Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review.
Abstract Among the neurodegenerative disorders, Alzheimer's disease (AD) represents the most common type of dementia and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increase in β-amyloid (Aβ) peptide concentration, appearance of neurofibrillary tangles, and others, all of them strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD, most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in ...
Source: ChemMedChem - July 16, 2019 Category: Chemistry Authors: Silva GM, Barcelos MP, Poiani JGC, Hage-Melim LIDS, Silva CHTP Tags: ChemMedChem Source Type: research

Azaaurones as potent antimycobacterial agents active against MDR- and XDR-TB.
R, Lopes F Abstract Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N-acetylazaaurones, against Mycobacterium tuberculosis. Aurones were inactive at 20 µM, while azaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 μM. In addition, several N-acetylazaaurones were found to be active against multidrug resistant (MDR) and extensively drug resistant (XDR) clinical M. tuberculosis isolates. The anti-mycobacterial mechanism of action of these compounds remains to...
Source: ChemMedChem - July 11, 2019 Category: Chemistry Authors: Campaniço A, Carrasco MP, Njoroge M, Seldon R, Chibale K, Perdigão J, Portugal I, Warner DF, Moreira R, Lopes F Tags: ChemMedChem Source Type: research

Roles of the Conserved Amino Acid Residues in Reduced Human Defensin  5: Cysteine and Arginine Are Indispensable for Its Antibacterial Action and LPS Neutralization.
In this study we investigated the role of structurally conserved amino acids in reduced human defensin 5 (HD5RED ), which is an endogenous peptide with antibacterial action and the ability to neutralize lipopolysaccharide (LPS). Cys residues and high Arg content, rather than Gly18 and Arg6 -Glu14 , were found to be indispensable for HD5RED binding to lipid A, for penetrating the bacterial outer and inner membranes, and for eliminating bacteria. Otherwise, all the conserved sites were requisite for HD5RED to block the interaction between LPS and LPS-binding protein and to suppress the TLR4-NF-κB signaling pathway ...
Source: ChemMedChem - July 10, 2019 Category: Chemistry Authors: Chen F, Tang Y, Zheng H, Xu Y, Wang J, Wang C Tags: ChemMedChem Source Type: research

-Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.
We report here the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on overall profile, 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided solubility of>30 mg/mL for parenteral administration and conversion to the active drug with a T1/2 of approximately 2 minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses...
Source: ChemMedChem - July 8, 2019 Category: Chemistry Authors: Cohen F, Aggen JB, Andrews LD, Assar Z, Boggs J, Choi T, Dozzo P, Easterday AN, Haglund CM, Hildebrandt DJ, Holt MC, Joly K, Jubb A, Kamal Z, Kane TR, Konradi AW, Krause KM, Linsell MS, Machajewski TD, Miroshnikova O, Moser HE, Nieto V, Phan T, Plato C, S Tags: ChemMedChem Source Type: research

[18F]PRIMATX, a new positron emission tomography tracer for in vivo imaging of autotaxin in lung and tumour tissues.
Abstract Autotaxin (ATX) is a secreted enzyme with tissue levels associated with tissue injury, which increase during wound healing and chronic fibrotic diseases. We selected [18F]-(R,E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl) phenyl)-1-(4-((5-(2-fluoroethoxy)pyridin-2-yl)methyl)-2-methylpiperazin-1-yl)prop-2-en-1-one ([18F]PRIMATX, [18F]2), a tracer for positron emission tomography, to image ATX expression in vivo. It successfully differentiates expression levels in lung tissue samples from idiopathic pulmonary fibrosis patients, and allows the detection of ATX-expressing tumours in living mice, confirm...
Source: ChemMedChem - July 4, 2019 Category: Chemistry Authors: Briard E, Joshi A, Shanmukhappa S, Ilovich O, Auberson YP Tags: ChemMedChem Source Type: research

Synthesis of substituted 5'-aminoadenosine derivatives and evaluation of their inhibitory potential towards CD73.
tes S Abstract Derivatives of 5'-amino-adenosine containing methyl carboxylate, methyl phosphonate, gem-bisphosphonate, bis(methylphosphonate), αlpha-carboxylmethylphosphonate or phosphonoacetic moieties were synthesized from a key intermediate 5'-aminonucleoside. These nucleos(t)ide analogues were envisaged as 5'-mono or diphosphate nucleoside mimics. All compounds were evaluated for CD73 inhibition in a cell-based assay (MDA-MB-231) and towards the purified recombinant protein. Most of them failed to reach significant inhibition of AMP hydrolysis by CD73 at 100 µM. Among the new compounds, the most i...
Source: ChemMedChem - July 2, 2019 Category: Chemistry Authors: Ghoteimi R, Nguyen TV, Rahimova R, Grosjean F, Cros-Perrial E, Uttaro JP, Mathé C, Chaloin L, Jordheim LP, Peyrottes S Tags: ChemMedChem Source Type: research

Synthesis of Nitrogen-Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity Against Cancer Cells.
Abstract Two series of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin chloro acrylamide (13e) displayed the lowest IC50 values for both MCF-7 (0.5 μM) and PC3 (0.3 μM) cells, about 26-fold more potent than goniothalamin (1). Besides its higher potency, compound 13e also displayed much higher selectivity than goniothalamin (1). In contrast, goniothalamin iso...
Source: ChemMedChem - July 1, 2019 Category: Chemistry Authors: Andrade Meirelles M, B Braga C, Ornelas C, Pilli RA Tags: ChemMedChem Source Type: research

Probing 2H-Indazoles as Template for SGK1, Tie2 and SRC Kinase Inhibitors.
te; M Abstract The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so far underrepresented aza-2H-indazole scaffold, indazoles were connected in N2-position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A...
Source: ChemMedChem - July 1, 2019 Category: Chemistry Authors: Schoene J, Gazzi T, Lindemann P, Christmann M, Volkamer A, Nazaré M Tags: ChemMedChem Source Type: research

Rational adaptation of L3MBTL1 inhibitors to create small-molecule Cbx7 antagonists.
We report here our efforts to create low-molecular weight inhibitors of Cbx7 by making rational structural adaptations of inhibitors of a different methyl reader protein, L3MBTL1-inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by a fluorescence-polarization assay (FP assay), and also confirmed binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR (STD NMR) spectroscopy. This work identified multiple small-molecule inhibitors with modest (257-500 μM) potency. PMID: 31254321 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - June 28, 2019 Category: Chemistry Authors: Simhadri C, Daze KD, Douglas SF, Milosevich N, Monjas L, Dev A, Brown TM, Hirsch AKH, Wulff JE, Hof F Tags: ChemMedChem Source Type: research

Structure and energetics of ligand-fluorine interactions with galectin-3 backbone and side-chain amides - insight into solvation effects and multipolar interactions.
In this study, fluorine interactions within a well-defined binding pocket on galectin-3 are investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at different positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine-amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide ...
Source: ChemMedChem - June 27, 2019 Category: Chemistry Authors: Kumar R, Ignjatović MM, Peterson K, Olsson M, Leffler H, Ryde U, Nilsson UJ, Logan DT Tags: ChemMedChem Source Type: research

Stability and Efficiency of Mixed Aryl Phosphonate Prodrugs.
Abstract A set phosphonate prodrugs of a butyrophilin ligand was synthesized and evaluated for plasma stability and cellular activity. The mixed aryl acyloxy esters were prepared either via a standard sequence through the phosphonic acid chloride, or through the more recently reported, and more facile, triflate activation. In the best of cases, this class of prodrugs shows cellular potency similar to that of bis-acyloxyalkyl phosphonate prodrugs and plasma stability similar to that of aryl phosphonamidates. For example, ((((3E)-5-hydroxy-4-methylpent-3-en-1-yl) (naphthalen-2-yloxy) phosphoryl) oxy) methyl 2,2-dime...
Source: ChemMedChem - June 21, 2019 Category: Chemistry Authors: Foust BJ, Li J, Hsiao CC, Wiemer DF, Wiemer AJ Tags: ChemMedChem Source Type: research

Rational Design of Efficient Organic Phototherapeutic Agents via Perturbation Theory for Enhancing Anticancer Therapeutics.
Abstract The development of efficient phototherapeutic agents (PTA) through rational and specific principles exhibits great significance to the biomedical field. Herein, a facile and rational strategy has been presented to design PTA via perturbation theory. According to the theory, through the rational optimization of donor-acceptor structure, heavy atom number and their functionalization position, which can effectively decrease energy gap between the singlet and triplet states and increase spin-orbit coupling constant, the enhanced intersystem crossing rate for singlet oxygen generation and nonradiative transiti...
Source: ChemMedChem - June 18, 2019 Category: Chemistry Authors: Xu Y, Zhao M, Wu L, Li F, Li M, Xie M, Liu S, Huang W, Zhao Q Tags: ChemMedChem Source Type: research

The Design of Potent, Selective and Drug-Like RGD αvβ1 Small Molecule Inhibitors Derived from non-RGD α4β1 Antagonists.
The Design of Potent, Selective and Drug-Like RGD αvβ1 Small Molecule Inhibitors Derived from non-RGD α4β1 Antagonists. ChemMedChem. 2019 Jun 17;: Authors: Hatley R Abstract Up to 45% of deaths in developed nations can be attributed to chronic fibroproliferative diseases, resulting in a requirement for effective therapies. The RGD integrin avb1 has recently been investigated for its role in fibrosis disease and warrants therapeutic targeting. Herein, we describe (i) the identification of non-RGD hit small molecule avb1 inhibitors; (ii) that avb1 activity is embedded in a range of...
Source: ChemMedChem - June 17, 2019 Category: Chemistry Authors: Hatley R Tags: ChemMedChem Source Type: research

