Cyclic Guanidines Research Articles

Synthesis and Carbonic Anhydrase I, II, IX, and XII Inhibition Studies with a Series of Cyclic Sulfonyl Guanidines.

A series of thirteen cyclic sulfonyl guanidines were prepared and evaluated against tumor-associated human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and hCA XII, as well as against off-target cytosolic isoforms hCA I and hCA II. The compounds reported here were generally inactive against both off-target isoforms (KI>100 μM), while all of them moderately inhibited both target isoforms hCA IX and XII in the submicromolar to micromolar ranges in which KI values spanned from 0.57 to 8.4 μM against hCA IX and from 0.34 to 9.7 against hCA XII. Due to the notable selectivity of the title compounds toward isoforms hCA IX and XII, they can be considered as useful scaffolds for further chemical optimization to develop new highly selective antitumor agents.

Polyheterocyclic peptidomimetics: Parallel solid phase synthesis of oligo cyclic guanidines and their inhibition activity against Mycobacterium tuberculosis DNA gyrase

Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable applications in various fields. We report the design and the parallel synthesis of novel linear oligocyclic guanidine peptidomimetics from predesigned reduced polyamides. A screening of these compounds identified active Mycobacterium tuberculosis DNA gyrase inhibitors which do not inhibit human DNA topoisomerase IIα and topoisomerase I.

A DFT Investigation of the Reactivity of Guanidinium Salts in Tandem aza-Michael Addition/Intramolecular Cyclization

A proposed mechanism of the reaction of guanidinium chlorides with dimethyl acetylenedicarboxylate in a tandem aza-Michael addition reaction/intramolecular cyclization was investigated by DFT M06-2X and B3LYP computational approaches. The energies of the products were compared against the G3, M08-HX, M11, and wB97xD data or experimentally obtained product ratios. The structural diversity of the products was interpreted by the concurrent formation of different tautomers formed in situ upon deprotonation with a 2-chlorofumarate anion. A comparison of relative energies of the characteristic stationary points along the examined reaction paths indicated that the initial nucleophilic addition is energetically the most demanding process. The overall reaction is strongly exergonic, as predicted by both methods, which is primarily due to methanol elimination during the intramolecular cyclization step producing cyclic amide structures. Formation of a five-membered ring upon intramolecular cyclization is highly favored for the acyclic guanidine, while optimal product structure for the cyclic guanidines is based on a 1,5,7-triaza [4.3.0]-bicyclononane skeleton. Relative stabilities of the possible products calculated by the employed DFT methods were compared against the experimental product ratio. The best agreement was obtained for the M08-HX approach while the B3LYP approach provided somewhat better results than the M06-2X and M11 methods.

ALLYLDIPHENYLGUANIDINE COMPLEX WITH ARYLTELLURIUM THRICHLORIDE

Functionalized acyclic and cyclic guanidines have a wide range of biological activity. In particular, they possess antitumor, antibacterial activities, are immunosuppressants, anesthetics, analgesics and analogues of natural alkaloids. The search of methods for the synthesis of new guanidine derivatives is an urgent problem.
 The introduction of an unsaturated alkyl substituent to the guanidine backbone opens the way to the synthesis of heterocyclic compounds of the azole or azine series using the method of electrophilic heterocyclization under the action of halogen-containing electrophilic agents. For this purpose, N-allyl-N ',N' '- diphenylguanidine was synthesized according to the described procedure. Allyl substituted guanidines are able to cyclize under the action of iodine. The use of a chalcogen halogen-containing electrophile may lead to the formation of a potentially biologically active acyclic or heterocyclic guanidine derivative. For this purpose, p-methoxyphenyltellurium trichloride was used as an electrophilic agent.
 Reaction of equimolar amounts of N-allyl-N',N''-diphenylguanidine and p-methoxy-phenyltellurium trichloride was performed in chloroform with a minor amount of THF. It was found that with 12 hours of reagents stirring, adducts of the substrate-electrophile composition 1: 1 are formed. The structure of the complex is proposed on a basis of spectral data and elemental analysis data. The increasing of the reaction time and temperature does not lead to the formation of addition or cyclization products.

