Search Results (207)

The discovery of a mechanism by which bile acids (BAs) regulate fat synthesis by modulating the activation of the farnesoid X receptor (FXR) in the liver and intestines has highlighted the central role of BAs in triglyceride synthesis in the liver. FXR has been reported as a promising drug target for primary biliary cholangitis, metabolic-dysfunction-associated steatohepatitis, and metabolic-dysfunction-associated steatotic liver disease. A large number of FXR modulators with various chemotypes have been developed by many research groups. Although several FXR modulators are advancing into clinical trials, ongoing efforts aim to develop new FXR modulators that minimize the adverse effects associated with long-term administration. To develop drug candidates targeting FXR, various heterocyclic and/or fused heteroaromatic rings have been employed as the core and/or parts of the structures, out of which benzimidazole has been recognized as a valuable structural motif due to its synthetic accessibility and its versatility in constructing structurally diverse target molecules. Herein, we report on the development of FXR modulators incorporating benzimidazole as a fused heteroaromatic ring. Full article

Benzodichalcogenophenes represent a valuable class of organic π-conjugated systems that have been investigated in a plethora of cutting-edge applications in the field of materials chemistry. Isomeric benzodifuran (BDF), benzodithiophene (BDT) and benzodiselenophene (BDS) analogs of phenanthrene, in which the two heteroaromatic rings are ortho-fused onto a benzene ring, represent convenient frameworks as functional materials in organic electronics. The orientation of the two condensed heteroaromatic rings with respect to the central benzene ring provides diverse structural isomers, which significantly differ in degrees of curvature, electronic and electrochemical properties. Furthermore, tailored modification and functionalization strategies enable fine-tuning of their intrinsic properties, leading to unique systems. This review offers a comprehensive overview of synthetic methodologies for constructing isomeric BDF, BDT and BDS skeletons, alongside an analysis of their electrochemical properties as influenced by the nature of heteroatoms. Finally, the most relevant applications of these systems, ranging from optoelectronics, supramolecular chemistry, and emerging biological studies, are discussed, providing valuable insights for future research direction. Full article

Fused-bicyclic heteroaromatic cores are a common framework in drugs and other biologically active compounds. Those containing azine rings are widely used in drug discovery campaigns. Although these cores are very common, C–H functionalization of their azine moieties remains challenging, especially in annulation reactions. Therefore, this review highlights the progress made over the years in C–H annulation reactions that have produced these essential 6,5-fused bicyclic heteroaromatic cores for drug discovery. For that, the review was divided according to the five-membered rings moiety (pyrrole, pyrazole, imidazole, furan, thiophen, and thiazole) fused to different azines (pyridine, pyrazine, pyridazine, pyrimidine, and triazine). Although some important advances have been made over the years, there remains a need for research in synthetic methodology to expand the use of these heteroaromatic cores in biologically active compounds. Full article

Background: Heteroaromatic iodine-containing compounds have been previously recognized for their broad-spectrum antimicrobial activity. This study aims to systematically investigate their potential repurposing as anticancer agents, with a particular focus on understanding the structural determinants that influence their cytotoxicity and selectivity toward malignant cells. Methods: A series of heteroaromatic iodine-containing derivatives were synthesized and evaluated for anticancer activity. Their cytotoxic effects were measured and compared between cancerous and normal cell lines to determine selectivity. Structural features, including heteroaromatic moieties and substituents, were analyzed to identify correlations with biological activity. Results: Among the tested compounds, derivatives 3e, 3g, and 3l demonstrated significant cytotoxic effects while exhibiting favorable selectivity indices. These findings indicate that these compounds preferentially target malignant cells over normal cells, thereby mitigating the issue of systemic toxicity often associated with traditional chemotherapeutics. The enhanced anticancer activity appears to be influenced by specific structural elements within the heteroaromatic framework. Conclusions: The study highlights the potential of heteroaromatic iodine-containing compounds as promising anticancer candidates. Rational structural modifications within these heterocyclic systems can effectively modulate bioactivity and improve therapeutic selectivity. These results support further development of this compound class for anticancer applications. Full article

A new series of 1H-pyrrolo[3,2-g]isoquinolines, diversely substituted at the 3-position either by a heteroaromatic scaffold or by propionate/acrylate side chains, were synthesized and evaluated as Haspin kinase inhibitors. The results of the kinase inhibitory potency study demonstrated that some of the new prepared compounds exhibited low nanomolar potencies toward Haspin. These results indicated that 3-substituted pyrrolo[3,2-g]isoquinolines could serve as intermediates for the development of PROTACs targeting Haspin, with the 3-position allowing further introduction of linkers to tether an E3 ligase ligand. However, this hypothesis remains to be demonstrated. Full article