A Hydrogen Peroxide-Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma.
In this study, we aimed to decrease adverse events on gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide (H2O2) levels in normal cells and cancer cells. We have designed and synthesized a novel boronate ester-caged prodrug that is activated by the high H2O2 concentration found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other ROS and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to t...
Source: ChemMedChem - June 17, 2019 Category: Chemistry Authors: Matsushita K, Okuda T, Mori S, Konno M, Eguchi H, Asai A, Koseki J, Iwagami Y, Yamada D, Akita H, Asaoka T, Noda T, Kawamoto K, Gotoh K, Kobayashi S, Kasahara Y, Morihiro K, Satoh T, Doki Y, Mori M, Ishii H, Obika S Tags: ChemMedChem Source Type: research

Fragment Growing to Design Optimized Inhibitors for Human Blood Group B Galactosyltransferase (GTB).
Abstract Human blood group B galactosyltransferase (GTB) catalyzes the galactosylation of the H antigen and is responsible for the formation of the blood group antigen of phenotype B. The ABO blood group system is well studied and routinely serotyped before transfusion and transplantation. Blood type subgroups have been repeatedly linked to an increased occurrence of diseases (e.g. a highly increased incidence rate for pancreatic cancer for individuals with blood group phenotype B). 3-Phenyl-5-(piperazin-1-yl)-1,2,4-thiadiazole 1 has previously been described to inhibit GTB with a Ki = 800 μM. In this work, we ...
Source: ChemMedChem - June 17, 2019 Category: Chemistry Authors: Strecker C, Peters H, Hackl T, Peters T, Meyer B Tags: ChemMedChem Source Type: research

Substituted aminoacetamides as novel leads for malaria.
amb AH, Winzeler EA, Waterson D, Campbell SF, Willis PA, Read KD, Gilbert I Abstract In this paper we describe the optimisation of a phenotypic hit against Plasmodium falciparum, based on an aminoacetamide scaffold. This led to a compound (28) with low nanomolar antimalarial activity against the intraerythrocytic stages of the malaria parasite and was inactive in a mammalian cell counter screen up to 50 μM. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimise the aqueous solubility and...
Source: ChemMedChem - June 12, 2019 Category: Chemistry Authors: Norcross NR, Wilson C, Baragaña B, Hallyburton I, Osuna-Cabello M, Norval S, Riley J, Fletcher D, Sinden R, Delves M, Ruecker A, Duffy S, Meister S, Antonova-Koch Y, Crespo B, de Cózar C, Sanz L, Gamo FJ, Avery VM, Frearson JA, Gray DW, Fairlamb AH, Win Tags: ChemMedChem Source Type: research

Structure-affinity relationships of fluorinated spirocyclic σ2 receptor ligands with an exocyclic benzylamino moiety.
Structure-affinity relationships of fluorinated spirocyclic σ2 receptor ligands with an exocyclic benzylamino moiety. ChemMedChem. 2019 Jun 12;: Authors: Wünsch B, Bergkemper M, Kronenberg E, Schepmann D, Ludwig FA, Brust P Abstract In order to detect a potent and selective σ2 receptor ligand appropriate for the development as PET tracer several fluorinated analogs of the spirocyclic lead compounds trans-6 and cis-6 were designed. In multi-step syntheses, an F-atom was introduced directly or as 2-fluoroethoxy moiety at the 2-benzopyran scaffold, at the dimethylbenzylamino moiety or at...
Source: ChemMedChem - June 12, 2019 Category: Chemistry Authors: Wünsch B, Bergkemper M, Kronenberg E, Schepmann D, Ludwig FA, Brust P Tags: ChemMedChem Source Type: research

Small-Molecule Activators of Glucose-6-phosephate Dehydrogenase (G6PD) Bridging the Dimer Interface.
Abstract We have recently identified AG1, a small-molecule glucose-6-phosphate dehydrogenase (G6PD) activator that functions by promoting oligomerization of the enzyme to the catalytically competent forms. Biochemical experiments indicate activation of G6PD by the original hit molecule (AG1) is noncovalent and that one C2-symmetric region of the G6PD homodimer is important for ligand function. Consequently, the disulfide in AG1 is not required for activation of G6PD and a number of analogs were prepared without this reactive moiety. Our Study supports a mechanism of action whereby AG1 bridges the dimer interface a...
Source: ChemMedChem - June 11, 2019 Category: Chemistry Authors: Raub A, Hwang S, Horikoshi N, Cunningham A, Rahighi S, Wakatsuki S, Mochly-Rosen D Tags: ChemMedChem Source Type: research

