Herein, we report our preliminary results concerning the first promising asymmetric synthesis of highly functionalized 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)] via the reaction of an enamine with isatylidene malononitrile derivatives in the presence of a chiral base organocatalyst. The moderate, but promising, enantioselectivity observed (30%-58% ee (enantiomeric excess)) opens the door to a new area of research for the asymmetric construction of these appealing spirooxindole skeletons, whose enantioselective syntheses are still very limited.
The
first cinchona-alkaloid-organocatalyzed enantioselective synthesis
of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona
catalyst 3b activates the Michael addition reaction between
malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very
few examples of the synthesis of chiral 1,4-dihydropyridines by an
enantioselective catalytic procedure. The highly substituted final
compounds are of interest for their potential biological activity.
This efficient protocol opens the door to a new area of research for
the asymmetric construction of these skeletons for which enantioselective
syntheses are still very limited.
This study reports the synthesis and biological investigation of three series of novel -lactams bearing a morpholine substituent of the nitrogen center. These products were synthesized via Staudinger's [2+2]-ketene-imine cycloaddition reaction. The cycloadducts were fully characterized by spectral data, including 1 H-NMR, 13 C-NMR, IR, mass spectroscopy and elemental analyses, and then evaluated for anti-inflammatory activity. A number of the derivatives demonstrated higher therapeutic ratios than dexamethasone and corticosteroid medication. In silico molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response.
In our ongoing search for bioactive compounds, a class of novel spiro-β-lactam isatin hybrids has been synthesized through a [2+2] cycloaddition reaction from 1-allyl-3-(arylimino)indolin-2-one, ketenes and various aryloxy acetic acids. The formation of all cycloadducts was confirmed by FTIR, 1 H NMR, 13 C NMR, and mass spectroscopy as well as elemental analyses. The new βlactams were subsequently evaluated for their biological activities demonstrating moderate to good activities against P. falciparum K1 strain. Among them, 4b and 4e lead to the best results with IC 50 of 5.04 and 7.18 µM, respectively. The molecular docking simulation of 4b with P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site presented several important intermolecular interactions. All the synthesized β-lactams were also evaluated for their antimicrobial activities against both Gram-positive (S. aureus ATCC 25923) and Gram-negative bacteria (E. coli ATCC 28922, P. aeruginosa ATCC 27853) but unfortunately MICs up to 200 µg/mL were encountered in all cases.
Several monocyclic β-lactams have been synthesized via a [2 + 2] ketene-imine cycloaddition reaction (Staudinger reaction) and evaluated for their biological activities. The structure of synthesized products was confirmed by spectral data and elemental analyses. β-Lactams 4 b and 4 h exhibited 31 and 27 anti-inflammatory ratios, respectively, which are as well as the well-known dexamethasone corticosteroid with a 32 antiinflammatory ratio. The two most active compounds 4 b and 4 h showed IC 50 values more than 200 μM against the HepG2 cell line, in comparison with doxorubicin (IC 50 < 1 μM), indicated biocompatibility and nontoxic behavior. 4 d, 4 j, 4 k, and 4 l, were active against S. aureus and E. coli and had broad spectrum property. The tested compounds were subjected to in silico prediction of pharmacokinetics properties (ADMET) to assess the potential in vivo effectiveness. The molecular docking study confirmed that the active inhibitors 4 b and 4 h are well fitted in the iNOS active site. This data suggests that 4 b and 4 h could potentially serve as effective iNOS inhibitors, a represent promising lead compounds for treating inflammatory disorders.
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