Supermolecular Confined Silicon Phosphorescence Nanoprobes for Time-Resolved Hypoxic Imaging Analysis.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to ∼158.7 µs) and high quantum yield (up to ∼30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from ∼0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (∼108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O2), offering opportunities for precision imaging analysis in a hypoxic environment.

Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLGA Nanoparticles Loaded with R848 for Treating Colon Cancer.

Purpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-ß-CD). Methods: R848-loaded PLGA nanoparticles modified with 2-HP-ß-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo. Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-ß-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival. Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.

Transport mechanism and pharmacology of the human GlyT1.

The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.

Zeolitic Imidazole Framework/Silica Nanocomposite for Targeted Cancer Therapeutics: Comparative Study of Chemo-Drug Cisplatin (CPt) and Green Platinum (GPt) Efficacy.

A chemo-drug such as cisplatin is effective for cancer treatment but remains non-specific, is susceptible to drug resistance, and induces several side effects on organ systems. Zeolitic imidazolate framework-8, a type of MOF, has gained attention, including as a drug delivery method for targeted cancer therapeutics. In this study, ZIF-8/Silica nanocomposite was synthesized using a one-pot hydrothermal technique using the Stober technique. We studied the effect of phyto-synthesized GPt and chemo-drug cisplatin CPt on ZIF-8/Silica for targeted efficacy of cancer therapy. The texture, morphology, and chemical environment of Pt on ZIF-8/Silica were analyzed using different characterization techniques such as XRD, FT-IR, BET, diffuse reflectance spectroscopy, SEM-EDX, TEM, zeta potential, and TGA analysis. The isothermal behavior of CPt and GPt adsorption was investigated using isotherm models like Langmuir, Freundlich, and Temkin isotherm. The adsorption kinetics indicating the adsorption efficiency of GPt and CPt are influenced by the concentration of Pt complex and the adsorption sites of ZIF-8/Silica. A high entrapment efficiency and loading capacity of GPt (86% and 4.3%) and CPt (91% and 4.5%) were evident on ZIF-8/Silica. The nanocomposite showed a pH-sensitive Pt release using a dialysis membrane technique. For instance, a high release of GPt (93%) was observed under pH = 6.6 in 72 h, while the release reduced to 50% at pH 7.4 in 72 h. The anti-cancer activity of nanoformulations was studied in vitro using MCF7 (breast cancer cells) and HFF-1 (human foreskin fibroblast) cells. The findings demonstrated that GPt is as effective as CPt; the EC50 value for MCF7 cells treated with ZIF-8/Silica/Cp/PEG was 94.86 µg/mL, whereas for ZIF-8/Silica/GPt/PEG it was 60.19 µg/mL.

Microbial-based metabolites associated with degradation of imidacloprid and its impact on stress-responsive proteins.

Imidacloprid (IMD), a neonicotinoid insecticide, is intensively used in agricultural fields for effective protection against aphids, cane beetles, thrips, stink bugs, locusts, etc., is causing serious environmental concerns. In recent years, seed treatment with Imidacloprid is being practiced mainly to prevent sucking insect pests. In India, due to the increase in application of this insecticide residue has been proven to have an impact on the quality of soil and water. In view of this, the current investigation is focussed on sustainable approach to minimize the residual effect of IMD in agricultural fields. The present study reveals a most promising imidacloprid resistant bacterium Lysinibacillus fusiformis IMD-Bio5 strain isolated from insecticide-contaminated soil. The isolated bacterial strain upon tested for its biodegradation potential on mineral salt medium (MSM) showed a significant survival growth at 150 g/L of IMD achieved after 3 days, whereas immobilized cells on MSM amended with 200 g/L of IMD as the sole carbon source provided degradation of 188 and 180 g/L of IMD in silica beads and sponge matrices, respectively. The liquid chromatography mass spectrometry was performed to test the metabolite responsive for IMD biodegradation potential of L. fusiformis IMD-Bio5 which showed the induced activity of the metabolite 6-Chloronicotinic acid. Furthermore, as compared to the untreated control, the Lysinibacillus fusiformis IMD-Bio5 protein profile revealed a range of patterns showing the expression of stress enzymes. Thus, results provided a most effective bacterium enabling the removal of IMD-like hazardous contaminants from the environment, which contributes to better agricultural production and soil quality, while long-term environmental advantages are restored.

Dissolution and regeneration of starch in hydroxyl-functionalized ionic liquid aqueous solution.