Experimental and computational evaluation of some piperonylic acid derived hydrazones bearing isatin moiety as dual inhibitors of cholinesterases and monoamine oxidases.
Abstract A set of piperonylic acid derived hydrazones with variable isatin moiety was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase A and B (MAO-A/B). The results of the in vitro studies revealed compounds possessing IC50 values in the micromolar range, with the majority of them showing higher selectivity towards MAO-B isoform. The compound N-(2-oxo-1-(prop-2-ynyl)indolin-3-ylidene)benzo[d][1,3]dioxole-5 carbohydrazide (compound 3) was identified as lead AChE inhibitor with IC50 = 0.052 ± 0.006 &mu...
Source: ChemMedChem - June 8, 2019 Category: Chemistry Authors: Raja Ayyannan S, M S V, V P, Kumar S Tags: ChemMedChem Source Type: research

Novel BQCA and TBPB derived M1 Receptor Hybrid-Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism.
r M Abstract Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant according to their exemplary role for the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1'-(2-tolyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective pu...
Source: ChemMedChem - June 5, 2019 Category: Chemistry Authors: Schramm S, Agnetta L, Bermudez M, Gerwe H, Littmann T, Irmen M, Holze J, Wolber G, Tränkle C, Decker M Tags: ChemMedChem Source Type: research

Synthesis and Study of Novel Multifunctional Cyclodextrin-Deferasirox Hybrids.
Abstract Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose un...
Source: ChemMedChem - June 4, 2019 Category: Chemistry Authors: Spencer J, Gascon JM, Oliveri V, McGown A, Kaya E, Chen YL, Austin C, Walker M, Platt F, Vecchio G Tags: ChemMedChem Source Type: research

Combining 1,3-ditriazolyl-benzene and quinoline to discover a new G-quadruplex interactive small molecule active against cancer stem-like cells.
In this study we used a fragment-based approach to create new flexible G-quadruplex (G4) DNA interactive small molecules with good calculated oral drug-like properties, based on quinoline and triazole heterocycles. G4 melting temperature and Polymerase Chain Reaction-stop assays showed that two of these compounds are selective G4 ligands, since they were able to induce and stabilize G4s in a dose- and DNA sequence-dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G-quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity...
Source: ChemMedChem - June 4, 2019 Category: Chemistry Authors: Mendes E, Cadoni E, Carneiro F, Afonso MB, Brito H, Lavrado J, Dos Santos DJVA, Vítor JB, Neidle S, Rodrigues CMP, Paulo A Tags: ChemMedChem Source Type: research

Combined Scaffold Evaluation and Systems-level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes.
In this study, we have combined scaffold-directed synthesis with a hybrid experimental and transcriptome analysis to identify bis-spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically-inspired synthesis and assay strategy for the accelerated identification of first-in-class cancer therapeutic candidates. PMID: 31140738 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - May 29, 2019 Category: Chemistry Authors: Rodriguez K, Howe E, Bacher E, Burnette M, Meloche J, Meisel J, Schnepp P, Tan X, Chang M, Zartman J, Zhang S, Ashfeld BL Tags: ChemMedChem Source Type: research

Computer-assisted selective optimization of side-activities - from cinalukast to a PPAR α modulator.
Computer-assisted selective optimization of side-activities - from cinalukast to a PPARα modulator. ChemMedChem. 2019 May 29;: Authors: Pollinger J, Schierle S, Neumann S, Ohrndorf J, Kaiser A, Merk D Abstract Automated computational analogue design and scoring can speed up hit-to-lead optimization and appears particularly promising in selective optimization of side-activities (SOSA) where possible analogue diversity is confined. Probing this concept, we employed the CysLT1R antagonist cinalukast as lead for which we discovered PPARα modulatory activity. We automatically generated a virtua...
Source: ChemMedChem - May 29, 2019 Category: Chemistry Authors: Pollinger J, Schierle S, Neumann S, Ohrndorf J, Kaiser A, Merk D Tags: ChemMedChem Source Type: research

Discovery of 6-arylurea-2-arylbenzoxazole and 6-arylurea-2-arylbenzimidazole derivatives as angiogenesis inhibitors: design, synthesis and in vitro biological evaluation.
Abstract Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anti-angiogenesis agents with previously reported imidazole kinase inhibitors as a lead compound. A library of 29 compounds has been synthesized. Several title compounds exhibited selective inhibitory activities against VEGFR-2 kinase than EGFR kinases, which also displayed selective anti-proliferation potency against three cancer cells. The newly synthesized compounds were evaluated for anti-angiogenesis capability by CAM assay. Among them, compound 5n showed the most potent anti-angiogenesis ability, the efficient...
Source: ChemMedChem - May 26, 2019 Category: Chemistry Authors: Jin Y, Zi M, Liu F, Wu D, Li K, Zhang D, Zhu C, Zhang Z, Li L, Zhang C, Xie M, Lin J, Zhang J Tags: ChemMedChem Source Type: research

