48 research outputs found
Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors
Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5'-dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length. IAS derivatives look like promising drug candidates for the treatment of AIDS and related infections in combination with other antiretroviral agents
Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes â NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases
Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors
Cannabinoid (CB) and opioid systems are both involved in analgesia, food intake, mood and behavior. Due to the co-localization of micro-opioid (MOR) and CB1 receptors in various regions of the central nervous system (CNS) and their ability to form heterodimers, bivalent ligands targeting to both these systems may be good candidates to investigate the existence of possible cross-talking or synergistic effects, also at sub-effective doses. In this work, we selected from a small series of new Rimonabant analogs one CB1R reverse agonist to be conjugated to the opioid fragment Tyr-D-Ala-Gly-Phe-NH2. The bivalent compound (9) has been used for in vitro binding assays, for in vivo antinociception models and in vitro hypothalamic perfusion test, to evaluate the neurotransmitters release
Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed ICâ
â = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes
Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed ICâ
â = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes
New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer
We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway
Profiling of non-esterified fatty acids in human plasma using liquid chromatography-electron ionization mass spectrometry
This paper focuses on the development of a
novel approach to analyze underivatized fatty acids in
human plasma. The method is based on liquidâliquid
extraction followed by reversed phase liquid chromatography
coupled to direct-electron ionization mass spectrometry
(LC-Direct-EI-MS). The assay is validated. Calibrations
show satisfactory linearity and precision in the investigated
range of linearity. Recoveries span from 75% to 104%. The
method limits of detection, varying from 0.53 to 5.35 ÎŒM,
are satisfactory for the quantitation of non-esterified fatty
acids (NEFAs) in plasma at physiological levels. The
method has been successfully applied to the NEFAs
profiling of plasma samples from healthy adult volunteers
and subjects affected by diabetes mellitus. Compared with
published protocols based on gas chromatographyâmass
spectrometry and liquid chromatography coupled to electrospray
ionization mass spectrometry, this method does not
require derivatization and does not show matrix effects,
thus simplifying sample preparation procedure and reducing
the total time of analysis to approximately 90 min. In
addition, Direct-EI-MS allows the acquisition of highquality
NIST library-matchable EI spectra, allowing an
easy-to-obtain identification of the target NEFAs
A new liquid chromatographyâmass spectrometry approach for generic screening and quantitation of potential genotoxic alkylation compounds without derivatization
One of the crucial tasks of pharmaceutical industry is to quantify the potential genotoxic impurities (PGIs)
coming from the process of drug production. The European Medicines Agency (EMEA) imposes analytical
testing limits in the order of g/g, depending on drug dosage and exposure period, that means the need of
a sensitive and selective method of analysis. Liquid chromatography coupled to electrospray ionization
mass spectrometry (LCâESI-MS) has been demonstrated as the most versatile approach to detect PGIs in
complex matrices. However, time consuming derivatization processes are needed to enhance sensitivity
and selectivity, and to overcome matrix effects (ME) that may arise from active pharmaceutical ingredients
(APIs) or excipients. We propose the use of the Direct-EI LCâMS as an alternative approach to detect
and quantify PGIs in drug formulations. The Direct-EI LCâMS interface is based on electron ionization (EI)
which is well suited for the detection of low molecular weight compounds of different polarity, without
derivatization and with no sign of ME. The method has been successfully applied to the detection of PGIs
belonging to the class of alkylation agents. Calibration experiments show satisfactory linearity and precision
data. Recoveries in low enriched samples spanned from 55 to 82%, and were not affected by ME. The
method limits of detection (LODs), varying from 0.13 to 1.5 g/g, were satisfactory for the quantitation
of the target PGIs at the level required by regulatory agencies
Determination of natural pyrethrins by liquid chromatography-electron ionisation-mass spectrometry.
Introduction â Pyrethrum extract is a mixture of six insecticidal compounds from the flower heads of Chrysanthemum cinerariaefolium
L.. Since they only have low to moderate mammalian toxicity they can be used as natural insecticides in agriculture
or to develop low cost and safe dermatological formulations. Because of the thermal instability of pyrethrins, analytical
methods based on liquid chromatography (LC) are preferred over those based on gas chromatography (GC). A few applications
using LC with mass spectrometry detection are presented in the literature. Current protocols for their characterisation
by LC rely on the use of less sophisticated detectors such as UV detection.
Objective â To develop the first liquid chromatographyâelectron ionisationâmass spectrometry (LCâEIâMS) method for pyrethrins
detection and quantitation in pyrethrum extracts.
Methodology â A commercial pyrethrum extract and various samples of flower heads from C. cinerariaefolium L. were investigated
using reversedâphase nanoâliquid chromatography coupled to direct electron ionisationâmass spectrometry (nanoLCdirect
EIâMS). The eluted compounds were identified through searches of the US National Institute of Standards and
Technology (NIST) library, exploiting the direct EI capability to produce high quality EI mass spectra.
Results â The method demonstrated satisfactory sensitivity (limit of detection (LOD) range: 0.04â0.38 mg/g), linearity (R2
range: 0.9740â0.9983) and precision (RSD% range: 4â13%) for the quantitation of the natural pyrethrins in extracts from
C. cinerariaefolium L.
Conclusion â The nanoLCâdirect EIâMS technique can be a useful tool for the detection of pyrethrins