Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1.

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.

Rapid reaction studies on the chemistry of flavin oxidation in urocanate reductase.

Urocanate reductase (UrdA) is a bacterial flavin-dependent enzyme that reduces urocanate to imidazole propionate, enabling bacteria to use urocanate as an alternative respiratory electron acceptor. Elevated serum levels of imidazole propionate are associated with the development of type 2 diabetes, and, since UrdA is only present in humans in gut bacteria, this enzyme has emerged as a significant factor linking the health of the gut microbiome and insulin resistance. Here, we investigated the chemistry of flavin oxidation by urocanate in the isolated FAD domain of UrdA (UrdA') using anaerobic stopped-flow experiments. This analysis unveiled the presence of a charge-transfer complex between reduced FAD and urocanate that forms within the dead time of the stopped-flow instrument (∼1 ms), with flavin oxidation subsequently occurring with a rate constant of ∼60 s-1. The pH dependence of the reaction and analysis of an Arg411Ala mutant of UrdA' are consistent with Arg411 playing a crucial role in catalysis by serving as the active site acid that protonates urocanate during hydride transfer from reduced FAD. Mutational analysis of urocanate-binding residues suggests that the twisted conformation of urocanate imposed by the active site of UrdA' facilitates urocanate reduction. Overall, this study provides valuable insight into the mechanism of urocanate reduction by UrdA.

RNA polymerase II trapped on a molecular treadmill: Structural basis of persistent transcriptional arrest by a minor groove DNA binder.

Elongating RNA polymerase II (Pol II) can be paused or arrested by a variety of obstacles. These obstacles include DNA lesions, DNA-binding proteins, and small molecules. Hairpin pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA in a sequence-specific manner and induce strong transcriptional arrest. Remarkably, this Py-Im-induced Pol II transcriptional arrest is persistent and cannot be rescued by transcription factor TFIIS. In contrast, TFIIS can effectively rescue the transcriptional arrest induced by a nucleosome barrier. The structural basis of Py-Im-induced transcriptional arrest and why TFIIS cannot rescue this arrest remain elusive. Here we determined the X-ray crystal structures of four distinct Pol II elongation complexes (Pol II ECs) in complex with hairpin Py-Im polyamides as well as of the hairpin Py-Im polyamides-dsDNA complex. We observed that the Py-Im oligomer directly interacts with RNA Pol II residues, introduces compression of the downstream DNA duplex, prevents Pol II forward translocation, and induces Pol II backtracking. These results, together with biochemical studies, provide structural insight into the molecular mechanism by which Py-Im blocks transcription. Our structural study reveals why TFIIS fails to promote Pol II bypass of Py-Im-induced transcriptional arrest.

"All in One" Strategy for Achieving Superprotonic Conductivity by Incorporating Strong Acids into a Robust Imidazole-Linked Covalent Organic Framework.

The fabrication of solid-state proton-conducting electrolytes possessing both high performance and long-life reusability is significant but challenging. An "all-in-one" composite, H3PO4@PyTFB-1-SO3H, including imidazole, sulfonic acid, and phosphoric acid, which are essential for proton conduction, was successfully prepared by chemical post-modification and physical loading in the rationally pre-synthesized imidazole-based nanoporous covalent organic framework (COF), PyTFB-1. The resultant H3PO4@PyTFB-1-SO3H exhibits superhigh proton conductivity with its value even highly up to 1.15 × 10-1 S cm-1 at 353 K and 98% relative humidity (RH), making it one of the highest COF-based composites reported so far under the same conditions. Experimental studies and theoretical calculations further confirmed that the imidazole and sulfonic acid groups have strong interactions with the H3PO4 molecules and the synergistic effect of these three groups dramatically improves the proton conductivity properties of H3PO4@PyTFB-1-SO3H. This work demonstrated that by aggregating multiple proton carriers into one composite, effective proton-conducting electrolyte can be feasibly achieved.

Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV.

BACKGROUND: The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. METHODS: Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). RESULTS: Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048). CONCLUSIONS: PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

Mutual influence of non-covalent interactions formed by imidazole: A systematic quantum-chemical study.

Imidazole is a five-membered heterocycle that is part of a number of biologically important molecules such as the amino acid histidine and the hormone histamine. Imidazole has a unique ability to participate in a variety of non-covalent interactions involving the NH group, the pyridine-like nitrogen atom or the π-system. For many biologically active compounds containing the imidazole moiety, its participation in formation of hydrogen bond NH⋯O/N and following proton transfer is the key step of mechanism of their action. In this work a systematic study of the mutual influence of various paired combinations of non-covalent interactions (e.g., hydrogen bonds and π-interactions) involving the imidazole moiety was performed by means of quantum chemistry (PW6B95-GD3/def2-QZVPD) for a series of model systems constructed based on analysis of available x-ray data. It is shown that for considered complexes formation of additional non-covalent interactions can only enhance the proton-donating ability of imidazole. At the same time, its proton-accepting ability can be both enhanced and weakened, depending on what additional interactions are added to a given system. The mutual influence of non-covalent interactions involving imidazole can be classified as weak geometric and strong energetic cooperativity-a small change in the length of non-covalent interaction formed by imidazole can strongly influence its strength. The latter can be used to develop methods for controlling the rate and selectivity of chemical reactions involving the imidazole fragment in larger systems. It is shown that the strong mutual influence of non-covalent interactions involving imidazole is due to the unique ability of the imidazole ring to effectively redistribute electron density in non-covalently bound systems with its participation.

Modulation of Buried Interface by 1-(3-aminopropyl)-Imidazole for Efficient Inverted Formamidinium-Cesium Perovskite Solar Cells.

Considering the direct influence of substrate surface nature on perovskite (PVK) film growth, buried interfacial engineering is crucial to obtain ideal perovskite solar cells (PSCs). Herein, 1-(3-aminopropyl)-imidazole (API) is introduced at polytriarylamine (PTAA)/PVK interface to modulate the bottom property of PVK. First, the introduction of API improves the growth of PVK grains and reduces the Pb2+ defects and residual PbI2 present at the bottom of the film, contributing to the acquisition of high-quality PVK film. Besides, the presence of API can optimize the energy structure between PVK and PTAA, which facilitates the interfacial charge transfer. Density functional theory (DFT) reveals that the electron donor unit (R-C ═ N) of the API prefers to bind with Pb2+ traps at the PVK interface, while the formation of hydrogen bonds between the R-NH2 of API and I- strengthens the above binding ability. Consequently, the optimum API-treated inverted formamidinium-cesium (FA/Cs) PSCs yields a champion power conversion efficiency (PCE) of 22.02% and exhibited favorable stability.

Biomimetic Helical Hydrogen Bonded Organic Framework Membranes for Efficient Uranium Recovery from Seawater.

Inspired by the uranyl-imidazole interactions via nitrogen's (N's) of histidine residues in single helical protein assemblies with open framework geometry that allows through migration/coordination of metal ions. Here, preliminary components of a stable hydrogen-bonded organic framework (HOF) are designed to mimic the stable single helical open framework with imidazole residues available for Uranium (U) binding. The imidazolate-HOF (CSMCRIHOF2-S) is synthesized with solvent-directed H-bonding in 1D array and tuned hydrophobic CH-π interactions leading to single helix pattern having enhanced hydrolytic stability. De-solvation led CSMCRIHOF2-P with porous helical 1D channels are transformed in a freestanding thin film that showcased improved mass transfer and adsorption of uranyl carbonate. CSMCRIHOF2-P thin film can effectively extract ≈14.8 mg g-1 in 4 weeks period from natural seawater, with > 1.7 U/V (Uranium to Vanadium ratio) selectivity. This strategy can be extended for rational designing of hydrolytically stable, U selective HOFs to realize the massive potential of the blue economy toward sustainable energy.

Nucleic acid-based small molecules as targeted transcription therapeutics for immunoregulation.

Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, the primary research focus in therapeutic gene modulation has been on small-molecule drugs that target epigenetic enzymes and critical signaling pathways. However, nucleic acid-based small molecules have gained popularity in recent years for their amenability to be pre-designed and realize operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole-imidazole polyamides (PIPs) are well-established DNA-based small-molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence-targeted specificity, versatile regulatory efficiency, and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanisms, and their potential as targeted transcription therapeutics for disease treatment by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.

Tunable Metal-Free Imidazole-Benzimidazole Electrocatalysts for Oxygen Reduction in Aqueous Solutions.