Two heteroaromatic hybrid compounds were synthesized and characterized using various analytical techniques. The results indicate that the benzimidazole/oxadiazole (BZ/OZ) metal derivative exhibits a tridentate coordination mode, where the carbonyl, imidazole and oxadiazole groups participate in coordination with the metal, in a ratio of 2:1 of the ligand to the metal. The antibacterial activities of the organic ligand and its metal complex were determined by in vitro tests against both Gram-positive bacterial strains and Gram-negative bacterial strains using the broth microdilution method. The metal complex showed greater antibacterial activities compared to the precursor ligand against all evaluated microorganisms. The results obtained through in silico predictions revealed significant toxicological differences among the analyzed molecules, suggesting special attention in the use of the ligand due to its possible carcinogenicity in mice and a need for structural modifications in the complex to reduce its carcinogenicity and toxicity. Furthermore, a biophysical study of the interaction of the BZ/OZ derivatives with different model membranes was explored through differential scanning calorimetry (DSC), simultaneous small- and wide-angle X-ray diffraction (SAXD and WAXD) and infrared spectroscopy (FT-IR). The results indicate that the compounds influenced membrane properties without significantly altering the lamellar organization. The findings suggest potential applications in understanding lipid interactions, elucidating toxicology and developing antibacterial agents. Full article

Reactions of (pyH)₅[MoOCl₄(H₂O)]₃Cl₂ with picolinic and pyrazinoic acids yielded three new dinuclear molybdenum(V) complexes: (pyH)₂[Mo₂O₄Cl₂(pic)₂]·CH₃CN (1), (pyH)₂[Mo₂O₄Cl₂(pic)₂]·CH₃CH₂CN (2) and (pyH)₂[Mo₂O₄Cl₂(pyraz)₂]·CH₃CN (3) (pic⁻ = picolinate, pyraz⁻ = pyrazinoate and pyH⁺ = protonated pyridine). The compounds were characterized by single-crystal X-ray diffraction, infrared and ¹H NMR spectroscopy, elemental analysis, and TG/DSC measurements. All display a robust {Mo^V₂O₄}²⁺ core with the heteroaromatic ligands bound in a N,O-bidentate chelating manner. Full article

Effect-based toxicity assessments are crucial for evaluating the risks of disinfection byproducts (DBPs), particularly unknown species, generated during drinking water chlorination. However, the accuracy of this approach is highly dependent on unbiased sample extraction. Conventional methods often employ single, low-pH extraction, which may fail to recover pH-sensitive amphoteric DBPs derived from amphoteric precursors (e.g., nitrogenous compounds). This study investigated how extraction pH affects the measured biotoxicity of DBPs formed from three model precursors: biopterin (Bip), cytosine (Cyt), and tryptophan (Trp). Under excess chlorine conditions, all three precursors degraded rapidly. The formation of aliphatic DBPs followed the order Trp > Cyt > Bip, and the maximum toxicity of the non-volatile extracts, assessed via a Vibrio fischeri bioassay, followed the reverse order: Bip > Trp > Cyt. This toxicity profile was significantly influenced by extraction pH, with maximum toxicity observed for Bip at around pH 4.0, under weakly acidic conditions for Trp, and under neutral to alkaline conditions for Cyt. For all precursors, the total organic carbon concentration remained constant throughout chlorination, indicating negligible mineralization and the predominant formation of non-aliphatic, likely heteroaromatic, products. These findings demonstrate that conventional extractions at a single low pH can lead to the incomplete recovery of toxic DBPs from amphoteric precursors. Therefore, pH-optimized extraction protocols are necessary for a more accurate risk assessment of chlorinated drinking water. Full article

Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce the water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B–N analogs in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole, and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the twenty-four molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three compounds displaying IC₅₀ values in the nanomolar range. We have therefore demonstrated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop active substances containing azaborine rings against other targets. Full article

Background: Inhibiting α-glucosidase and α-amylase is a well-established strategy for managing postprandial hyperglycemia in type 2 diabetes mellitus. However, the adverse effects of current α-glucosidase inhibitors (α-GIs) underscore the need for safer alternatives. Methods: This study introduces an efficient, metal-free, and environmentally friendly protocol for the selective, high-yield synthesis of 1,2-disubstituted benzimidazoles. The reaction between o-phenylenediamine and various aromatic aldehydes proceeds smoothly in water at room temperature, using cost-effective and eco-friendly catalysts such as acetylsalicylic acid (ASA) or salicylic acid (SA). The methodology exhibits broad versatility, enabled by the use of different o-phenylenediamines and a wide range of aromatic and heteroaromatic aldehydes. Results: Selected compounds were assessed for their inhibitory activity against α-glucosidase and α-amylase. While all exhibited low α-amylase inhibition, several showed significant α-glucosidase inhibition, with compounds 8s (IC₅₀ = 0.39 ± 0.04 μM), 8k (IC₅₀ = 7.4 ± 1.6 μM) and 8r (IC₅₀ = 13.8 ± 2.7 μM) emerging as the most promising candidates. Notably, none of these compounds affected Caco-2 cell viability at concentrations up to 30 μM. Additionally, compounds 8r and 8s exhibited antioxidant properties, which may be relevant in counteracting the excessive production of free radicals associated with diabetes. Preliminary molecular docking and 500 ns molecular dynamics (MD) simulations were carried out on compounds 3k, 8i, 8k, and 8p–8s to support and interpret the experimental biological findings qualitatively. Full article

