Search Results (55)

The development of positron emission tomography (PET) tracers targeting α-synuclein (α-syn) aggregates is critical for the early diagnosis, differential classification, and therapeutic monitoring of synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Despite recent advances, challenges including the low abundance of α-syn aggregates (10–50× lower than amyloid-beta (Aβ) or Tau), structural heterogeneity (e.g., flat fibrils in PD vs. cylindrical forms in DLB), co-pathology with Aβ/Tau, and poor metabolic stability have hindered PET tracer development for this target. To optimize our previously reported pyridothiophene-based radiotracer, [¹⁸F]asyn-44, we present the synthesis and evaluation of novel S,N-heterocyclic scaffold derivatives for α-syn. A library of 49 compounds was synthesized, with 8 potent derivatives (LMD-006, LMD-022, LMD-029, LMD-044, LMD-045, LMD-046, LMD-051, and LMD-052) demonstrating equilibrium inhibition constants (K_i) of 6–16 nM in PD brain homogenates, all of which are amenable for radiolabeling with fluorine-18. This work advances the molecular toolkit for synucleinopathies and provides a roadmap for overcoming barriers in PET tracer development, with lead compounds that can be considered for biomarker-guided clinical trials and targeted therapies. Full article

Two series of imidazole-2(3H)-thiones inspired by naturally occurring lepidiline alkaloids, bearing either one or two benzyl-type substituents located at the N(1)/N(3) atoms, respectively, were prepared and examined in reactions with in situ generated C-trifluoromethyl-N-aryl nitrile imines. N,N-Dibenzylated imidazole-2-thiones served exclusively as C=S dipolarophiles to afford hitherto unknown CF₃-functionalized spiro [1,3,4-thiadiazole-5,2′-imidazole] derivatives formed through the (3+2)-cycloaddition pathway. In contrast, the enolizable N-monobenzylated imidazole-2-thiones provided acyclic products, i.e., hydrazonothioates, resulting from nucleophilic addition of the respective en(thio)late onto the C-termini of the 1,3-dipole. The presented results extend the scope of both fluorinated products available via trapping of the in situ generated CF₃-nitrile imines as well as synthetic analogues of lepidilines. In addition, spectroscopic analysis of the obtained products and the known related systems revealed ¹³C NMR chemical shifts attributed to the C-(CF₃) atom as useful probes to differentiate the open-chain hydrazonothioates (δ = 112–120), 2,2-diaryl/dialkyl-2,3-dihydro-1,3,4-thiadiazoles (δ = 130–145), and more strained spiro-1,3,4-thiadiazole derivatives (δ = 166–170) reported herein. Full article

This study describes the synthesis of heterocyclic derivatives containing multiple nitrogen atoms serving as important moieties for developing novel antidiabetics through a simple synthetic pathway. We herein describe the synthesis and characterization of novel pyrimidine derivatives using one-pot reactions in a catalyst-free and efficient manner through a two-stage process involving the synthesis of 2-amino-4-hydrazinyl-6-methoxy pyrimidine, followed by a reaction with phenyl isothiocyanate derivatives. The structures of all the new compounds were confirmed via physical and spectral analysis. Furthermore, we evaluated the synthesized pyrimidine derivatives’ biological activities in relation to their potential roles as novel anti-diabetic agents by testing their activity profiles against the enzymes α-glucosidase and α-amylase. Compound 4 expressed the highest level of activity against α-glucosidase and α-amylase, with a greater inhibitory concentration (IC₅₀ of 12.16 ± 0.12 µM and IC₅₀ 11.13 ± 0.12 µM) compared to that of acarbose (IC₅₀ = 10.60 ± 0.17 µM and IC₅₀ = 11.30 ± 0.12 µM), which is widely used as a standard antidiabetic drug. The primary structure activity relationship analysis identified the impact of an electron- withdrawing group, especially with respect to fluorine on inhibitory activity. This was further confirmed in molecular docking studies, which demonstrated that both compounds exhibited similar inhibition patterns and emphasized the significance of incorporating a lipophilic electron-withdrawing substituent on the phenyl ring, along with the 2,4-diaminopyrimidine scaffold. Full article

In this study, we develop a concise and efficient synthetic strategy for the construction of eight-membered cyclic diaryl sulfides by undertaking [3+2] cycloaddition, 1,2-hydrogen shift, and C(sp²)-S bond cleavage steps on 2-methylenebenzothiophene-3-ones with aryne, using TBAT as the fluorine source. This transformation proceeds well under mild conditions and affords the target products in high to excellent yields (up to 93% yields). The process provides a practical route to achieving sulfur-containing medium-sized heterocycles. Full article