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo- β-Lactamases.
Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo-β-Lactamases. ChemMedChem. 2019 May 24;: Authors: Chen AY, Thomas PW, Cheng Z, Xu NY, Tierney DL, Crowder MW, Fast W, Cohen SM Abstract New Delhi metallo-β-lactamase-1 (NDM-1) poses an immediate threat to our most effective and widely prescribed drugs, the β-lactam-containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM-1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM-1 make up...
Source: ChemMedChem - May 24, 2019 Category: Chemistry Authors: Chen AY, Thomas PW, Cheng Z, Xu NY, Tierney DL, Crowder MW, Fast W, Cohen SM Tags: ChemMedChem Source Type: research

Synthesis and Antibacterial Evaluation of Bis-thiazolium, Bis-imidazolium, and Bis-triazolium Derivatives.
Abstract Given the worldwide spread of bacterial drug resistance, there is an urgent need to develop new compounds that exhibit potent antibacterial activity and that are unimpaired by this phenomenon. Quaternary ammonium compounds have been used for many years as disinfectants, but recent advances have shown that polycationic derivatives exhibit much stronger activity and are less prone to bacterial resistance than commonly used monocationic compounds. In this sense, we prepared three series of new bis-cationic compounds: bis-thiazoliums, bis-imidazoliums, and bis-1,2,4-triazoliums. If some compounds of the first...
Source: ChemMedChem - May 22, 2019 Category: Chemistry Authors: Thomas B, Duval RE, Fontanay S, Varbanov M, Boisbrun M Tags: ChemMedChem Source Type: research

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy.
Abstract This work is focused on the synthesis, characterization, and preliminary biological evaluation of bio-conjugated AuIII and CuII complexes with the aim of overcoming the well-known side effects of chemotherapy by improving the selective accumulation of an anticancer metal payload in malignant cells. For this purpose, carbohydrates were chosen as targeting agents, exploiting the Warburg effect that accounts for the overexpression of glucose-transporter proteins (in particular GLUTs) in the phospholipid bilayer of most neoplastic cells. We linked the dithiocarbamato moiety to the C1 position of three differe...
Source: ChemMedChem - May 15, 2019 Category: Chemistry Authors: Pettenuzzo N, Brustolin L, Coltri E, Gambalunga A, Chiara F, Trevisan A, Biondi B, Nardon C, Fregona D Tags: ChemMedChem Source Type: research

The Outcomes of Decorated-Prolines in Discovering Novel Antimicrobial Peptides from Temporin-L.
In this study, a series of analogues, where the position 3 was substituted with non-natural proline derivatives, was investigated for the correlation between the conformational properties of the compounds and their antibacterial, cytotoxic and hemolytic activities. Non-natural proline analogues with substituents at position 4 of the pyrrolidine ring were considered. Structure-activity relationship studies of these analogues were performed by means of antimicrobial and cytotoxicity assays along with circular dichroism (CD) and NMR spectroscopy analysis for selected compounds. The most promising peptides were additionally ev...
Source: ChemMedChem - May 14, 2019 Category: Chemistry Authors: Grieco P, Buommino E, Carotenuto A, Antignano I, Bellavita R, Casciaro B, Loffredo MR, Merlino F, Novellino E, Mangoni ML, Nocera FP, Brancaccio D, Punzi P, Roversi D, Ingenito R, Bianchi E Tags: ChemMedChem Source Type: research

Development of tetrahydroindazole-based potent and selective sigma-2 receptor ligands.
Abstract The sigma-2 receptor has been shown to play important roles in a number of important diseases, including CNS disorders and cancer. However, mechanisms by which sigma-2 contributes to these diseases remain unclear. Development of new sigma-2 ligands that can be used to probe the function of this protein and potentially as drug discovery leads are therefore of great importance. Here we report the development of a series of tetrahydroindazole compounds that are highly potent and selective for sigma-2. The structure-activity relationship data was used to generate a pharmacophore model which summarizes the com...
Source: ChemMedChem - May 9, 2019 Category: Chemistry Authors: Iyamu ID, Lv W, Malik N, Mishra RK, Schiltz GE Tags: ChemMedChem Source Type: research

Synthesis and evaluation of new nifurtimox-adamantane adducts with trypanocidal activity.
Abstract The synthesis and pharmacological evaluation of the C-1 substituted adamantane hydrazones 1a-d, their C-2 substituted isomers 2a-d and the C-1 substituted adamantane furanoic carboxamides 3a-c is described. The new adamantane derivatives exhibited an interesting pharmacological profile, in terms of trypanocidal activity and selectivity. Of the compounds tested, the phenylacetoxy hydrazone 1b showed the most promising profile against African trypanosomes (EC50=11 ± 0.9 nM; SI=770). PMID: 31066972 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - May 8, 2019 Category: Chemistry Authors: Foscolos AS, Papanastasiou I, Tsotinis A, Taylor MC, Kelly JM Tags: ChemMedChem Source Type: research