A series of metal-free imidazole-benzimidazole catalysts (ImBenz-H, ImBenz-NO2 , ImBenz-OCH3 ) for oxygen reduction reaction (ORR) were prepared. We demonstrate that the electrocatalytic O2 reduction by ImBenz-NO2 with the electron-withdrawing group showed high selectivity toward H2 O with the number of electrons transferred (n=3.7) in a neutral aqueous solution. The highest ORR selectivity toward H2 O2 was achieved using ImBenz-H (n=2.4) in an alkaline solution. Electrochemical studies of reaction kinetics disclosed that the highest turnover frequencies were obtained from ImBenz-H in both neutral and alkaline aqueous solutions. The results prove that the ORR selectivity is tunable by modulating the substituent of the ImBenz catalysts. Furthermore, DFT calculations suggested that the ORR mechanism of ImBenz-H involves the electron transfer from imidazole-benzimidazole to O2 resulting in the formation of H2 O2 which supports the redox active properties of the catalysts ImBenz.

Synthesis, Characterization, and Cytotoxicity Evaluation of Novel Water-Soluble Cationic Platinum(II) Organometallic Complexes with Phenanthroline and Imidazolic Ligands.

Platinum-based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water-soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η1-C2H4OEt)(phen)] (1, phen=1,10-phenanthroline) precursor, specifically [Pt(NH3)(η1-C2H4OEt)(phen)]Cl (2), [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl (3), and [Pt(1-hexyl-1H-benzo[d]imidazole)(η1-C2H4OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki-1), and normal human renal cells (HK-2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki-1) among the tested complexes, compared to healthy cells (HK-2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum-based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties.

Oxidation-state sensitive light-induced dynamics of Ruthenium-4H-Imidazole complexes.

Oxidized molecular states are key intermediates in photo-induced redox reactions, e. g., intermolecular charge transfer between photosensitizer and catalyst in photoredox catalysis. The stability and longevity of the oxidized photosensitizer is an important factor in optimizing the respective light-driven reaction pathways. In this work the oxidized states of ruthenium(II)-4H-imidazole dyes are studied. The ruthenium complexes constitute benchmark photosensitizers in solar energy interconversion processes with exceptional chemical stability, strong visible light absorption, and favourable redox properties. To rationalize the light-induced reaction in the oxidized ruthenium(III) systems, we combine UV-vis absorption, resonance Raman, and transient absorption spectroelectrochemistry (SEC) with time-dependent density functional theory (TDDFT) calculations. Three complexes are compared, which vary with respect to their coordination environment, i. e., combining an 4H-imidazole with either 2,2'-bipyridine (bpy) or 2,2';6'2"-terpyridine (tpy) coligands, and chloride or isothiocyanate ligands. While all oxidized complexes have similar steady state absorption properties, their excited state kinetics differ significantly; the study thus opens the doorway to study the light-driven reactivity of oxidized molecular intermediates in intermolecular charge transfer cascades.

Ferrocenyl Azoles: Versatile N-Containing Heterocycles and their Anticancer Activities.

The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.

Discovery of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent and selective heparanase-1 inhibitor utilizing an improved synthetic approach.

Heparanase-1 (HPSE1) is an endo-ß-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson's reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-ß-d-glucuronidase (GUSß) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson's reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSß and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSß and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.

Photochemistry of Imidazole-2-carbaldehyde in Droplets as a Potential Source of H2O2 and Its Oxidation of SO2.

Hydrogen peroxide (H2O2) plays a crucial role as an oxidizing agent within the tropospheric environment, making a substantial contribution to sulfate formation in hydrated aerosols and cloud and fog droplets. Field observations show that high levels of H2O2 are often observed in heavy haze events and polluted air. However, the source of H2O2 remains unclear. Here, using the droplets formed in situ by the deliquescence of hygroscopic compounds under a high relative humidity (RH), the formation of H2O2 by the photochemistry of imidazole-2-carbaldehyde (2-IC) under ultraviolet irradiation was explored. The results indicate that 2-IC produces IM-C•-OH and IM-C•═O radicals via H transfer itself to its excited triplet state and generates H2O2 and organic peroxides in the presence of O2, which has an evident oxidizing effect on SO2, suggesting the potential involvement of this pathway in the formation of atmospheric sulfate. H2O2 formation is limited in acidic droplets or droplets containing ammonium ions, and no H2O2 is detected in droplets containing nitrate, whereas droplets containing citric acid have an obvious promotion effect on H2O2 formation. These findings provide valuable insights into the behaviors of atmospheric photosensitizers, the source of H2O2, and the formation of sulfate in atmospheric droplets.

Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis.

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 µM and ≤ 41 µM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 µM), 1e (IC50 4.8 µM), and 1i (IC50 5.2 µM) exhibited potencies equivalent to MTZ (IC50 4.9 µM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 µM) and 48 h (IC50 2.1 µM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 µM) or low cytotoxicity (CC50 between 69 and 100 µM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.

Development of multifunctional pyrrole-imidazole polyamides that increase hepatocyte growth factor and suppress transforming growth factor-ß1.

PURPOSE: The DNA recognition peptide compounds pyrrole-imidazole (PI) polyamides bind to the minor groove and can block the binding of transcription factors to target sequences. To develop more PI polyamides as potential treatments for fibrotic diseases, including chronic renal failure, we developed multifunctional PI polyamides that increase hepatocyte growth factor (HGF) and decrease transforming growth factor (TGF)-ß1. METHODS: We designed seven PI polyamides (HGF-1 to HGF-7) that bind to the chicken ovalbumin upstream promoter transcription factor-1 (COUP-TF1) binding site of the HGF promoter sequence. We selected PI polyamides that increase HGF and suppress TGF-ß1 in human dermal fibroblasts (HDFs). FINDINGS: Gel shift assays showed that HGF-2 and HGF-4 bound the appropriate dsDNAs. HGF-2 and HGF-4 significantly inhibited the TGF-ß1 mRNA expression in HDFs stimulated by phorbol 12-myristate 13-acetate. HGF-2 and HGF-4 significantly inhibited the TGF-ß1 protein expression in HDFs with siRNA targeting HGF, indicating that HGF-2 and HGF-4 directly inhibited the expression of TGF-ß1. CONCLUSION: The designed and synthetic HGF PI polyamides targeting the HGF promoter, which increased the expression of HGF and suppressed the expression of TGF-ß, will be a potential practical medicine for fibrotic diseases, including progressive renal diseases.

Synthesis, Crystal Structure, DFT and Fluorescence Quenching Study of Novel syringe aldehyde-derived hydrazinyl-imidazole Based Schiff base Chemosensor.

In this study, we report a new syringe aldehyde-derived hydrazinyl-imidazole based fluorescent sensor (L) for sensitive detection of different inorganic quenchers (halide ions, bicarbonate ion, sulphide ion and transition metal ions). The chromophore (L) was obtained in good yield by the 1:1 condensation reaction of 2-hydrazino-4,5-dihydroimidazole hydrobromide and 4-hydroxy-3,5-dimethoxy benzaldehyde. L exhibited strong fluorescence in the visible region (around 380 nm) and its interaction with different quenchers was studied in details via fluorescence technique. For the halide ions series, its sensitivity is higher for NaF (Climit = 4 × 10- 4 M) than for NaCl while the fluorescence quenching occurred mainly through a dynamic process. Similar considerations were observed for HCO3- and S2- quencher too, when static and dynamic quenching take place simultaneously. Regarding transition metal ions, at a fixed ion concentration (4 × 10- 6 M), best performance was achieved for Cu2+ and Fe2+ (fluorescence intensity was reduced by 79% and 84.9% respectively), while for other metal ions, the sensor performance was evaluated and found to be very less (< 40%). Thus, minimum detection limits (10- 6 - 10- 5 M range) recommended the use of such derivatives as highly sensitive sensors capable to monitor delicate changes in varied environments.

Design and synthesis of novel imidazole-chalcone derivatives as microtubule protein polymerization inhibitors to treat cervical cancer and reverse cisplatin resistance.

Using the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activity with IC50 values ranging from 2.28 to 7.77 µM and a resistance index (RI) of 1.63, while showing minimal toxicity to normal H8 cells. When compound 5a was coadministered with cisplatin, the RI of cisplatin to HeLa/DDP cells decreased from 6.04 to 2.01, while compound 5a enhanced the fluorescence intensity of rhodamine 123 in HeLa/DDP cells. Further studies demonstrated that compound 5a arrested cells at the G2/M phase, induced apoptosis, reduced colony formation, inhibited cell migration, and inhibited cell invasion. Preliminary mechanistic studies revealed that compound 5a decreased the immunofluorescence intensity of α-/ß-tubulin in cancer cells, reduced the expression of polymerized α-/ß-tubulin, and increased the expression of depolymerized α-/ß-tubulin. Additionally, the molecular docking results demonstrate that compound 5a can interact with the tubulin colchicine binding site and generate multiple types of interactions. These results suggested that compound 5a has anticancer effects and significantly reverses cervical cancer resistance to cisplatin, which may be related to its inhibition of microtubule and P-glycoprotein (P-gp) activity.