Direct synthesis of N2-unprotected five-membered cyclic guanidines by regioselective [3 + 2] annulation of aziridines and cyanamides

This work disclosed the first direct synthesis of N2-unprotected five-membered cyclic guanidines via a regioselective ring-opening/5-exo-dig cyclization strategy between aziridines and cyanamides under mild conditions.

Pd-Catalyzed Alkene Diamination Reactions with O-Benzoylhydroxylamine Electrophiles: Evidence Supporting a Pd(II/IV) Catalytic Cycle, the Role of 2,4-Pentanedione Derivatives as Ligands, and Expanded Substrate Scope.

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a PdII complex, followed by reductive elimination from PdIV to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate that these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2] Cycloaddition of α-Haloamides with Organo-cyanamides.

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

Cyclic guanidines are found in many biologically active compounds and natural products. Further, the formation of the atypical seven-membered ring of cyclic guanidine remains challenging because of...

Gas-phase basicity of cyclic guanidine derivatives – a DFT study

Density functional theory calculations (B3LYP) were employed in the study of gas-phase basicity (GB) and pKa of three different types of cyclic guanidines differing in the number of nitrogen atoms incorporated in rings.

Generation and Reactivity of 2-Amido-1,3-diaminoallyl Cations: Cyclic Guanidine Annulations via Net (3 + 2) and (4 + 3) Cycloadditions.

Toward a method for direct conversion of alkenes to cyclic guanidines, we report that 1,3-dipolar cycloadditions of 2-amido-1,3-diamino allylic cations with alkenes provide a new method for direct cyclic guanidine annulation. Generated under oxidative conditions, the 2-amido-1,3-diaminoallyl cations react as 1,3-dipoles providing rapid access to 2-amino imidazolines through net (3 + 2) cycloadditions. The utility is demonstrated through a concise synthesis of the oroidin alkaloid, phakellin. The described 1,3-dipole also participates in net (4 + 3) cycloadditions with dienes.

Theoretical studies of perimidine and its derivatives: structures, energies, and spectra

Theoretical calculations at the B3LYP/6-311++G(d,p) level plus GIAO calculations for NMR absolute shieldings have been carried out for the parent perimidine and several of its derivatives. These include its anion and cation and the acid-base equilibria and other examples of annular tautomerism, such as the 2-hydroxy (and their radical cations), 2-thiol, 2-amino, and 2-alkyl perimidines, and the functional tautomers, such as the benzologues of perimidone. The protonation of 2-aminoperimidines (cyclic guanidines) and the properties of perimidine carbene (dimerization and addition to carbon dioxide), biperimidine, dihydroperimidine, and spiro bidihydroperimidine were also studied.

3‐Bromo N‐Alkyl Cyanamides as Versatile Building Blocks

3‐Bromo N‐alkyl cyanamides are accessible in one simple synthetic operation from N‐alkyl azetidines reacting with cyanogen bromide. These unexplored building blocks combine two extremely useful electrophilic moieties: an alkyl bromide and a cyanamide. We demonstrate herein that they can be transformed into a range of nitrogen‐containing molecules, and especially cyclic guanidines, accessible in enantiomerically pure form. Considering the large structural diversity of available azetidines, this contribution complements the use of these strained heterocycles in diversity‐oriented synthesis.

Pd-Catalyzed Alkene Diamination Reactions of Nitrogen Electrophiles: Synthesis of Cyclic Guanidines and Ureas Bearing Dialkylaminomethyl Groups.

The Pd-catalyzed coupling of N-allylguanidines or N-allylureas with O-benzoylhydroxylamine derivatives affords cyclic guanidines or cyclic ureas bearing dialkylaminomethyl groups. The desired products are obtained in good yield, and substrates bearing substituents at the allylic position are transformed with moderate diastereoselectivity. The mechanism of these reactions appears to involve anti-aminopalladation of the alkene, followed by a rare sp3C-sp3N bond-forming reductive elimination from an alkylpalladium complex that contains β-hydrogen atoms.