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-Activity-Relationship, and Sleep-Promoting Properties in the Rat.
Abstract The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts towards a novel DORA. We started our investigation with N-linked benzoxazole 3, a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP-3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine-scaffold was essential to improve potency on the ...
Source: ChemMedChem - May 8, 2019 Category: Chemistry Authors: Brotschi C, Roch C, Gatfield J, Treiber A, Williams JT, Sifferlen T, Heidmann B, Jenck F, Bolli MH, Boss C Tags: ChemMedChem Source Type: research

Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes.
Abstract Hdm2 (human MDM2) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Here, we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds. We also rev...
Source: ChemMedChem - May 8, 2019 Category: Chemistry Authors: Kallen J, Izaac A, Chau S, Wirth E, Schoepfer J, Mah R, Schlapbach A, Stutz S, Vaupel A, Guagnano V, Masuya K, Stachyra TM, Salem B, Chene P, Gessier F, Holzer P, Furet P Tags: ChemMedChem Source Type: research

Stabilizing p-dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release.
Abstract Exploiting the redox-sensitivity of disulfide bonds is a prevalent strategy adopted in targeted prodrug designs. Compared with aliphatic disulfides, the p-thiobenzyl-based disulfides have rarely been used for prodrug designs due to their intrinsic instability caused by the low pKa of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pKa effect on the thiol-disulfide exchange reactions and uncovered a new thiol-disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central-leaving group shifting effect in our DMTB-linkers, whic...
Source: ChemMedChem - April 24, 2019 Category: Chemistry Authors: Zheng Y, Shen Y, Meng X, Wu Y, Zhao Y, Wu C Tags: ChemMedChem Source Type: research

Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assay against Colorectal Cancer.
Abstract A series of deuterated curcuminoids were synthesized, bearing two to six OCD3 groups, in some cases in combination with OCH3 groups, and in others together with fluorines. A model ring deuterated hexamethoxy-CUR-BF2 and its corresponding CUR compound were also synthesized form a 2,4,6-trimethoxybenzaldehyde-3,5-d2 precursor. As with their protio-analogues, the deuterated compounds remained exclusively in the keto-enolic form. The anti-proliferative activity of these compounds were studied by in-vitro bioassay against a panel of 60 cancer cell lines, and more specifically in human colorectal cancer (CRC) c...
Source: ChemMedChem - April 17, 2019 Category: Chemistry Authors: Laali KK, Zwarycz A, Bunge S, Borosky G, Nukaya M, Kennedy G Tags: ChemMedChem Source Type: research

Aryl and arylalkyl substituted 3-hydroxypyridin(1H)-2-ones: Synthesis and evaluation as inhibitors of influenza A endonuclease.
We report herein on the structure-activity relationships associated with various para-substituted 5-phenyl derivatives of 6-(p-fluorophenyl)-3-hydroxypyridin (1H)-2-one and the effect of using naphthyl, benzyl, and napthylmethyl groups as alternatives to the p-fluorophenyl substituent on their activity as endonuclease inhibitors. PMID: 30983160 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - April 14, 2019 Category: Chemistry Authors: LaVoie EJ, Sagong HY, Bauman JD, Nogales A, Martínez-Sobrido L, Arnold E Tags: ChemMedChem Source Type: research

Characterization of disulfide bond rebridged Fab-drug conjugates prepared using a dual maleimide pyrrolobenzodiazepine cytotoxic payload.
We describe the characterization of antigen binding fragments (Fab)-drug conjugates prepared using a dual maleimide pyrrolobenzodiazepine dimer cytotoxic payload (SG3710). Pyrrolobenzodiazepine dimers, which are DNA cross-linkers, are a class of payloads used in antibody-drug conjugates (ADCs). SG3710 was designed to rebridge two adjacent cysteines, such as those that form the canonical interchain disulfide bond between the light and heavy chain in Fab fragments. The rebridging generated homogeneous Fab-conjugates, with a drug-to-Fab ratio of one, as demonstrated by the preparation of rebridged Fabs derived from the anti-H...
Source: ChemMedChem - April 13, 2019 Category: Chemistry Authors: Ruddle BT, Fleming R, Wu H, Gao C, Dimasi N Tags: ChemMedChem Source Type: research

Design of natural-product-inspired multi-target ligands by machine learning.
Abstract A virtual screening protocol based on machine learning models was used to identify mimetics of the natural product (-)-galantamine. This fully automated approach identified eight compounds with bioactivities on at least one of the macromolecular targets of (-)-galantamine, with different polypharmacological profiles. Two of the computer-generated hits possess an expanded spectrum of bioactivity on targets relevant to the treatment of Alzheimer's disease and are suitable for hit-to-lead expansion. These results advocate multi-target drug design by advanced virtual screening protocols based on chemically-in...
Source: ChemMedChem - April 11, 2019 Category: Chemistry Authors: Grisoni F, Merk D, Friedrich L, Schneider G Tags: ChemMedChem Source Type: research

