Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics. Among them, the Ugi reaction is a popular way for the synthesis of peptidomimetics because it provides peptide-like products. The Ugi reaction consists of the condensation of an aldehyde or ketone, a carboxylic acid, an amine, and an isocyanide usually giving a linear peptidomimetic. In order to obtain other linear, cyclic or polycyclic peptidomimetics, the acyclic products have to undergo additional transformations or cyclizations. This review covers the years from 2018-2023, regarding the synthesis of linear, cyclic and polycyclic peptidomimetics, employing Ugi reactions eventually followed by post-Ugi transformations. Organo-catalyzed reactions, base-promoted reactions, and metal-free reactions toward peptidomimetics are highlighted.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Pseudo Four-Component Synthesis of 5,6-Dihydroindolo[2,1-a]isoquinolines.

An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1-a]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,ß-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1-a]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1-a]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1-a]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.

Synthesis of pyrrolo[2,3-d]pyridazines and pyrrolo[2,3-c]pyridines (6-azaindoles). Experimental and theoretical study.

A new synthetic route towards 6-azaindoles (pyrrolo[2,3-c]pyridines) and pyrrolo[2,3-d]pyridazines starting from 4-aroyl pyrroles is described. This overall protocol involves: (i) the Vilsmeier-Haack reaction to obtain pyrrolo-2,3-dicarbonyles and (ii) condensation with hydrazines or glycine methyl ester. The reaction mechanism between pyrrolo-2,3-dicarbonyl with phenyl hydrazine and glycine methyl ester has been modelled using DFT calculations to prove the formation of one from two possible isomers of condensation.

Visible light-mediated halogenation of organic compounds.

The use of visible light and photoredox catalysis emerged as a powerful and sustainable tool for organic synthesis, showing high value for distinctly different ways of bond creation. Halogenated compounds are the cornerstone of contemporary organic synthesis: it is almost impossible to develop a route towards a pharmaceutical reagent, agrochemical, natural product, etc. without the involvement of halogen-containing intermediates. Moreover, the halogenated derivatives as final products became indispensable for drug discovery and materials science. The idea of this review is to understand and summarise the impact of visible light-promoted chemistry on halogenation and halofunctionalisation reactions.

Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.

Azo Coupling of Indoles Revisited: Synthesis of Biindolyl Photoswitches via the Azo-Coupling/C-H Functionalization Domino Approach.

When azo coupling of aryldiazonium salts with indoles was carried out in aprotic nonpolar solvent on air, a pseudo-three-component reaction has been discovered. Azo coupling is followed by a nucleophilic addition of a second indole unit to the indolium intermediate; aromatization and oxidation are achieved under air.

Domino Approach for the Synthesis of Pyridinium Salts and 1,2,3,8a-Tetrahydroimidazo[1,2-a]pyridines from 2-Imidazolines and Propiolic Acid Esters.

Adducts of 1-alkyl-2-imidazolines and two molecules of alkyl propiolate, possessing an N-propargyl-ß-enaminoester fragment, easily undergo a domino reaction to form pyridinium salts with ß-(alkylammonio)ethyl group at the nitrogen atom in the presence of 2 equiv of a protic acid. Treatment of the above reaction mixture with a base gives 1,2,3,8a-tetrahydroimidazo[1,2-a]pyridines. Reaction of the latter compounds with acid chlorides affords pyridinium salts with ß-(alkylamido)ethyl moiety at the nitrogen atom.

Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity.

About twenty molecules sharing 1H-chromeno[3,2-c]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1H-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-c]pyridin-10-ones (1,2,3,4-THCP-10-ones, 1) or 2,3-dihydro-2-methyl-1H-chromeno[3,2-c]pyridines (2,3-DHPCs, 2). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives 2 inhibit MAO A (IC50 about 1 µM) preferentially; (ii) the 1,2,3,4-THCP-10-one 3a, bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC50 0.51 µM) and moderate inhibitor of both ChEs (IC50s 7-8 µM); (iii) the 1H-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog 6c achieving MAO B IC50 of 3.51 µM. The MAO B inhibitor 3a deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog 6c exerts anti-tumor activity with IC50s in the range 4.83-11.3 µM.

Synthesis of Novel Benzo[b][1,6]naphthyridine Derivatives and Investigation of Their Potential as Scaffolds of MAO Inhibitors.

In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl (5), 1-indol-3-yl (8), and azocino[4,5-b]quinoline (10) derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, 5c-h proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog 5g achieved an IC50 of 1.35 µM, a value close to that of the well-known MAO B inhibitor pargyline.

