Ramona Danac

Antimycobacterial activity of nitrogen heterocycles derivatives: Bipyridine derivatives. Part III [13,14]

Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.

New indolizines with phenanthroline skeleton: Synthesis, structure, antimycobacterial and anticancer evaluation.

We report herein a feasible study concerning the design, synthesis, structure and in vitro antimycobacterial and anticancer activity of two new classes (containing four and five fused rings) of indolizine with phenanthroline skeleton. The preparation is straight and efficient, involving a Huisgen [3+2] dipolar cycloaddition of cycloimmonium ylides to alkynes or alkenes dipolarophiles. The cycloaddition reactions are highly stereo- or regioselective, according with the dipolarophiles nature. The structure of the new compounds was assigned unambiguously, X-ray analysis including. The primary antimycobacterial screening reveals that one of the thirteen tested compounds had a good activity against Mycobacterium tuberculosis H37Rv under aerobic conditions. The antiproliferative evaluation against a NCI 60 human tumor cell line panel, revealed that two indolizine with phenanthroline skeleton exhibit a selective and significant antitumor growth inhibitory activity against Breast Cancer (MCF7 and T-47D) and a slightly moderate activity against some forms of Leukemia, Non-Small Cell Lung Cancer, Renal Cancer and Breast Cancer (MDA-MB-468). The X-ray diffraction study of the indolizines with phenanthroline skeleton prove a flat coplanar structure which, corroborated with their anticancer activity, allow us to suggest that an interaction with DNA (via an intercalation mechanism) would be reasonable.

Design, synthesis and antimycobacterial evaluation of some new azaheterocycles with the 4,7-phenanthroline skeleton. Part VI

A feasible study concerning the synthesis, structure and in vitro antimycobacterial evaluation of new 4,7-phenanthroline derivatives is reported. The preparation is straight and efficient, involving an N -alkylation reaction of 4,7-phenanthroline. The structure of the new compounds have been proved by elemental and spectral (IR, 1 H and 13 C NMR) analysis. The in vitro antimycobacterial evaluation of five synthesized compounds was investigated against Mycobacterium tuberculosis H37Rv under aerobic conditions, two of them being active. A certain influence of substituents from the para position of the benzoyl moiety was observed, the 4,7-phenanthrolin-4-ium salt substituted with ( p )chloro-benzoyl showing the most pronounced antimycobacterial activity.

New cycloimmonium ylide ligands and their palladium(II) affinities

Ten new stable 4-(4′-pyridyl)pyridinium disubstituted monoylides were synthesized by the reaction of 4-(4′-pyridyl)pyridinium monosubstituted ylides with electrophiles as aromatic isocyanates and isothiocyanates. The facile synthesis and high stability of the new ylides were attributed not only to the delocalization of both negative and positive charges, but also to the intramolecular hydrogen bond. This bond was proved to be present both in solution (by NMR) and solid phase (by X-ray crystallography). The computational studies using density functional theory calculations (DFT) suggest, as well, an important charge delocalization in gas-phase structures for simplified model disubstituted cycloimmonium ylides. The palladium complexation for two of the new ylides was studied using NMR titrations and quantified using UV-visible spectroscopy titrations.

Novel cyclodextrin-based pH-sensitive supramolecular host–guest assembly for staining acidic cellular organelles

The preparation and characterization of a supramolecular host–guest inclusion complex between a fluorescent indolizinyl-pyridinium salt and β-cyclodextrin is reported. The formation of the inclusion complex was investigated by ESI-MS experiments, transmission electron microscopy, Jobs plot investigations and molecular docking studies, proving the formation of 1 : 1 and 1 : 2 species. Several interesting features of the investigated fluorescent indolizinyl-pyridinium salt/β-cyclodextrin inclusion complexes like the absence of cytotoxicity, cellular permeability, long-lived intracellular fluorescence and selective accumulation within acidic organelles made them remarkable candidates for the intracellular labelling of acidic organelles (lysosomes or mitochondria). Taking into account that a number of reported or commercially available cell staining dyes with low toxicity and solubility have already been used in cyclodextrin formulations with good results regarding the improvement of their properties, our results showed that this approach may also work with new and interesting toxic dyes capable of forming host–guest inclusion complexes with cyclodextrins.

Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII8–12

Abstract A series of 13 compounds having a monoindolizine mono-salt skeleton was designed and synthesised in order to evaluate their antimycobacterial activity. The synthesis is efficient, involving only three steps: two alkylations and one 3 + 2 dipolar cycloaddition. The antimicrobial activity against Mycobacterium tuberculosis H37Rv grown under aerobic conditions was evaluated, eight compounds showing a very good antimycobacterial activity. SAR correlation reveals a certain influence of the R substituent from the para position of benzoyl moiety at position 3 of indolizine. The most active five compounds passed the second stage of anti-TB testing, the assay demonstrating that they are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to high cytotoxicity. For one compound showing a promising anti-TB profile, a complete ADMET study has been performed.

New conjugates of calix[4]arenes bearing dipyridine and indolizine heterocycles

A simple route to introduce various heterocycles, derivatives of dipyridyls and indolizines on the lower rim of the para-tert-butylcalix[4]arene via ester bond formation to afford 1,3-disubstituted conjugates is described. The conformation of the new compounds and some intermolecular interactions are discussed on the basis of X-ray and NMR analyses. Preliminary complexation properties of some of the new tert-butylcalix[4]arene heterocyclic conjugates with Cu (II), Co (II) and Ni (II) were studied by means of UV–Vis titration.

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Abstract A study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c][4,7]phenanthroline skeleton is described. The strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. Stereo- and regiochemistry of cycloaddition reactions were discussed. The structure of the new compounds was proven unambiguously, single-crystal X-ray diffraction studies including. The antimycobacterial and anticancer activity of a selection of new synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv under aerobic conditions and 60 human tumour cell line panel, respectively. Five of the tested compounds possess a moderate antimycobacterial activity, while two of the compounds have a significant antitumor activity against renal cancer and breast cancer.