unknown synthetic drugs or chemicals is a common and dangerous phenomenon of alternative medicine, it is important to modify and validate analytical tools to monitor and evaluate these herbal drugs.

The 57Fe hyperfine interactions in human liver ferritin and its iron-polymaltose analogues: the heterogeneous iron core model

Human liver ferritin and its iron-polymaltose pharmaceutical analogues Ferrum Lek, Maltofer® and Ferrifol® were studied using Mossbauer spectroscopy at 295 and 90 K. The Mossbauer spectra were fitted on the basis of a new model of heterogeneous iron core structure using five quadrupole doublets. These components were related to the corresponding more or less close-packed iron core layers/regions demonstrating some variations in the 57Fe hyperfine parameters for the studied samples.

Different 57Fe microenvironments in the nanosized iron cores in human liver ferritin and its pharmaceutical analogues on the basis of temperature dependent Mössbauer spectroscopy

Mössbauer spectra of human liver ferritin and its pharmaceutical analogues Ferrum Lek and Maltofer® measured at various temperatures within the range of 295–83K were fitted using five quadrupole doublets related to different 57Fe microenvironments in various layers/regions of the ferrihydrite and akaganéite iron cores. The observed anomalous temperature dependences of some Mössbauer parameters were considered as a result of low temperature structural rearrangements in different layers/regions in the iron core.

PREVENTION OF MYELOSUPPRESSION BY COMBINED TREATMENT WITH ENTEROSORBENT AND GRANULOCYTE COLONY-STIMULATING FACTOR

Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. Simultaneous administration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy.

Evaluation of the Debye temperature for iron cores in human liver ferritin and its pharmaceutical analogue, Ferrum Lek, using Mössbauer spectroscopy

An iron–polymaltose complex, Ferrum Lek, used as antianemic drug and considered as a ferritin analogue and human liver ferritin were investigated in the temperature range of 295–90K using 57Fe Mössbauer spectroscopy with a high velocity resolution (in 4096 channels). This study aimed to make a comparison of the Fe atom dynamics in the Ferrum Lek and ferritin iron cores by means of evaluation of the Debye temperature using the temperature dependence of the spectral center shift obtained with two different fitting procedures and the second order Doppler shift approach. The Debye temperature, evaluated as ΘD=502±24K for Ferrum Lek and ΘD=461±16K for human liver ferritin, demonstrated a very small difference in the Fe atom vibrations, reflecting a slightly smaller rigidity in the iron cores in human liver ferritin.

Anomalous Mössbauer line broadening for nanosized hydrous ferric oxide cores in ferritin and its pharmaceutical analogue Ferrum Lek in the temperature range 295–90 K

Mossbauer spectra of ferritin and its pharmaceutical analogue Ferrum Lek, both containing nanosized hydrous ferric oxides cores in the forms of ferrihydrite and akaganeite, respectively, were measured in the temperature range 295–90 K. An anomalous line broadening with temperature decrease was observed for ferritin below ~150 K and for Ferrum Lek below ~130 K. Some anomalies were also observed below these temperatures for spectral area and quadrupole splitting.

FTY720-induced human pulmonary endothelial barrier enhancement is mediated by c-Abl

Strategies to improve pulmonary endothelial barrier function are needed to reverse the devastating effects of vascular leak in acute respiratory distress syndrome. FTY720 is a pharmaceutical analogue of the potent barrier-enhancing phospholipid sphingosine 1-phosphate (S1P). FTY720 decreases vascular permeability by an incompletely characterised mechanism that differs from S1P. Here, we describe its barrier-promoting effects on intracellular signalling and junctional assembly formation in human pulmonary endothelium. Permeability of cultured human pulmonary endothelial cells was assessed using transendothelial electrical resistance and dextran transwell assays. Junctional complex formation was assessed using membrane fractionation and immunofluorescence. Pharmacological inhibitors and small interfering (si)RNA were utilised to determine the effects of individual components on permeability. Unlike S1P, FTY720 failed to induce membrane translocation of adherens junction or tight junction proteins. β-catenin, occludin, claudin-5 or zona occludens protein (ZO)-1/ZO-2 siRNAs did not alter FTY720-induced barrier enhancement. FTY720 induced focal adhesion kinase (FAK) phosphorylation and focal adhesion formation, with FAK siRNA partially attenuating the prolonged phase of barrier enhancement. Inhibition of Src, protein kinase (PK)A, PKG, PKC or protein phosphatase 2A failed to alter FTY720-induced barrier enhancement. FTY720 increased c-Abl tyrosine kinase activity and c-Abl siRNA attenuated peak barrier enhancement after FTY720. FTY720 enhances endothelial barrier function by a novel pathway involving c-Abl signalling.