Two pyrene derivatives, substituted at position 1 with isoxazole or NH-pyrazole, were synthesized in 85–87% yield starting from 1-acetylpyrene and via the cyclocondensation reaction of a β-enaminone intermediate with hydroxylamine or hydrazine. The photophysics of the two 5-(1-pyrenyl)-1,2-azoles were explored, revealing that only the isoxazole derivative exhibits good emission properties (ϕ_F ≥ 74%) but without solvatofluorochromism behavior. However, both probes exhibited noticeable photophysics in the aggregated state (in the presence of H₂O and/or in the solid state) and through acid–base interactions (using TFA and TBACN), leveraging the basic and acidic character of the analyzed 1,2-azoles, which was also investigated by ¹H NMR spectroscopy. Therefore, the selective incorporation of N-heteroaromatic units into the pyrene scaffold effectively modulates the photophysics and environmental sensitivity of the corresponding probes. Full article

Herein, we report a one-pot palladium- and ligand-free tandem Sonogashira coupling/regioselective 6-endo-dig oxacyclization reaction of 2,4-diiodo-1-methyl-imidazole-5-carboxylic acid with terminal alkynes mediated by Copper(I). This impressive approach offers a straightforward, practical, and efficient tandem procedure for accessing 2-alkynylated pyrano[4,3-d]imidazol-4-one in moderate to good yields with an exclusive 6-endo-dig oxacyclization. Notably, this cost-effective methodology demonstrates broad substrate compatibility with various commercially available aliphatic and (hetero)aromatic terminal alkynes. Furthermore, DFT studies were performed to elucidate the origin of this regioselective 6-endo-dig oxacyclization reaction. Full article

Background: Natural products play a crucial role in cancer treatment due to their ability to selectively target cancer cells. Andrographolide, a major constituent of Andrographis paniculata, exhibits potential anticancer properties. Considering the pharmacological importance of nitrogen-based heteroaromatic scaffolds, particularly pyrazole motifs, this study aimed to integrate the pyrazole pharmacophore with the andrographolide scaffold to develop novel therapeutic candidates. Methods: Twenty novel 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide were synthesized and characterized using UV-Vis, FT-IR, NMR, and HRMS. Initial anticancer screening was conducted by the National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The most promising compound, 1f (R = 4-F), was selected for further biological evaluation in the MDA-MB-231 breast cancer cell line. Results: The MTT assay results demonstrated that compound 1f exhibited strong, dose-dependent anti-proliferative effects. The apoptosis analysis of 1f revealed a time-dependent increase in apoptotic cells, and cell cycle studies indicated S phase arrest in MDA-MB-231 cells. Antioxidant activity via the DPPH assay identified compounds 1b (R = 3-NO₂) and 2b (R = 3-NO₂) as the most effective radical scavengers. The most active compounds were also evaluated for drug-likeness using in silico Lipinski’s rule assessments. Conclusions: The synthesized 3,19-(N-phenyl-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide exhibited promising anticancer and antioxidant properties. Among them, compound 1f showed the most significant activity, supporting its potential as a lead candidate for further anticancer drug development. Full article

Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies. Full article

Pyrazolopyridines and pyrazolopyrimidines are 5:6 aza-fused N-heteroaromatic compounds (NHACs) comprising a pyrazole ring fused to a pyridine or pyrimidine ring. They exhibit dipolar behavior due to their π-excessive and π-deficient characteristics conferred by their five- and six-membered rings. These features favor their stability, reactivity, and structural diversity, offering numerous modular and functional derivatives (e.g., pyrazolo[1,2-a]pyridines, pyrazolo[1,5-a]pyrimidines, etc.). They have been utilized to obtain relevant chemicals in pharmaceuticals, photophysics, industry, and materials science; thus, their synthesis is highly desirable for discovering novel or improved applications. Therefore, this review focuses on recent advances in the synthesis and applications of these compounds, considering reports from the last decade (2015–2024), with particular emphasis on photophysics, as they contain dipolar 5:6 aza-fused rings as essential scaffolds for this purpose. Full article