Synthesis, Characterization and Cytotoxic Evaluation of New Pyrrolo[1,2-b]pyridazines Obtained via Mesoionic Oxazolo-Pyridazinones.

New pyrrolo[1,2-b]pyridazines were synthesized by 3 + 2 cycloaddition reaction between mesoionic oxazolo-pyridazinones and methyl/ethyl propiolate. The mesoionic compounds were generated in situ by action of acetic anhydride on 3(2H)pyridazinone acids obtained from corresponding esters by alkaline hydrolysis followed by acidification. The structures of the compounds were confirmed by elemental analyses and IR, 1H-NMR, 13C-NMR, and X-ray diffraction data. The regioselectivity of cycloaddition was evidenced by NMR spectroscopy and confirmed by X-ray analysis. The compounds were evaluated for their cytotoxicity on plant cells (Triticum aestivum L.) and crustacean animal cells (Artemia franciscana Kellogg and Daphnia magna Straus). The results indicated that the tested compounds exhibited low toxicity on the plant cell (IC50 values higher than 200 µM), while on Artemia nauplii no lethality was observed. Daphnia magna assay showed that pyrrolo[1,2-b]pyridazines 5a and 5c could exhibit toxic effects, whereas, for the other compounds, toxicity was low to moderate. Also, the cytotoxic effects of the compounds were tested on three human adenocarcinoma-derived adherent cell lines (colon LoVo, ovary SK-OV-3, breast MCF-7). The in vitro compound-mediated cytotoxicity assays, performed by the MTS technique, demonstrated dose- and time-dependent cytotoxic activity for several compounds, the highest anti-tumor activity being observed for 5a, 2c, and 5f, especially against colon cancer cells.

Insights into the Microbicidal, Antibiofilm, Antioxidant and Toxicity Profile of New O-Aryl-Carbamoyl-Oxymino-Fluorene Derivatives.

The unprecedented increase in microbial resistance rates to all current drugs raises an acute need for the design of more effective antimicrobial strategies. Moreover, the importance of oxidative stress due to chronic inflammation in infections with resistant bacteria represents a key factor for the development of new antibacterial agents with potential antioxidant effects. Thus, the purpose of this study was to bioevaluate new O-aryl-carbamoyl-oxymino-fluorene derivatives for their potential use against infectious diseases. With this aim, their antimicrobial effect was evaluated using quantitative assays (minimum inhibitory/bactericidal/biofilms inhibitory concentrations) (MIC/MBC/MBIC), the obtained values being 0.156-10/0.312-10/0.009-1.25 mg/mL), while some of the involved mechanisms (i.e., membrane depolarization) were investigated by flow cytometry. The antioxidant activity was evaluated by studying the scavenger capacity of DPPH and ABTS•+ radicals and the toxicity was tested in vitro on three cell lines and in vivo on the crustacean Artemia franciscana Kellog. The four compounds derived from 9H-fluoren-9-one oxime proved to exhibit promising antimicrobial features and particularly, a significant antibiofilm activity. The presence of chlorine induced an electron-withdrawing effect, favoring the anti-Staphylococcus aureus and that of the methyl group exhibited a +I effect of enhancing the anti-Candida albicans activity. The IC50 values calculated in the two toxicity assays revealed similar values and the potential of these compounds to inhibit the proliferation of tumoral cells. Taken together, all these data demonstrate the potential of the tested compounds to be further used for the development of novel antimicrobial and anticancer agents.

New Pyrrole Derivatives as Promising Biological Agents: Design, Synthesis, Characterization, In Silico, and Cytotoxicity Evaluation.

The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, 1H-NMR and 13C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., Triticum aestivum L.) and animal cells using aquatic crustaceans (i.e., Artemia franciscana Kellogg and Daphnia magna Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on Triticum aestivum L., while on Artemia franciscana Kellogg nauplii, only compounds 2c and 4c had moderate toxicity. On Daphnia magna, 4b and 4c showed high toxicity; 2a, 2b, and 2c moderate to high toxicity; only 4a and 4d were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by 4a and its homologue 4d, especially against LoVo colon cells.

Synthesis and Toxicity Evaluation of New Pyrroles Obtained by the Reaction of Activated Alkynes with 1-Methyl-3-(cyanomethyl)benzimidazolium Bromide.

A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new tri- and tetra-substituted N-arylpyrroles were synthesized by the one-pot reaction of 1-methyl-3-cyanomethyl benzimidazolium bromide with substituted alkynes having at least one electron-withdrawing substituent, in 1,2-epoxybutane, acting both as the solvent and reagent to generate the corresponding benzimidazolium N3-ylide. The structural characterization of the new substituted pyrroles was based on IR, NMR spectroscopy as well as on single crystal X-ray analysis. The toxicity of the new compounds was assessed on the plant cell using Triticum aestivum L. species and on the animal cell using Artemia franciscana Kellogg and Daphnia magna Straus crustaceans. The compounds showed minimal phytotoxicity on Triticum rootlets and virtually no acute toxicity on Artemia nauplii, while on Daphnia magna, it induced moderate to high toxicity, similar to nifedipine. Our research indicates that the newly synthetized pyrrole derivatives are promising molecules with biological activity and low acute toxicity.

New O-Aryl-Carbamoyl-Oxymino-Fluorene Derivatives with MI-Crobicidal and Antibiofilm Activity Enhanced by Combination with Iron Oxide Nanoparticles.

Antimicrobial resistance is one of the major public health threats at the global level, urging the search for new antimicrobial molecules. The fluorene nucleus is a component of different bioactive compounds, exhibiting diverse pharmacological actions. The present work describes the synthesis, chemical structure elucidation, and bioactivity of new O-aryl-carbamoyl-oxymino-fluorene derivatives and the contribution of iron oxide nanoparticles to enhance the desired biological activity. The antimicrobial activity assessed against three bacterial and fungal strains, in suspension and biofilm growth state, using a quantitative assay, revealed that the nature of substituents on the aryl moiety are determinant for both the spectrum and intensity of the inhibitory effect. The electron-withdrawing inductive effect of chlorine atoms enhanced the activity against planktonic and adhered Staphylococcus aureus, while the +I effect of the methyl group enhanced the anti-fungal activity against Candida albicans strain. The magnetite nanoparticles have substantially improved the antimicrobial activity of the new compounds against planktonic microorganisms. The obtained compounds, as well as the magnetic core@shell nanostructures loaded with these compounds have a promising potential for the development of novel antimicrobial strategies.