- The syntheses of isotopically labelled CB-1 antagonists for the treatment of obesity
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BMS-725519, BMS-811064, and BMS-812204 are potent and selective central cannabinoid receptor antagonists that have been investigated for the treatment of human obesity. To further understand their biotransformation profiles, radiolabelled and stable-labelled products were required. This paper describes the utility of [14C]1,1-carbonyldiimidazole as a radiolabelling reagent for the syntheses of carbonyl-labelled [14C]BMS-725519, [14C]BMS-811064, and [14C]BMS-812204. The syntheses of stable-labelled [13C6]BMS-725519 and [13CD3 13CD2]BMS-812204 synthesized from of [13C6]4-chloroacetophenone and [13CD3 13CD2]iodoethane, respectively, are also described.
- Tran, Scott B.,Maxwell, Brad D.,Burrell, Richard,Bonacorsi, Samuel J.
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Read Online
- Synthesis and structural study of some N-acyl-4-allylsemicarbazides and the product of their cyclization with a potential antimicrobial activity
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In this paper semicarbazide (2a-2h) and 1,2,4-trazole (3a-3h) derivatives with allyl group were synthesized. All compounds were tested in vitro for their antimicrobial activity showing different activity to E. coli, S. aureus, S. epidermidis, M. smegmatis, M. phlei and M. tuberculosis H37Ra. The antimicrobial activity is showed 2g against S. epidermidis, 3g against E. coli and S. epidermidis and 3h against E. coli. The crystal structure of determinations of 2b, 2d, 3b, 3c and 3e were undertaken in order to confirm the synthesis pathway and identification of their tautomeric forms in the crystalline state. Theoretical calculations showed that the physico-chemicals (logP) and electronic properties (MEP distribution, energy localization of HOMO and LUMO orbitals) are related to observed antimicrobial activity of investigated compounds. The molecular docking study carried out for the most active against M. tuberculosis compound 3b using the M. tuberculosis cytochrome P450 CYP121 showed that this compound binds to the active site of P450 by hydrogen bonds via water molecule with the amino acid residue of Met86A and molecule of hem.
- Drozd, Monika,Ginalska, Grazyna,Karczmarzyk, Zbigniew,Kowalczuk, Dorota,Morawiak, Maja,Pitucha, Monika,Swatko-Ossor, Marta,Urbanczyk-Lipkowska, Zofia,Wysocki, Waldemar
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- Synthesis, in vitro screening and docking studies of new thiosemicarbazide derivatives as antitubercular agents
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A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei, M. smegmatis, M. timereck. The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81–31.25 μg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 μg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 μg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.
- Pitucha, Monika,Karczmarzyk, Zbigniew,Swatko-Ossor, Marta,Wysocki, Waldemar,Wos, Maciej,Chudzik, Kamil,Ginalska, Grazyna,Fruzinski, Andrzej
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- Tetrazolylhydrazides as selective fragment-like inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
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The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr=142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases. Anchor fragment: To develop non-promiscuous metalloenzyme inhibitors, a metal-complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.
- Rüger, Nicole,Roatsch, Martin,Emmrich, Thomas,Franz, Henriette,Schüle, Roland,Jung, Manfred,Link, Andreas
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supporting information
p. 1875 - 1883
(2015/11/10)
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- Synthesis, experimental and theoretical study on the structure of some semicarbazides with potential antibacterial activity
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A series of 1,4-disubstituted semicarbazide and 4,4'-bis[1-substituted semicarbazide]diphenyl-methane derivatives were synthesized to explore their antibacterial activity. New compounds were characterized by elemental analysis and spectroscopic data. In order to find the tautomeric equilibrium for the molecules energy calculations for each possible tautomeric form of model compound 2, and for the most antibacterially active compound 7 in the investigated series, were calculated for the gas phase at the RHF/SCF/6-31G** level of theory.
- Pitucha, Monika,Karczmarzyk, Zbigniew,Kosikowska, Urszula,Malm, Anna
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scheme or table
p. 505 - 511
(2011/06/28)
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- Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3, 4-dihydrospiro[chromene-2,4′-piperidine] analogs
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In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol- 2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID 50 = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC 50 (mouse) = 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
- Uto, Yoshikazu,Ueno, Yuko,Kiyotsuka, Yohei,Miyazawa, Yuriko,Kurata, Hitoshi,Ogata, Tsuneaki,Yamada, Makiko,Deguchi, Tsuneo,Konishi, Masahiro,Takagi, Toshiyuki,Wakimoto, Satoko,Ohsumi, Jun
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supporting information; experimental part
p. 4788 - 4796
(2010/12/18)
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- NAPHTHYRIDINE INTEGRASE INHIBITORS
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The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
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