Assembly of 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines via the Domino Reaction of 2-Imidazolines and Terminal Electron-Deficient Alkynes.

The transformation of 2-imidazolines into 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines has been realized. A pseudo-three-component reaction of 2-imidazolines with terminal electron-deficient alkynes (2 equiv) first generates imidazolidines, containing an N-vinylpropargylamine fragment. The latter can then undergo a base-catalyzed domino aza-Claisen rearrangement/cyclization reaction sequence, simultaneously constructing pyrrole and pyrazine rings. The process works in a broad substrate scope, delivering pyrrolo[1,2-a]pyrazines in good to excellent yields (45-90%). This two-step approach can be carried out in a one-pot fashion without a noticeable decrease in yield. Remarkably, a three-component protocol for the introduction of two different alkynes has been also developed.

Chemoselective Divergent Transformations of N-(Propargyl)indole-2-carbonitriles with Nitrogen Nucleophiles: Alkyne Hydroamination or Domino Cyclizations.

Interactions of N-(propargyl)indole-2-carbonitriles with nitrogen nucleophiles were studied. It was found that lithium hexamethyldisilazane (LiHMDS)-promoted reactions give mixtures of two product types, originating from an initial attack onto carbon-carbon or carbon-nitrogen triple bonds. Performing the reaction at reduced temperature and in the presence of catalytic amounts of LiHMDS delivered alkyne hydroamination products exclusively. On the contrary, the one-pot reaction of N-(propargyl)indole-2-carbonitriles with methanol and LiHMDS on heating, followed by the addition of a nitrogen nucleophile, allowed a selective domino cyclization sequence toward 1-aminopyrazino[1,2-a]indoles. Anilines and nitrogen heterocycles could be employed as N-nucleophiles to obtain products of both types. Moreover, an alternative one-pot route toward a third product type has been developed. When N-(propargyl)indole-2-carbonitrile was first combined with aniline and LiHMDS at reduced temperature, further heating of the in situ generated hydroamination product led to the intramolecular cyclization into 1-imino-2-phenylpyrazino[1,2-a]indoles. Thus, chemodivergent transformations of the same starting material into three compound classes were investigated. The possible reaction routes were studied, and N-(allenyl)indole-2-carbonitrile was identified as the key intermediate. Acyclic and cyclic products exhibit fluorescence emission in the blue to green range.

Synthesis of 8-phenyl substituted 3-benzazecines with allene moiety, their thermal rearrangement and evaluation as acetylcholinesterase inhibitors.

Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (Ki) in the low micromolar range.

A Three-Component Synthesis of 3-Functionally Substituted 5,6-Dihydropyrrolo[2,1-a]isoquinolines.

Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active.

Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity.

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 µM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 µM), but 90-fold more water-soluble.

Facile synthesis of pyrrolo[2,1-a]isoquinolines by domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated ketones, nitroalkenes and nitriles.

A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,ß-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used.

Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines.

A multicomponent reaction of isocyanides with aryl(indol-3-yl)methylium salts and amines has been found. A series of aryl(indol-3-yl)acetimidamides was obtained in up to 96% yields. In the case of ethyl isocyanoacetate, the reaction is followed by cyclization to form 3,5-dihydro-4H-imidazol-4-one derivatives.

Synthetic Strategies in the Preparation of Phenanthridinones.

Phenanthridinones are important heterocyclic frameworks present in a variety of complex natural products, pharmaceuticals and displaying wide range of pharmacological actions. Its structural importance has evoked a great deal of interest in the domains of organic synthesis and medicinal chemistry to develop new synthetic methodologies, as well as novel compounds of pharmaceutical interest. This review focuses on the synthesis of phenanthridinone scaffolds by employing aryl-aryl, N-aryl, and biaryl coupling reactions, decarboxylative amidations, and photocatalyzed reactions.

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 µM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 µM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 µM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced ß-amyloid (Aß)1-40 aggregation (IC50 = 13 µM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.

Photoredox-Catalyzed Hydrosulfonylation of Arylallenes.

(Het)Arylallenes undergo hydrosulfonylation under photoredox-catalyzed conditions. The reaction gives vinyl sulfones in a regio- and diastereoselective manner, employing sodium sulfinates as the sulfonyl source and eosin Y as the photocatalyst. Indol-1-yl, pyrrol-1-yl, phenyl, and naphtylallenes might be used. Aliphatic allenes are incompatible with the reaction conditions.