The U.S. Food and Drug Administration (FDA) has authorized 50 new drugs in 2024, which matches the average figure for recent years (2018–2023). The approval of 13 monoclonal antibodies (mAbs) sets a new record, with these molecules accounting for more than 25% of all drugs authorized this year. Three proteins have been added to the list of biologics, and with the inclusion of four TIDES (two oligonucleotides and two peptides), only one in three approved drugs this year is a small molecule. As of 2023, no antibody-drug conjugates (ADCs) have reached the market this year. Two deuterated drugs have been approved, bringing the total approvals for this class of compounds to four. This year saw the authorization of two more PEGylated drugs—both peptides—highlighting a renewed interest in this strategy for extending drug half-life, despite the setback caused by the withdrawal of peginesatide from the market in 2014 due to adverse side effects. N-aromatic heterocycles and fluorine atoms are present in two-thirds of all the small molecules approved this year. Herein, the 50 new drugs authorized by the FDA in 2024 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins), TIDES (oligonucleotides and peptides), combined drugs, natural products, F-containing molecules, nitrogen aromatic heterocycles, aromatic compounds, and other small molecules. Full article

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. Full article

The luminescent properties of Au(I) and Pt(II) compounds are commonly tuned by exploiting the alkynyl ligand with varying electron density. Herein, we describe the synthesis of three new emissive transition metal compounds, ^tbpyPt(C₂pym)₂, Ph₃PAuC₂pym, and Cy₃PAuC₂pym (where HC₂pym = 2-ethynylpyrimidine), verified by ¹H-NMR, EA, and a single-crystal X-ray diffraction analysis. The ^tbpyPt(C₂pym)₂ complex crystallized as an Et₂O solvate in the orthorhombic space group Pbca with Z = 24 with three unique Pt(II) species within the unit cell. The Cy₃PAuC₂pym species crystallizes in a monoclinic space group with one unique complex in the asymmetric unit. Changing the identity of the phosphine from Cy₃P to Ph₃P influences interactions within the unit cell. Ph₃PAuC₂pym, which also crystalizes in a monoclinic space group, has an aurophilic bonding interaction Au–Au distance of 3.0722(2) Å, which is not present in crystalline Cy₃PAuC₂pym. Regarding optical properties, the use of an electron-deficient heterocycle provides an alternate approach to blue-shifting the emission of Pt(II) transition metals’ compounds, where the aryl moiety is made more electron-deficient by exploiting nitrogen within this moiety instead of the typical strategy of decorating the aryl ring with electron withdrawing substituents (e.g., fluorines). This is indicated by the blue-shift in emission that occurs in ^tbpyPt(C₂pym)₂ (λ_max, emission = 512 nm) compared to the previously reported ^tbpyPt(C₂2-py)₂ (where HC₂2-py = 2-ethynylpyridine) complex (λ_max, emission = 520 nm). Full article

With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody–drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year’s harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules. Full article

One of the main causes of mortality in humans continues to be infectious diseases. Scientists are searching for new alternatives due to the fast increase in resistance of some harmful bacteria to the frontline antibiotics. To effectively treat pathogenic infections, it is crucial to design antibiotics that can prevent the development of pathogenic resistance. For this purpose, a set of 39 quaternary pyridinium and bis-pyridinium salts with different lengths of side alkyl or fluorinated chains, heterocyclic spacers, and counter ions were tested on diverse reference bacterial ATCC (American Type Culture Collection) strains, such as S. aureus and E. coli. Subsequently, 6 out of the 39 pyridinium salts showing relevant MIC (Minimum Inhibitory Concentration) values were tested on clinically isolated, resistant strains of S. aureus, S. epidermids, S. haemolyticus, K. pneumoniae, A. baumannii, and P. aeruginosa. Additional tests have been performed to assess if the minimum concentration detected through MIC assay may limit the growth of biofilms. Full article

The review focuses on recent advances in the methodologies for the formation or introduction of the CH₂F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH₂F sources (for example, ICH₂F) and the assembly of N-heterocyclic structures from CH₂F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH₂SO₂Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH₃, -CH₂OH, -CH₂NH₂, -CH₂CH₃, -CH₂NO₂ and -CH₂SH moieties. Bioisosteric replacement with the CH₂F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates. Full article

Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using ¹⁸F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022. Full article

Direct oral anticoagulants are an important and relatively new class of synthetic anticoagulant drugs commonly used for the pharmacotherapy of thromboembolic disorders. However, they still have some limitations and serious side effects, which continuously encourage medicinal chemists to search for new active compounds acting as human-activated coagulation factor X (FXa) inhibitors. Isosteviol is a nontoxic hydrolysis product of naturally occurring stevioside and possesses a wide range of therapeutic properties, including anticoagulant activity. The present contribution describes the in silico design of novel oxime ether isosteviol derivatives as well as a molecular modeling approach based on QSAR analysis and a docking simulation for searching for novel isosteviol-based compounds as potential FXa inhibitors. The elaborated ANN model, encompassing topological and geometrical information, exhibited a significant correlation with FXa-inhibitory activity. Moreover, the docking simulation indicated six of the most promising isosteviol-like compounds for further investigation. Analysis showed that the most promising derivatives contain heterocyclic, aromatic, five-membered moieties, with substituents containing chlorine or fluorine atoms. It is anticipated that the findings reported in the present work may provide useful information for designing effective FXa inhibitors as anticoagulant agents. Full article

Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC₅₀ values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E₂. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure–activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments. Full article

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, ¹H-NMR, ¹³C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations. Full article