There have been continuous quests for suitable solvents for starch, given the importance of effective starch dissolution in its modification and subsequent materials production. In light of this, the potential of hydroxyl-functionalized ionic liquid (IL) as a promising solvent for starch was investigated. Within this study, a hydroxyl-functionalized IL 1-(2,3-dihydroxypropyl)-3-methylimidazole chloride ([Dhpmim][Cl]) was synthesized, and the dissolution of starch in this IL and its aqueous solutions was examined. Starch (5.35 wt%) was completely dissolved in [Dhpmim][Cl] within 2 h at 100 °C. The solubility of starch in [Dhpmim][Cl]-water mixtures initially increased and then decreased with rising water content. The optimal ratio was found to be 1:9 (wt/wt) water:[Dhpmim][Cl], achieving the highest solubility at 9.28 wt%. Density functional theory (DFT) simulations elucidated the possible interactions between starch and solvents. After dissolution and regeneration in the 1:9 water:[Dhpmim][Cl] mixture, starch showed no discernible change in the molecular structure, with no derivatization reaction observed. Regenerated starch exhibited a transformation in crystalline structure from A-type to V-type, and its relative crystallinity (12.4 %) was lower than that of native starch (25.2 %), resulting in decreased thermal stability. This study suggests that the hydroxyl-functionalized IL, [Dhpmim][Cl], and its aqueous solutions serve as effective solvents for starch dissolution.

Discovery of novel dihydronaphthalene-imidazole ligands as potential inhibitors of Staphylococcus aureus multidrug resistant NorA efflux pump: A combination of experimental and in silico molecular docking studies.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

Performance of 4,5-diphenyl-1H-imidazole derived highly selective 'Turn-Off' fluorescent chemosensor for iron(III) ions detection and biological applications.

Two fluorescent chemosensors, denoted as chemosensor 1 and chemosensor 2, were synthesized and subjected to comprehensive characterization using various techniques. The characterization techniques employed were Fourier-transform infrared (FTIR), proton (1 H)- and carbon-13 (13 C)-nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization (ESI) mass spectrometry, and single crystal X-ray diffraction analysis. Chemosensor 1 is composed of a 1H-imidazole core with specific substituents, including a 4-(2-(4,5-c-2-yl)naphthalene-3-yloxy)butoxy)naphthalene-1-yl moiety. However, chemosensor 2 features a 1H-imidazole core with distinct substituents, such as 4-methyl-2-(4,5-diphenyl-1H-imidazole-2-yl)phenoxy)butoxy)-5-methylphenyl. Chemosensor 1 crystallizes in the monoclinic space group C2/c. Both chemosensors 1 and 2 exhibit a discernible fluorescence quenching response selectively toward iron(III) ion (Fe3+ ) at 435 and 390 nm, respectively, in dimethylformamide (DMF) solutions, distinguishing them from other tested cations. This fluorescence quenching is attributed to the established mechanism of chelation quenched fluorescence (CHQF). The binding constants for the formation of the 1 + Fe3+ and 2 + Fe3+ complexes were determined using the modified Benesi-Hildebrand equation, yielding values of approximately 2.2 × 103 and 1.3 × 104 M-1 , respectively. The calculated average fluorescence lifetimes for 1 and 1 + Fe3+ were 2.51 and 1.17 ns, respectively, while for 2 and 2 + Fe3+ , the lifetimes were 1.13 and 0.63 ns, respectively. Additionally, the applicability of chemosensors 1 and 2 in detecting Fe3+ in live cells was demonstrated, with negligible observed cell toxicity.

Biospeciation of Oxidovanadium(IV) Imidazolyl-Carboxylate Complexes and Their Action on Glucose-Stimulated Insulin Secretion in Pancreatic Cells.

