A new series of 1-benzyl-3-(imidazol-1-ylmethyl)indoles were synthesized according to a previous 3D-QSAR predictive model and assayed for their antiparasitic activity upon Leishmania mexicana ...promastigotes. The biological results obtained for these twelve molecules showed an IC50 ranging from 2.3 to 32 μM and mainly illustrated the importance of the hydrophobic parameter the para-position of the benzyl group. In order to improve the activities of these compounds and to check the potential influence of the electronic parameter on this particular position, a Craig diagram was used to select original electro-donating and lipophilic substituents. Synthesis and biological evaluation of ten new compounds (IC50 between 2.5 and 5.4 μM) confirmed that only the hydrophobic field is essential for a high level of activity.
A series of 1-(
N-benzylamino)-2-phenyl-3-(1
H-1,2,4-triazol-1-yl)propan-2-ols were synthesized for their antifungal activity on two strains of
Candida albicans and
Aspergillus fumigatus. Synthesis ...and SAR studies that led to the most active compound
7b are discussed with the help of molecular modeling.
A series of 1-(
N-benzylamino)-2-phenyl-3-(1
H-1,2,4-triazol-1-yl)propan-2-ols
6a–
c,
7a–
c,
8a, and
9a were prepared in five steps and evaluated for their antifungal activity. The most active compound
7b was docked into a home-made 3D model of the targeted enzyme confirming the importance of Tyr118, His377, and Ser378 residues in its binding mode.
We recently described a novel series of CA1A2X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A1A2 residue. ...Extensive exploration of structure−activity relationships revealed that replacement of cysteine by substituted benzylimidazoles provided nanomolar FTIs with in vitro activities (18e, IC50 = 4.60 nM on isolated enzyme, EC50 = 20.0 nM for growth inhibition on a tumor cell line). The molecular docking of 18e and 19e in the active site of the enzyme provided details of key interactions with the protein and showed that the methionine or phenylalanine residue fits into the aryl binding site.
A series of 1-(1
H-indol-5-ylmethyl)amino-2-phenyl-3-(1
H-1,2,4,-triazol-1-yl)propan-2-ols were synthesized and evaluated in vitro against
Candida
albicans and
Aspergillus
fumigatus strains. All the ...compounds exhibited potent MICs (<65
ng
mL
−1) against
C. albicans strain. The SAR studies behind the indole scaffold will be discussed.
We previously reported on the design and synthesis of 1-((hetero)aryl- or piperidinylmethyl)amino-2-phenyl-3-(1
H-1,2,4-triazol-1-yl)propan-2-ols showing various degrees of antifungal activity against
Candida albicans and
Aspergillus fumigatus strains. Now we have identified a series of 1-(1
H-indol-5-ylmethyl)amino derivatives which exhibited potent MICs (<65
ng
mL
−1) against
C. albicans strain. The synthesis and SAR behind the indole scaffold will be discussed.
Very little is known about chemical interactions between fungi and their mollusc host within marine environments. Here, we investigated the metabolome of a Penicillium restrictum MMS417 strain ...isolated from the blue mussel Mytilus edulis collected on the Loire estuary, France. Following the OSMAC approach with the use of 14 culture media, the effect of salinity and of a mussel-derived medium on the metabolic expression were analysed using HPLC-UV/DAD-HRMS/MS. An untargeted metabolomics study was performed using principal component analysis (PCA), orthogonal projection to latent structure discriminant analysis (O-PLSDA) and molecular networking (MN). It highlighted some compounds belonging to sterols, macrolides and pyran-2-ones, which were specifically induced in marine conditions. In particular, a high chemical diversity of pyran-2-ones was found to be related to the presence of mussel extract in the culture medium. Mass spectrometry (MS)- and UV-guided purification resulted in the isolation of five new natural fungal pyran-2-one derivatives—5,6-dihydro-6S-hydroxymethyl-4-methoxy-2H-pyran-2-one (1), (6S, 1’R, 2’S)-LL-P880β (3), 5,6-dihydro-4-methoxy-6S-(1’S, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (4), 4-methoxy-6-(1’R, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (6) and 4-methoxy-2H-pyran-2-one (7)—together with the known (6S, 1’S, 2’S)-LL-P880β (2), (1’R, 2’S)-LL-P880γ (5), 5,6-dihydro-4-methoxy-2H-pyran-2-one (8), (6S, 1’S, 2’R)-LL-P880β (9), (6S, 1’S)-pestalotin (10), 1’R-dehydropestalotin (11) and 6-pentyl-4-methoxy-2H-pyran-2-one (12) from the mussel-derived culture medium extract. The structures of 1-12 were determined by 1D- and 2D-MMR experiments as well as high-resolution tandem MS, ECD and DP4 calculations. Some of these compounds were evaluated for their cytotoxic, antibacterial, antileishmanial and in-silico PTP1B inhibitory activities. These results illustrate the utility in using host-derived media for the discovery of new natural products.
Potassium 6-oxo-7,13,16,22-tetraazatetracyclo12.6.2.1sup.8,12.0sup.17,21tricosa-1(20),8(23),9,11,14,16,18,21-octaen-2-yne-15-carboxylate was synthesized through a multi-step pathway, starting from ...commercially available 3-iodo-1,2-phenylenediamine. Structure characterization of this new substituted macrocyclic quinoxaline compound was achieved using sup.1H NMR, sup.13C NMR, and HRMS spectral analysis. This new macrocyclic derivative demonstrated submicromolar potency on both Pim-1 and Pim-2 isoforms, with an interesting selectivity profile against a selected panel of human kinases.
This paper reports the design and synthesis of a novel series of 8-arylpyrido3′,2′:4,5thieno3,2-dpyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole ...series, 3-amino-5-bromothieno2,3-bpyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N′-(5-bromo-2-cyanothieno2,3-bpyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido3′,2′:4,5thieno3,2-dpyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido3′,2′:4,5thieno3,2-dpyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido3′,2′:4,5thieno3,2-dpyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido3′,2′:4,5thieno3,2-dpyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity.
A three-dimensional (3-D) structure of human aromatase (CYP19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 ...and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles of Asp309 and His480 in the aromatization of the steroid A ring.
The condensation of 2-aminoindole-3-carbonitriles and their 3-aminoindole-2-carbonitrile isomers with various DMF-dialkoxyacetals was investigated under microwaves. The appearance of reactive and ...versatile alkoxyiminium species allowed convenient access to indole precursors of building blocks with potential biological activity. The experimental results have been rationalised using DFT calculations of theoretical descriptors based on the electrostatic potential.
DMF-dialkoxyacetals allowed the appearance of reactive alkoxyiminium species for convenient access to indole precursors of various building blocks.
A concise approach to 5-arylamino-4
H-pyran-4-ones is described via palladium-catalyzed amination reaction.
A concise approach to 5-arylamino-4
H-pyran-4-ones is described via palladium-catalyzed ...amination reaction. The methodology involved in this Letter is based on protection/deprotection protocols and on manipulation of the 5-hydroxy group of readily available kojic acid. It would provide a new entry to a range of 5-arylamino-4
H-pyran-4-ones via Buchwald–Hartwig-type amination reaction on 4
H-pyran-4-one unit.
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