Development of Fibrates as Important Scaffold in Medicinal Chemistry.
Abstract Fibrates are a class of phenoxy-isobutyric acid derivatives mainly used as antihyperlipidemic agents. The fibrates scaffold has undergone a variety of chemical modifications providing a wide spectrum of biological activities. Within the last years, the majority of new synthetic fibrates derivatives have demonstrated hypolipidemic activity by the PPARα activation. However, some compounds containing fibrate scaffold have shown different pharmacological properties, also independent from PPARα activation, such as anti-inflammatory, analgesic, anti-oxidant and antiplatelet. The aim of this review i...
Source: ChemMedChem - April 8, 2019 Category: Chemistry Authors: Giampietro L, Ammazzalorso A, Amoroso R, De Filippis B Tags: ChemMedChem Source Type: research

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3-Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1.
KT Abstract A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized regarding their inhibitory potency at mGAT1-4 and binding affinity for mGAT1. Compounds of the described class are defined by a four-carbon atom allenyl spacer connecting the nitrogen of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the nipecotic acid derivative 21p, possessing an o-terphenyl residue, was identified as highly selective and most potent mGAT1 inhibitor in this study. For the (R)-nipecotic acid derived form of 21p, the inhibitory potency in [3H]G...
Source: ChemMedChem - April 8, 2019 Category: Chemistry Authors: Schaarschmidt M, Höfner G, Wanner KT Tags: ChemMedChem Source Type: research

The discovery of LML134, a histamine H3 receptor inverse agonist for the clinical treatment of excessive sleep disorders.
PMID: 30957954 [PubMed - as supplied by publisher] (Source: ChemMedChem)
Source: ChemMedChem - April 8, 2019 Category: Chemistry Authors: Troxler T, Feuerbach D, Zhang X, Yang C, Lagu B, Perrone M, Wang TL, Briner K, Bock M, Auberson YP Tags: ChemMedChem Source Type: research

Histone Deacetylase Inhibitors as Multitarget Ligands: New Players in Alzheimer's Disease Drug Discovery?
Abstract Molecules able to interfere with epigenetic mechanisms, aimed at controlling change in gene expressions without altering the structure of DNA, represent one of the major breakthroughs in drug discovery. Among these agents, histone deacetylases inhibitors (HDACIs) are of highly importance. Indeed, HDACIs control gene expression by modulating the acetylation status of histone proteins. Furthermore, they modulate the activity of cytoplasmic non-histone proteins. Due to the role of HDACs in neurodevelopment, memory formation and cognitive processes, HDACIs has been proposed as innovative agents in the context...
Source: ChemMedChem - April 8, 2019 Category: Chemistry Authors: Milelli A, De Simone A Tags: ChemMedChem Source Type: research

Optimization of Drug Candidates that Inhibit the D-loop Activity of RAD51.
Abstract RAD51 is the central protein in homologous recombination repair (HR), where it first binds ssDNA and then catalyzes strand invasion via a D-loop intermediate. Additionally, RAD51 plays a role in faithful DNA replication by protecting stalled replication forks; this requires RAD51 to bind DNA but may not require the strand invasion activity of RAD51. We previously described a small-molecule inhibitor of RAD51 named RI(dl)-2 (RAD51 inhibitor of D-loop formation #2 hereafter called 2h), which inhibits D-loop activity while sparing ssDNA binding. However, 2h is limited in its ability to inhibit HR in vivo, pr...
Source: ChemMedChem - April 7, 2019 Category: Chemistry Authors: Budke B, Tueckmantel W, Miles K, Kozikowski AP, Connell PP Tags: ChemMedChem Source Type: research

Synthesis of benzophenones and in vitro evaluation of their anticancer potential in breast and prostate cancer cells.
Abstract Breast and prostate cancers are frequently treated with chemotherapy. Several novel chemicals are being reported for this purpose, particularly synthetic and natural benzophenones. This work reports the synthesis of substituted 2-hydroxybenzophenones via 1,4-conjugate addition/ intramolecular cycloaddition/ dehydration of nitromethane on the key intermediate chromones. Structures were extensively studied by 2-dimensional Nuclear Magnetic Resonance (2D-NMR) and single-crystal X-ray diffraction studies. Their cytotoxicity was evaluated in vitro, in two breast cancer cell lines (MDA-MB-231 and T47-D) and one...
Source: ChemMedChem - April 4, 2019 Category: Chemistry Authors: Saidi L, Rocha DHA, Talhi O, Bentarzi Y, Nedjar-Kolli B, Bachari K, Almeida Paz FA, Helguero LA, Silva AM Tags: ChemMedChem Source Type: research

