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SAR Studies Leading to the Identification of a Novel Series of Metallo-beta-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-beta-lactamase (MBL) and serine-beta-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new beta-lactamase inhibitors to be used in conjunction with carbapenems and other beta-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-beta-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Comparative equilibrium and structural studies of new pentamethylcyclopentadienyl rhodium complexes bearing (O,N) donor bidentate ligands

Complex formation processes of the (O,N) donor ligands 6-methylpicolinic acid (6-Mepic), quinoline-2-carboxylic acid (2-QA) and 3-isoquinolinecarboxylic acid (3-iQA) with the organometallic moiety (eta5-pentamethylcyclopentadienyl)rhodium(III) (RhCp*) were studied in aqueous solution by the combined use of pH-potentiometry, 1H NMR spectroscopy and UV-Vis spectrophotometry. The solid phase structures of the [RhCp*(L)Cl] complexes bearing 6-Mepic and 2-QA were characterized by single-crystal X-ray diffraction analysis. Studies revealed the exclusive formation of mono complexes of the form [RhCp*(L)(H2O)]+ (L = deprotonated form of the ligands) and [RhCp*(L)(OH)]. The positively charged aqua species predominate at physiological pH even in the micromolar concentration range. The H2O/Cl? co-ligand exchange constants showed that all complexes preferably retain the chlorido ligand at the third coordination site at chloride ion concentrations present in the serum. In addition in vitro cytotoxicity of these [RhCp*(L)Cl] complexes was evaluated in three human cancer cell lines (A549, SW480 and CH1/PA-1) where they showed minor cytotoxic potency.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Heptapeptide-based modification leading to enhancing the action of MTCA on activated platelets, P-selectin, GPIIb/IIIa

Aim: The modification of platelet inhibitor to enhance its targeting capacity toward platelets is of clinical importance. Thus, (1R, 3S)-1-methyl-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA), a platelet inhibitor, was modified with Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (KKV), platelet targeting peptide, to form MTCA-KKV. Materials & methods: MTCA and MTCA-KKV were synthesized to identify the effect of KKV modification on MTCA and platelets. Results: Atomic force microscopy imaged MTCA-KKV effectively accumulated on activated platelets. UV spectra showed that MTCA-KKV concentration dependently changed P-selectin and GPIIb/IIIa conformations. For platelet aggregation, the IC50 of MTCA-KKV was approximately 1/10 folds of MTCA. Conclusion: KKV modification led to forming MTCA-KKV that is superior to MTCA in terms of accumulating on activated platelets, targeting P-selectin and GPIIb/IIIa and inhibiting platelet aggregation. MTCA-KKV could be a promising lead for further investigation.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

Emerging evidence indicates that dysfunctional glutamate neurotransmission is critical in the initiation and development of alcohol and drug dependence. Alcohol consumption induced downregulation of glutamate transporter 1 (GLT-1) as reported in previous studies from our laboratory. Glutamate is the major excitatory neurotransmitter in the brain, which acts via interactions with several glutamate receptors. Alcohol consumption interferes with the glutamatergic signal transmission by altering the functions of these receptors. Among the glutamate receptors involved in alcohol-drinking behavior are the metabotropic receptors such as mGluR1/5, mGluR2/3, and mGluR7, as well as the ionotropic receptors, NMDA and AMPA. Preclinical studies using agonists and antagonists implicate these glutamatergic receptors in the development of alcohol use disorder (AUD). Therefore, the purpose of this review is to discuss the neurocircuitry involving glutamate transmission in animals exposed to alcohol and further outline the role of metabotropic and ionotropic receptors in the regulation of alcohol-drinking behavior. This review provides ample information about the potential therapeutic role of glutamatergic receptors for the treatment of AUD.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Whole-cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular

Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis. Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1H-indol-3-yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo. The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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NOVEL ANTIPRION COMPOUNDS

Described herein are novel compositions and methods of treatment addressing diseases such as neurodegenerative diseases, including prion diseases and Alzheimer’s disease.

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2,3-Diamino acid modifying 3S-tetrahydroisoquinoline-3-carboxylic acids: Leading to a class of novel agents with highly unfolded conformation, selective in vitro anti-platelet aggregation and potent in vivo anti-thrombotic activity

In the preparation of anti-thrombotic agents the 2- and 3-positions of 3S-tetra-hydroisoquinoline-3-carboxylic acid (THIQA) were simultaneously modified with amino acids to form 20 novel N-(3S-N-aminoacyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino acids (8a-t). On an in vitro platelet aggregation model 8a-t selectively inhibit ADP-induced platelet aggregation and their IC50 values are leas than 3.5 nM. On an extracorporeal circulation of arterioveinos cannula model of rats both orally and intraveously effective doses of 8a-t are less than 30 nmol/kg. Cerius2 based stereoview of explores 8a-t having highly unfolded conformation. 3D QSAR analysis gives the importance of the unfolded conformation to high in vitro anti-platelet aggregation and in vivo anti-thrombotic potency rational understanding.

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Isoquinoline – Wikipedia,
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Organocatalytic decarboxylative alkylation of N-hydroxy-phthalimide esters enabled by pyridine-boryl radicals

The decarboxylative alkylation of N-hydroxyphthalimide (NHPI) based reactive esters with olefins has been achieved via an organocatalytic strategy. Control experiments and density functional theory calculations suggest that these reactions involve a boryl-radical mediated decarboxylation pathway, which is different from the single electron transfer involved in decarboxylative alkylation reactions reported previously. This metal-free decarboxylative alkylation reaction features good functional compatibility, and broad substrate scope illustrated by the transformations of both the alkyl and aryl carboxylic acid derivatives.

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CHEMICAL COMPOUNDS

A compound which is a pyridine or isoquinoline derivative of formula (I), or a pharmaceutically acceptable salt thereof, which is useful in the inhibition of gamma- butyrobetaine hydroxylase (BBOX). The compounds are particularly useful in treatment of cardiovascular disease and diabetes. (I)

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ARYL AND HETEROARYL COMPOUNDS AND METHODS TO MODULATE COAGULATION

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are useful in a variety of applications including the management, treatment and/or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem