Modern Strategies for Heterocycle Synthesis

none1noopenFavi, GianfrancoFavi, Gianfranc

Marine Alkaloid 2,2-Bis(6-bromo-3-indolyl) Ethylamine and Its Synthetic Derivatives Inhibit Microbial Biofilms Formation and Disaggregate Developed Biofilms

The antimicrobial activity of the marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl) ethylamine (1) and related synthetic analogues (compounds 2–8) against target microorganisms was investigated by Minimum Inhibitory Concentration (MIC) determination. Compound 1 showed the greatest antimicrobial activity with the lowest MIC (8 mg/L) against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae, while the derivatives exhibited higher MICs values (from 16 to 128 mg/L). Compounds 1, 3, 4, and 8, the most active ones, were then tested against E. coli, S. aureus, K. pneumoniae, and Candida albicans during biofilms formation as well as on 24 h developed biofilms. The natural alkaloid 1 inhibited the biofilm formation of all the tested microorganisms up to 82.2% and disaggregated biofilms of E. coli, S. aureus, K. pneumoniae, and C. albicans after 30 min of contact, as assessed by viable plate count and crystal violet (CV) staining (optical density at 570 nm). Synthetic derivatives 3, 4, and 8 displayed anti-biofilm activity toward individual bacterial populations. This study highlights the potential of marine bisindole alkaloid 1 as anti-biofilm agent and shows, through a preliminary structure activity relationship (SAR), the importance of halogens and ethylamine side chain for the antimicrobial and antibiofilm activities of this bisindole series

Synthesis and Evaluation of Saccharide-Based Aliphatic and Aromatic Esters as Antimicrobial and Antibiofilm Agents

A small library of sugar-based (i.e., glucose, mannose and lactose) monoesters containing hydrophobic aliphatic or aromatic tails were synthesized and tested. The antimicrobial activity of the compounds against a target panel of Gram-positive, Gram-negative and fungi was assessed. Based on this preliminary screening, the antibiofilm activity of the most promising molecules was evaluated at different development times of selected food-borne pathogens (E. coli, L. monocytogenes, S. aureus, S. enteritidis). The antibiofilm activity during biofilm formation resulted in the following: mannose C10 > lactose biphenylacetate > glucose C10 > lactose C10. Among them, mannose C10 and lactose biphenylacetate showed an inhibition for E. coli 97% and 92%, respectively. At MICs values, no toxicity was observed on Caco-2 cell line for all the examined compounds. Overall, based on these results, all the sugar-based monoesters showed an interesting profile as safe antimicrobial agents. In particular, mannose C10 and lactose biphenylacetate are the most promising as possible biocompatible and safe preservatives for pharmaceutical and food applications

Practical and sustainable preparation of pyrrolo[2,3-b]indoles by Cu/Fe catalyzed intramolecular C(sp2)–H amination

A practical, robust and chemoselective approach toward the synthesis of pyrrolo[2,3-b]indoles via direct intramolecular C–H bond amination of α-indolylhydrazones has been achieved. This base and oxidant-free chemoselective transformation relies on a Cu/Fe co-catalyst system that operates at 50 °C in air with water as the only reaction medium. The easy product isolation together with the recyclable catalyst aqueous system (reused at least five times, maintaining over 50% of its catalytic activity) can provide an effective environmentally benign approach to fused N-heterocycles of remarkable interest in pharmaceutical and medicinal chemistry. The ability of the hydrazone residue to act as a chelating/directing group as well as an aminating agent guarantees the success of this C–H functionalization

Divergent Construction of Pyrazoles via Michael Addition of N‑Arylhydrazones to 1,2-Diaza-1,3-dienes

partially_open4noThe base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3-dienes (DDs) produces unprecedented β-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents (d1 synthon) and DDs as α-electrophiles (a2 synthon) of carbonyl compounds open the way to two important classes of pyrazole compounds.embargoed_20160409Serena mantenuto; Fabio Mantellini; Orazio Attanasi; Gianfranco FaviMantenuto, Serena; Mantellini, Fabio; Attanasi, ORAZIO ANTONIO; Favi, Gianfranc

FeCl3-catalyzed formal [3 + 2] cyclodimerization of 4-carbonyl-1,2-diaza-1,3-dienes

none6noSubstituted 1-aminopyrroles are easily accessible by means of iron-catalyzed cascade reaction that requires as starting materials the solely 1,2-diaza-1,3-dienes. Mechanistically, the formal [3 + 2] cyclodimerization is hypothesized to proceed through a [4 + 2] cyclodimerization of 4-substitued 1,2-diaza-1,3-dienes followed by intramolecular ring closure to fused diaziridin-pyrrolines whose successive opening results in a ring contraction process with consequent generation of the pyrrole moiety. The presence of activated hydrogen in the terminal position of the azo-enic moiety is crucial for the success of the synthesis.openGiacomo Mari, Matteo Corrieri, Lucia De Crescentini, Gianfranco Favi, Stefania Santeusanio, Fabio MantelliniMari, Giacomo; Corrieri, Matteo; DE CRESCENTINI, Lucia; Favi, Gianfranco; Santeusanio, Stefania; Mantellini, Fabi

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1H-pyridazino[3,4-b]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazine to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles

Synthesis of Azacarbolines via PhIO2‑Promoted Intramolecular Oxidative Cyclization of α‑Indolylhydrazones

An unprecedented synthesis of polysubstituted indolefused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO2) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere

A Novel Solvent-free Approach to Imidazole containing Nitrogen-Bridgehead Heterocycles

A very simple domino reaction under solvent free conditions of various piridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines and imidazo[2,1-a]isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without pre-functionalization of the starting heterocycles