The reaction of the vanadyl ion (VO2+) with imidazole-4-carboxylic acid (Im4COOH), imidazole-2-carboxylic acid (Im2COOH) and methylimidazole-2-carboxylic acid (MeIm2COOH), respectively, in the presence of small bioligands (bL) [oxalate (Ox), lactate (Lact), citrate (Cit) and phosphate (Phos)] and high-molecular-weight (HMW) human serum proteins [albumin (HSA) and transferrin (hTf)] were studied in aqueous solution using potentiometric acid-base titrations. The species distribution diagrams for the high-molecular-mass (HMM) proteins with oxidovanadium(IV) under physiological pH were dominated by VO(HMM)2, VOL(HMM) for unsubstituted ligands (L- = Im4COO- and Im2COO-). However, for the N-substituted MeIm2COOH, the species distribution diagrams under physiological pH were dominated by VOL2, VO(HMM)2 and VO2L2(HMM). These species were further confirmed by LC-MS, MALDI-TOF-MS and EPR studies. The glucose-stimulated insulin secretion (GSIS) action of the complexes was investigated using INS-1E cells at a 1 µM concentration, which was established through cytotoxicity studies via the MTT assay. The neutral complexes, especially VO(MeIm2COO)2, showed promising results in the stimulation of insulin secretion than the cationic [VO(MeIm2CH2OH)2]2+ complex and the vanadium salt. Oxidovanadium(IV) complexes reduced insulin stimulation significantly under normoglycaemic levels but showed positive effects on insulin secretion under hyperglycaemic conditions (33.3 mM glucose media). The islets exposed to oxidovanadium(IV) complexes under hyperglycaemic conditions displayed a significant increase in the stimulatory index with 1.19, 1.75, 1.53, 1.85, 2.20 and 1.29 observed for the positive control (sulfonylurea:gliclazide), VOSO4, VO(Im4COO)2, VO(Im2COO)2, VO(MeIm2COO)2 and VO(MeIm2CH2OH)22+, respectively. This observation showed a potential further effect of vanadium complexes towards type 2 diabetes and has been demonstrated for the first time in this study.

Comparative investigation into the anticancer activity of analogs of marine coelenterazine and coelenteramine.

Cancer is still one of the most challenging diseases to treat, making the pursuit for novel molecules with potential anticancer activity an important research topic. Herein, we have performed a comparative investigation into the anticancer activity of analogs of marine coelenterazine and coelenteramine. The former is a well-known bioluminescent substrate, while the latter is a metabolic product of the resulting bioluminescent reaction. While both types of analogs showed anticancer activity toward lung and gastric cancer cell lines, we have obtained data that highlight relevant differences between the activity of these two types of compounds. More specifically, we observed relevant differences in structure-activity relationships between these types of compounds. Also, coelenteramine analogs showed time-dependent activity, while coelenterazine-based compounds usually present time-independent activity. Coelenterazine analogs also appear to be relatively safer toward noncancer cells than coelenteramine analogs. There was also seen a correlation between the activity of the coelenterazine-based compounds and their light-emission properties. Thus, these results further indicate the potential of the marine coelenterazine chemi-/bioluminescent system as a source of new molecules with anticancer activity, while providing more insight into their modes of action.

Supramolecular interactions between functional saccharide-based ionic liquids and cellulose macromolecules.

Interactions between polysaccharides and ionic liquids (ILs) at the molecular level are essential to elucidate the dissolution and/or plasticization mechanism of polysaccharides. Herein, saccharide-based ILs (SILs) were synthesized, and cellulose membrane was soaked in different SILs to evaluate the interactions between SILs and cellulose macromolecules. The relevant results showed that the addition of SILs into cellulose can effectively reduce the intra- and/or inter-molecular hydrogen bonds of polysaccharides. Glucose-based IL showed the intensest supramolecular interactions with cellulose macromolecules compared to sucrose- and raffinose-based ILs. Two-dimensional correlation and perturbation-correlation moving window Fourier transform infrared techniques were for the first time used to reveal the dynamic variation of the supramolecular interactions between SILs and cellulose macromolecules. Except for the typical HO⋯H interactions of cellulose itself, stronger -Cl⋯HO hydrogen bonding interactions were detected in the specimen of SILs-modified cellulose membranes. Supramolecular interactions of -Cl⋯H, HO⋯H, C-Cl⋯H, and -C=O⋯H between SILs and cellulose macromolecules sequentially responded to the stimuli of temperature. This work provides a new perspective to understanding the interaction mechanism between polysaccharides and ILs, and an avenue to develop the next-generation ILs for dissolving or thermoplasticizing polysaccharide materials.

Heme Spin Distribution in the Substrate-Free and Inhibited Novel CYP116B5hd: A Multifrequency Hyperfine Sublevel Correlation (HYSCORE) Study.

The cytochrome P450 family consists of ubiquitous monooxygenases with the potential to perform a wide variety of catalytic applications. Among the members of this family, CYP116B5hd shows a very prominent resistance to peracid damage, a property that makes it a promising tool for fine chemical synthesis using the peroxide shunt. In this meticulous study, we use hyperfine spectroscopy with a multifrequency approach (X- and Q-band) to characterize in detail the electronic structure of the heme iron of CYP116B5hd in the resting state, which provides structural details about its active site. The hyperfine dipole-dipole interaction between the electron and proton nuclear spins allows for the locating of two different protons from the coordinated water and a beta proton from the cysteine axial ligand of heme iron with respect to the magnetic axes centered on the iron. Additionally, since new anti-cancer therapies target the inhibition of P450s, here we use the CYP116B5hd system-imidazole as a model for studying cytochrome P450 inhibition by an azo compound. The effects of the inhibition of protein by imidazole in the active-site geometry and electron spin distribution are presented. The binding of imidazole to CYP116B5hd results in an imidazole-nitrogen axial coordination and a low-spin heme FeIII. HYSCORE experiments were used to detect the hyperfine interactions. The combined interpretation of the gyromagnetic tensor and the hyperfine and quadrupole tensors of magnetic nuclei coupled to the iron electron spin allowed us to obtain a precise picture of the active-site geometry, including the orientation of the semi-occupied orbitals and magnetic axes, which coincide with the porphyrin N-Fe-N axes. The electronic structure of the iron does not seem to be affected by imidazole binding. Two different possible coordination geometries of the axial imidazole were observed. The angles between gx (coinciding with one of the N-Fe-N axes) and the projection of the imidazole plane on the heme were determined to be -60° and -25° for each of the two possibilities via measurement of the hyperfine structure of the axially coordinated 14N.

A conformationally-locked p-hydroxybenzylidene imidazolinone derivative for detecting Aß42 aggregation.

Alzheimer's disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aß species, amyloid-ß 42 (Aß42) aggregates are proposed to be more neurotoxic than that of Aß40, and oligomeric Aß42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aß42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aß42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aß42 aggregation over that of Aß40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aß species in AD.

Synthesis and Evaluation of Imidazole Derivatives Bearing Imidazo[2,1-b] [1,3,4]thiadiazole Moiety as Antibacterial Agents.

BACKGROUND: Drug-resistant infections kill hundreds of thousands of people globally every year. In previous work, we found that tri-methoxy- and pyridine-substituted imidazoles show strong antibacterial activities. OBJECTIVE: The aim of this work was to investigate the antibacterial activities and bacterial resistances of imidazoles bearing an aromatic heterocyclic, alkoxy, or polycyclic moiety on the central ring. METHODS: Three series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4- yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (13a-e, 14a-d, and 15a-f) were synthesized and their antibacterial activity was evaluated. The structures were confirmed by their 1H NMR, 13C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive, Gramnegative, and multidrug-resistant bacterial strains. RESULTS: More than half of the compounds showed moderate or strong antibacterial activity. Among them, compound 13e (MICs = 1-4 µg/mL) showed the strongest activity against Gram-positive and drug-resistant bacteria as well as high selectivity against Gram-negative bacteria. Furthermore, it showed no cytotoxicity against HepG2 cells, even at 100 µM, and no hemolysis at 20 µM. CONCLUSION: These results indicate that compound 13e is excellent candicate for further study as a potential antibacterial agent.

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.

Heterobifunctional Cross-Linker with Dinitroimidazole and N-Hydroxysuccinimide Ester Motifs for Protein Functionalization and Cysteine-Lysine Peptide Stapling.

A heterobifunctional cross-linker with one sulfhydryl-reactive dinitroimidazole end and another amine-reactive N-hydroxysuccinimide (NHS) ester end was designed and synthesized. The two motifs of this cross-linker, dinitroimidazole and NHS ester, proved to react with thiol and amine, respectively, in an orthogonal way. The cross-linker was further applied to construct stapled peptides of different sizes and mono- and dual functionalization (including biotinylation, PEGylation, and fluorescence labeling) of protein.

One-pot synthesis, spectral characterization, biological evaluation, molecular docking studies and in silico ADME/Tox profiling of new 2,4,5 triaryl imidazole derivatives as anti tubercular agents.

