Discovery of novel fluorescent azaindoles with cytotoxic action in A2780 ovarian carcinoma cells.

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3a-d) and N-methyl-N-benzylamine (azaindoles 4a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4b and 4c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives.

Synthesis and Biological Evaluation of Hybrid 1,5- and 2,5-Disubstituted Indoles as Potentially New Antitubercular Agents.

BACKGROUND: Tuberculosis (TB) is the second leading cause of mortality worldwide being a highly contagious and insidious illness caused by Mycobacterium tuberculosis, Mtb. Additionally, the emergence of multidrug-resistant and extensively drug-resistant strains of Mtb, together with significant levels of co-infection with HIV and TB (HIV/TB) make the search for new antitubercular drugs urgent and challenging. METHODS: This work was based on the hypothesis that an active compound could be obtained if substituents present in some other active compounds were attached on a core of an important structure, in this case the indole scaffold, thus generating a hybrid compound. A QSAR-oriented design based on classification and regression models along with the estimation of physicochemical and biological properties have also been used to assist in the selection of compounds. Chosen compounds were synthesized using various synthetic procedures and evaluated against M. tuberculosis H37Rv strain. RESULTS: Selected compounds possess substituents at positions C5, C2 and N1 of the indole ring. The substituents involve p-halophenyl, pyridyl, benzyloxy and benzylamine groups. Four compounds were synthesised using suitable synthetic procedures to attain the desired substitution at the indole core. From these, three compounds are new and have been fully characterized, and tested in vitro against the H37Rv ATCC27294T Mtb strain, using isoniazid as a control. One of them, compound 2, with the pyridyl group at N1, has an experimental log (1/MIC) very close to 5 and can be considered as being (weakly) active. In fact, it is more active than 64% of all indole molecules in our data sets of experimental results from literature. The most active indole in this data sets has log (1/MIC)=5.93 with only 6 compounds with log (1/MIC) above 5.5. CONCLUSION: Despite the lower activity found for the tested compounds, when compared to other reported indole-derivatives, these structures, which rely on a hybrid design concept, may constitute interesting scaffolds to prepare a new family of TB inhibitors with improved activity.

Prediction of 1H NMR coupling constants with associative neural networks trained for chemical shifts.

Fast accurate predictions of 1H NMR spectra of organic compounds play an important role in structure validation, automatic structure elucidation, or calibration of chemometric methods. The SPINUS program is a feed-forward neural network (FFNN) system developed over the last 8 years for the prediction of 1H NMR properties from the molecular structure. It was trained using a series of empirical proton descriptors. Ensembles of FFNNs were incorporated into Associative Neural Networks (ASNN), which correct a prediction on the basis of the observed errors for the k nearest neighbors in an additional memory. Here we show a procedure to estimate coupling constants with the ASNNs trained for chemical shifts-a second memory is linked consisting of coupled protons and their experimental coupling constants. An ASNN finds the pairs of coupled protons most similar to a query, and these are used to estimate coupling constants. Using a diverse general data set of 618 coupling constants, mean absolute errors of 0.6-0.8 Hz could be achieved in different experiments. A Web interface for 1H NMR full-spectrum prediction is available at http://www.dq.fct.unl.pt/spinus.

Synthesis of analogue structures of the p-quinone methide moiety of kendomycin.

[reaction: see text] The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally applicable. Additionally, it was found that oxidation of a benzofuran by NaIO(4) on silica produced a long-lived semiquinone radical.

Toward the synthesis of the carbacylic ansa antibiotic kendomycin.

The convergent synthesis of a benzofuran analog of the carbacyclic ansa compound kendomycin has been achieved by assembling three major fragments by means of epoxide opening and directed ortho lithiation. The crucial tetrahydropyran ring was formed by a highly stereoselective cationic cyclization. Analysis of all synthesized tetrahydropyran-arene compounds reveals a hindered sp(2)-sp(3) rotation, which results in rotational isomers or atropisomers affecting macrocyclization reactions. The latter could only be achieved by means of Horner-Wadsworth-Emmons olefination.

A novel approach toward the synthesis of kendomycin: selective synthesis of a C-aryl glycoside as a single atropisomer.

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.