Chemical validation of DegS as a target for the development of antibiotics with a novel mode of action.
Abstract Despite the availability of hundreds of antibiotic drugs, infectious diseases continue to remain one of the most notorious health issues. In addition, the disparity between the spreading of multidrug resistant pathogens and the development of novel classes of antibiotics exemplify an important unmet medical need that can only be addressed by identifying novel targets. Here we demonstrate by the development of the first in vivo active DegS inhibitors based on a pyrazolo[1,5-a]-1,3,5-triazine scaffold that DegS and the cell envelope stress response pathway sigmaE represent a target for generating antibiotic...
Source: ChemMedChem - April 4, 2019 Category: Chemistry Authors: Bongard J, Schmitz AL, Wolf A, Zischinsky G, Pieren M, Schellhorn B, Bravo-Rodriguez K, Schillinger J, Koch U, Nussbaumer P, Klebl B, Steinmann J, Buer J, Sanchez-Garcia E, Ehrmann M, Kaiser M Tags: ChemMedChem Source Type: research

Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-based p38 MAP Kinase Inhibitors: Part 1.
Abstract We identified a lead series of p38 mitogen-activated protein kinase inhibitors using a structure-based design strategy from high-throughput screening of hit compound 1. X-ray crystallography of 1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure-based design strategy was to conduct scaffold transformation of 1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4,5-...
Source: ChemMedChem - April 4, 2019 Category: Chemistry Authors: Kaieda A, Takahashi M, Fukuda H, Okamoto R, Morimoto S, Gotoh M, Miyazaki T, Hori Y, Unno S, Kawamoto T, Tanaka T, Itono S, Takagi T, Sugimoto H, Okada K, Snell G, Bertsch R, Nguyen J, Sang BC, Miwatashi S Tags: ChemMedChem Source Type: research

Antibacterial small molecules that potently inhibit Staphylococcus aureus lipoteichoic acid biosynthesis.
Abstract The rise of antibiotic resistance, especially in staphylococcus aureus, and the increasing death rate due to multi-resistant bacteria have been well documented. The need for new chemical entities and/or the identification of novel targets for antibacterial drug development is high. Lipoteichoic acid (LTA), a membrane attached anionic polymer, is important for the growth and virulence of many Gram-positive bacteria and interest has been high in the discovery of LTA biosynthesis inhibitors. Thus far only a handful of LTA biosynthesis inhibitors have been described with moderate (MIC = 5.34 µg/mL) to l...
Source: ChemMedChem - April 2, 2019 Category: Chemistry Authors: Sintim HO, Naclerio GA, Karanja CW, Opoku-Temeng C Tags: ChemMedChem Source Type: research

Synthesis and cytotoxicity of octahydroepoxyisoindole-7-carboxylic acids and norcantharidin-amide hybrids as norcantharidin analogues.
Abstract Octahydroepoxyisoindole analogues (7a-n) of norcantharidin were accessed through a Diels-Alder reaction of an amine substituted furan with maleic anhydride and subsequent reduction of the bicycle[2.2.1]heptane olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity with norcantharidin, none of these analogues displayed noteworthy cytotoxicity against the 11 cell lines examined herein: HT29 (colon); MCF-7 (breast); A2780 (ovarian); H460 (lung); A431 (skin); Du145 (prostate); BE2-C (neuroblastoma); SJ-G2 and U87 (glioblastoma); MIA (pancreatic); and SMA (spon...
Source: ChemMedChem - April 1, 2019 Category: Chemistry Authors: Hizartzidis L, Gilbert J, Gordon CP, Sakoff JA, McCluskey A Tags: ChemMedChem Source Type: research

Fast NMR methods for measuring in direct and/or competition mode the dissociation binding constants of chemical fragments interacting with a receptor.
ieu M Abstract Ligand based NMR screening represents a powerful method in fragment based drug discovery for the identification of chemical matter interacting with the receptor of interest. The large dynamic range of these methods allows the detection of very weak binding affinity ligands. However, the methodology has not been extensively used for quantifying the strength of these interactions. This knowledge is important for ranking the fragments according to their binding strength and for prioritizing structure based and medicinal chemistry activities. Rapid NMR methods for measuring the dissociating binding cons...
Source: ChemMedChem - March 29, 2019 Category: Chemistry Authors: Rak A, Dalvit C, Parent A, Vallée F, Mathieu M Tags: ChemMedChem Source Type: research

Towards the characterization of DAPT interaction with γ-secretase.
In this study, we employed the density map data to assign a possible binding pose of DAPT to characterize its dynamic behaviour through different molecular dynamics simulation approaches. Our simulations showed a high preference of DAPT for the intramembrane region of the protein and also that its entry site is located between TM2 and TM3 of PS1. DAPT interaction with the active site led to a decrease flexibility of key PS1 regions related to the recognition and internalization of GS substrates. Moreover, our study showed that the proximity of DAPT to the catalytic aspartic acids should be able to modify its protonation st...
Source: ChemMedChem - March 29, 2019 Category: Chemistry Authors: Aguayo-Ortiz R, Guzmán-Ocampo DC, Dominguez L Tags: ChemMedChem Source Type: research