A series of 9-fluoren-9-one substituents were synthesized and evaluated for imaging cerebral α7-nAChRs. -iodine substituted 9-fluorenone with high binding affinity ( = 9.3 nM) and selectivity was radiolabeled with I. Fully and studies of [I] have been performed. [I] exhibited well brain uptake with a peak concentration of 7.5 ± 0.9% ID/g in mice brains. Moreover, autoradiography studies and micro single-photon emission computed tomography (micro-SPECT/CT) dynamic imaging in mice confirmed its imaging properties. Besides, molecular docking and MD studies were also performed to interpret the binding mechanisms of the two series of ligands towards α7-nAChRs. To conclude, the -iodine substituted 9-fluorenone [I] could be a promising tracer for imaging α7-nAChRs.

The high storage capacities and excellent biocompatibilities of zinc(ii) metal-organic frameworks (Zn-MOFs) have made them outstanding candidates as drug delivery carriers. Recent studies on the pH-responsive processes based on carrier-drug interactions have proven them to be the most efficient and effective way to control the release profiles of drugs. To satisfy the ever-growing demand in cancer therapy, great efforts are being devoted to the development of methods to precisely control drug release and achieve targeted use of an active substance at the right time and place. In this review article, we discuss the diverse stimuli based on Zn-MOFs carriers that have been achieved upon external activation from single pH-stimulus-responsive or/and multiple pH-stimuli-responsive viewpoints. Also, the perspectives and future challenges in this type of carrier system are discussed.

Formyl peptide receptor 1 (FPR1) is expressed on a variety of immune system cells and is a key regulator of the inflammatory environment. Therefore, the development of FPR1 antagonists may represent a novel approach for modulating innate immunity and treating inflammatory diseases. Starting from a dipeptide scaffold that is structurally related to the natural product aurantiamide, we investigated the structure-activity relationships of the dipeptide (2,2')-, which was reported as an FPR1 antagonist. We found that the absolute configuration 2,2' was preferred to obtain potent and selective FPR1 antagonists. The structural modifications performed on the terminal fragments of the molecule suggest that the size of the substituents can greatly influence the interaction with FPR1. These compounds behaved as antagonists in human neutrophils and were able to inhibit formyl peptide-induced chemotaxis. Since FPR1 is a key regulator of the inflammatory environment, the dipeptide derivatives described here may represent important leads for the development of new potent and selective FPR1 antagonists for the treatment of neutrophil-mediated inflammatory diseases.

Orexin 2 receptor (OXR) is thought to play an important role in the arousal-promoting function, but its distribution and function in the pathophysiology of orexin-mediated disorders remains to be fully elucidated. In the present study, we synthesized and characterized a novel F-labeled 2,5-diarylnicotinamide (DAN) derivative as a potential positron emission tomography (PET) probe for imaging of OXR. In binding experiments, [F]DAN-1 selectively bound to OXR. In a biodistribution study using normal mice, [F]DAN-1 displayed moderate brain uptake (2.10% ID per g at 10 min post-injection). In addition, the radioactivity in the mouse brain at 30 min post-injection was significantly decreased by co-injection with nonradioactive DAN-1, but high nonspecific binding was observed. These results suggested that further structural modifications of [F]DAN-1 are needed to use it for imaging OXR in the brain.

The biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)-the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes-has been validated as a target through extensive genetic knockdown studies in . Moreover, it has been identified as the molecular target of the fungal natural product CJ-15,801 that shows selective activity against and the malaria parasite . As such, CJ-15,801 and 4'-phospho-CJ-15,801 (its metabolically active form) are excellent tool compounds for use in the development of new antimicrobial PPCS inhibitors. Unfortunately, further study and analysis of CJ-15,801 is currently being hampered by several unique challenges posed by its synthesis. In this study we describe how these challenges were overcome by using a robust palladium-catalyzed coupling to form the key -acyl vinylogous carbamate moiety with retention of stereochemistry, and by extensive investigation of protecting groups suited to the labile functional group combinations contained in this molecule. We also demonstrate that using TBAF for deprotection causes undesired off-target effects related to the presence of residual tertiary ammonium salts. Finally, we provide a new method for the chemoenzymatic preparation of 4'-phospho-CJ-15,801 on multi-milligram scale, after showing that chemical synthesis of the molecule is not practical. Taken together, the results of this study advances our pursuit to discover new antimicrobials that specifically target CoA biosynthesis and/or utilization.

In a proof-of-concept study, solid phase synthesis allowed the rapid generation of a small molecule drug conjugate in which the glutamate carboxypeptidase II (GCPII) targeting small molecule DUPA was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The targeted SMDC contained a cathepsin B cleavable linker, which was shown to be active and selective against cathepsin B over-expressing and GCPII-expressing tumour cell lines.

Effective treatment of tuberculosis is challenged by the rapid development of () multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, -benzylidene-'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel -benzylidene-'-thiazol-2-yl-hydrazine derivatives into active sites of LeuRS (LeuRS) and MetRS (MetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against LeuRS and 28 compounds active against MetRS. The hit compounds display dual inhibitory potency as demonstrated by IC values for both enzymes. Compound is active against H37Rv cells in bioassays.

New benzimidazoles were synthesized based on the previously identified sirtuin inhibitor BZD9L1. The compounds were screened for their sirtuin (SIRT1, SIRT2 and SIRT3) inhibitory activities. Compound was determined to be a pan-SIRT1-3 inhibitor. Furthermore, the proliferation of various cancer cells was inhibited by . It was shown that elicits a cytostatic effect by inducing cell cycle arrest at the G/M phase while also showing a prominent induction of apoptosis against oral cancer cells.

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate -alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound (a d-galactose derivative) being the most potent inhibitor (IC = 0.17 μM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (; IC = 2.75 μM). Moreover, the ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, studies demonstrated that the two most potent compounds against BuChE ( and ) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying. Consequently, there is an urgent need for a cure. Although the cause of this debilitating condition remains poorly understood, it is believed that several factors may be involved in combination - including, health and lifestyle, environmental, and genetic factors. In recent years, a number of hallmarks of the disease have also been discovered, and it is believed that these factors may play an important role in the development of AD. Amyloid aggregation is one such factor which has been highly investigated, in addition to cholinesterase enzymes and tau aggregation. In the last decade, multi-target drugs have been increasingly investigated for their application to AD treatment. By combining two or more pharmacophores in a single compound, it is possible to synthesise a drug which can target several factors that are involved in AD development. This is a particularly attractive approach as it would avoid the use of combination therapies. As a result, it could reduce the burden on carers and families, and decrease healthcare and social care costs. Many active pharmacophores have been employed for the development of hybrid drugs, due to their abilities to inhibit the factors currently widely recognised to be involved in AD. These compounds have demonstrated promising results; however, research is still required to optimise the pharmacological profiles of the drugs, in addition to their potencies. Meanwhile, extensive research is continuously being performed into other potential targets for the treatment of AD. Based on the results obtained thus far, it is likely that multi-target compounds will continue to be increasingly studied in the future as potential treatments for AD.

Previously we identified a series of amidoalkylindoles as potent and selective CB partial agonists. In the present study, we report our continuous effort to improve the aqueous solubility by introducing N atoms to the amidoalkylindole framework. Synthesis, characterization, and pharmacology evaluations were described. Bioisosteric replacements of the indole nucleus with an indazole, azaindole and benzimidazole were explored. Benzimidazole (EC = NA, EC = 0.067 μM) and azaindole (EC = NA, EC = 0.048 μM) were found to be potent and selective CB receptor partial agonists, both with improved aqueous solubility.

Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders. The outcomes of initial clinical trials with the first generation of MMP inhibitors proved disappointing. However, our growing understanding of the complexities of the MMP function in disease, and an increased understanding of MMP protein architecture and control of activity now provide new opportunities and avenues to develop MMP-focused therapies. Natural products that affect MMP activities have been of strong interest as templates for drug discovery, and for their use as chemical tools to help delineate the roles of MMPs that still remain to be defined. Herein, we highlight the most recent discoveries of structurally diverse natural product inhibitors to these proteases.

Rigidification of the isobutyl side chain of drug-like AT receptor agonists and antagonists that are structurally related to the first reported selective AT receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers , , , , , , and bind to the AT receptor with moderate ( = 54-223 nM) to high affinity ( = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives and are among the most potent AT receptor antagonists reported so far. As illustrated by the enantiomer pairs / and /, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT receptor, and can convert agonists to antagonists and .

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4'. The most promising compound was further evaluated through changes at position 3 of the psoralen ring. Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able to improve the selectivity against other subunits of both the immunoproteasome and the constitutive proteasome. The most potent compounds discriminated between both proteasome types in cell lysates and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.