BACKGROUND: Tuberculosis still looms large on the global epidemiological radar and warrants continuous effort in the direction of developing new anti TB drugs to battle evolving resistance mechanisms of the causative agent Mycobacterium tuberculosis. METHODS: In the present paper, synthesis of n has been attempted. All the synthesized compounds were characterized by 1H-NMR, 13C-NMR, IR and Mass spectroscopy. Anti TB profile of the synthesized compounds were tested by MABA assay employing M.tb H37Rv strain. RESULTS: Two compounds namely N-(2-acetoxy)-N-methyl-4-(4,5-diphenyl-1H-imidazole-2-yl) benzenamine and 2-(N-(4-(4,5-bis(4-methoxyphenyl)-1H-imidazole-2-yl)phenyl)-N-methylamino) ethanol exhibited impressive anti TB inhibitory potential with an MIC of 3.125 µg/mL. To visualize the binding interactions of the active compounds molecular docking studies were carried out on putative target M. tuberculosis Glutamine synthetase (MtGS) in complex with a trisubstituted imidazole. To ascertain their drug likeliness and safety profile in silico ADME/T prediction was performed on all the synthesized compounds. CONCLUSION: Three compounds 1a, 2g and 2c exhibited good inhibitory potency against M.tb H37Rv and all the synthesized compounds also show promising antifungal activity.

Structural and Functional Insights into the Biomineralized Zeolite Imidazole Frameworks.

Biomineralization is a natural process of mineral formation mediated by biomacromolecules, allowing access to hierarchical structures integrating biological, chemical, and material properties. In this contribution, we comprehensively investigate the biomineralization of zeolite imidazole frameworks (ZIFs) for one-step synthesis of an enzyme-MOF biocomposite, in terms of differential crystallization behaviors, fine microstructure of resultant ZIF biominerals, the enzyme's conformation evolution, and protective effect of ZIF mineral. We discover that the biomineralization ability is ZIF organic linker dependent and the biocatalytic function is highly related to the ZIF mineral species and their distinguishable topologies and defect structures. Importantly, a side-by-side analysis suggests that the protective effect of ZIF mineral toward the hosted enzyme is highly associated with the synergistic effect of size dimension and chemical microenvironment of the ZIF pores. This work provides important insight into the ZIF-dependent biomineralization behaviors and highlights the important role of the ZIF microstructure in its biocatalytic activity and durability, which has been underestimated previously.

Synthesis and Biophysical and Biological Studies of N-Phenylbenzamide Derivatives Targeting Kinetoplastid Parasites.

The AT-rich mitochondrial DNA (kDNA) of trypanosomatid parasites is a target of DNA minor groove binders. We report the synthesis, antiprotozoal screening, and SAR studies of three series of analogues of the known antiprotozoal kDNA binder 2-((4-(4-((4,5-dihydro-1H-imidazol-3-ium-2-yl)amino)benzamido)phenyl)amino)-4,5-dihydro-1H-imidazol-3-ium (1a). Bis(2-aminoimidazolines) (1) and bis(2-aminobenzimidazoles) (2) showed micromolar range activity against Trypanosoma brucei, whereas bisarylimidamides (3) were submicromolar inhibitors of T. brucei, Trypanosoma cruzi, and Leishmania donovani. None of the compounds showed relevant activity against the urogenital, nonkinetoplastid parasite Trichomonas vaginalis. We show that series 1 and 3 bind strongly and selectively to the minor groove of AT DNA, whereas series 2 also binds by intercalation. The measured pKa indicated different ionization states at pH 7.4, which correlated with the DNA binding affinities (ΔTm) for series 2 and 3. Compound 3a, which was active and selective against the three parasites and displayed adequate metabolic stability, is a fine candidate for in vivo studies.

α-amylase inhibition and in silico studies of novel naphtho[2,3-d]imidazole-4,9-dione linked N-acyl hydrazones.

Aim: To enrich the pool of α-amylase inhibitors to manage Type 2 diabetes. Methods: Synthesis, conformational study, α-amylase inhibitory action and various in silico studies of novel N'-(arylbenzylidene)-2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-1-yl)acetohydrazides carried out. Results: Compound H6 demonstrated the highest activity (IC50 = 0.0437 µmol mL-1) among the tested compounds. Structure-activity relationship study suggested that variable substitution at the aryl ring has a pivotal role in determining the inhibitory action of tested compounds. Docking simulations of the most active compound (H6) confirmed its interaction potential with active site residues of A. oryzae α-amylase. The root-mean-square deviation fluctuations substantiated the stability of protein-ligand complex. Absorption, distribution, metabolism and excretion prediction revealed optimal values for absorption, distribution, metabolism and excretion parameters. Conclusion: The developed molecules could be beneficial for the development of novel α-amylase inhibitors to treat Type 2 diabetes.