We describe the inhibition of the starch utilization system (Sus) belonging to various strains of in a non-lethal manner using the small molecule probe, acarbose. Concentrations of acarbose as low as 5 μM significantly impede the growth of and increase the doubling time of cultures. The successful inhibition of this species of is relevant to several disease states including type I diabetes mellitus. This method continues to explore a new, potential route to intervene in illnesses associated with aberrant changes in the composition of the human gut microbiota through the strategic manipulation of its constituents.

Pritelivir (AIC316, BAY 57-1293) was discovered as a highly potent drug against herpes simplex viruses with a novel mode of action, inhibition of the viral helicase-primase. A side by side comparison of the oral form against Valtrex™ in patients with genital herpes, showed superiority in phase II testing for Pritelivir. A number of different solid forms have been generated for additional, systemic, or topical applications.

The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with -ethyl morpholine moieties (compounds ) were designed, synthesized and biologically evaluated. Compounds , , , and exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC(CB1)/EC(CB2) greater than 1000). The most active compound, compound , was more potent than the standard drug GW405833 for agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound had a dose-dependent reversal for hyperalgesia with an estimated ED value of 1.097 mg kg. Moreover, compound significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound on inflammatory pain were superior to those of GW405833, suggesting that compound may be a promising therapeutic drug that needs further validation.

This review is about the significance of the use of lipidomic analysis for identifying susceptibility to skin diseases. Exactly this article describes the use of lipidomic analysis in different studies to detect abnormalities in the lipid composition of the skin to diagnose and prevent various dermatological diseases.

(trioxatriangulenium ion) is a close-shelled carbocation known to intercalate strongly with the DNA double helix (J. Reynisson, G. B. Schuster, S. B. Howerton, L. D. Williams, R. N. Barnett, C. L. Cleveland, U. Landman, N. Harrit, J. B. Chaires, 2003, , 2072). The cytotoxicity of and its four close structural analogues, , , and were tested against the breast cancer cell line MDA-MB-231 and colon cancer cell line HCT116. The most potent derivatives and had IC values of ∼80 nM for MDA-MB-231 but slightly higher for HCT116 in the low hundreds nM range. A 3D model assay of HCT116 spheroids was also used, mimicking a tumour environment, again both and were very active with IC values of 38 nM and 21 nM, respectively. Molecular modelling suggest that the planar derivatives intercalate between the base pairs of the DNA double helix. However, only modest DNA double stranded DNA cleavage was observed using the γH2AX assay as compared to camptothecin, a topoisomerase I poison suggesting a different mechanism. Finally, a robust density functional theory (DFT) model was built to predict the p stability values, , to design derivatives, which predominantly have a non-intercalating buckled form in healthy tissues followed by a nucleophilic attach of water on the central carbon, but a planar form at relatively low pH values rendering them only cytotoxic in the interior of tumours.

belongs to a group of rapidly growing mycobacteria (RGM) and accounts for approximately 65-80% of lung disease caused by RGM. It is highly pathogenic and is considered the prominent Mycobacterium involved in pulmonary infection in patients with cystic fibrosis and chronic pulmonary disease (CPD). FosM is a putative 134 amino acid fosfomycin resistance enzyme from subsp. bolletii that shares approximately 30-55% sequence identity with other vicinal oxygen chelate (VOC) fosfomycin resistance enzymes and represents the first of its type found in any Mycobacterium species. Genes encoding VOC fosfomycin resistance enzymes have been found in both Gram-positive and Gram-negative pathogens. Given that FosA enzymes from Gram-negative bacteria have evolved optimum activity towards glutathione (GSH) and FosB enzymes from Gram-positive bacteria have evolved optimum activity towards bacillithiol (BSH), it was originally suggested that FosM might represent a fourth class of enzyme that has evolved to utilize mycothiol (MSH). However, a sequence similarity network (SSN) analysis identifies FosM as a member of the FosX subfamily, indicating that it may utilize water as a substrate. Here we have synthesized MSH and characterized FosM with respect to divalent metal ion activation and nucleophile selectivity. Our results indicate that FosM is a Mn-dependent FosX-type hydrase with no selectivity toward MSH or other thiols as analyzed by NMR and mass spectroscopy.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from and protocols for growing, extracting and derivatising it are reported A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on anti-leukaemic activity and calculated "drug-likeness" properties, and pharmacokinetics studies and hERG liability testing. studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine used in the generation of .