Guanidine-Catalyzed Reductive Amination of Carbon Dioxide with Silanes: Switching between Pathways and Suppressing Catalyst Deactivation

A mechanistic investigation into the guanidine-catalyzed reductive amination of CO2, using a combination of 1H, 29Si NMR, FT-IR, MS, and GC profiling, is reported. Inexpensive and readily available N,N,N′,N′-tetramethylguanidine (TMG) was found to be an equally effective catalyst compared to more elaborate cyclic guanidines. Different catalytic pathways to formamide 2, aminal 4, and N-methylamine 3 were identified. A pathway to formamide product 2 dominates at 23 °C. Increasing the reaction temperature to 60 °C enables a competitive, higher-energy pathway to 4 and 3, which requires direct reduction of CO2 with PhSiH3 to formoxysilane E. Reduction of aminal 4, in the presence of CO2 and the catalyst, led to formation of a 1:1 ratio of 2 and 3. The catalyst itself can be formylated under the reaction conditions, resulting in its deactivation. Thus, alkylated TMGs were found to be more stable and more active catalysts than TMG, leading to a successful organocatalyzed reductive functionalization of CO2 with s...

Bis(2-aminoimidazolines) and Bisguanidines: Synthetic Approaches, Antiparasitic Activity and DNA Binding Properties.

Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2-phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs. In addition, different classes of bis(2-iminoimidazolidines) and bisguanidines have been shown to have antimicrobial activity against other pathogens (e.g. bacteria, fungi, parasitic worms). Due to their structural and physicochemical properties, these dibasic compounds, which are dications at physiological pH, are prone to bind to the minor groove of DNA at AT-rich sites. In several cases, such interaction is thought to be responsible for their antimicrobial activity. In this review, we give a comprehensive view of the synthetic methods used to introduce the 2-aminoimidazoline scaffold in a molecule. Synthetic routes that give access to these cyclic guanidines (i.e. unsubstituted, 1-, 4-, and 5-substituted 2-aminoimidazolines) are detailed. The in vitro and in vivo antiprotozoal activity of bis(2-aminoimidazolines) and bisguanidines against kinetoplastid parasites (T. brucei, T. cruzi, Leishmania), Plasmodium spp. and other pathogens (e.g. ESKAPE bacteria, Candida spp., M. tuberculosis, E. multilocularia) is also reviewed. Finally, the targets that are involved in the antimicrobial activity (e.g. DNA) or other biological activities (e.g. α-adrenergic receptors, imidazoline binding sites, kinases) of this class of dicationic compounds are discussed.

Integration of Bromine and Cyanogen Bromide Generators for the Continuous‐Flow Synthesis of Cyclic Guanidines

AbstractA continuous‐flow process for the in situ on‐demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane‐separation technology is described. In order to circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate–bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in‐line FTIR technology. With the Br2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8 m solution of BrCN in dichloromethane. The modular Br2/BrCN generator was employed for the synthesis of a diverse set of biologically relevant five‐ and six‐membered cyclic amidines and guanidines. The set‐up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi‐batch mode.

Integration of Bromine and Cyanogen Bromide Generators for the Continuous-Flow Synthesis of Cyclic Guanidines.

A continuous-flow process for the in situ on-demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane-separation technology is described. In order to circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate-bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in-line FTIR technology. With the Br2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8 m solution of BrCN in dichloromethane. The modular Br2 /BrCN generator was employed for the synthesis of a diverse set of biologically relevant five- and six-membered cyclic amidines and guanidines. The set-up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi-batch mode.

Ph3P/I2-Mediated Synthesis of N,N',N″-Substituted Guanidines and 2-Iminoimidazolin-4-ones from Aryl Isothiocyanates.

A convenient one-pot procedure for the synthesis of acyclic and cyclic guanidines mediated by the Ph3P/I2 system is described. Sequential condensation of aryl isothiocyanates with amines followed by dehydrosulfurization and guanylation could lead to both symmetric and unsymmetric N,N',N″-substituted derivatives. Through a tandem guanylation-cyclization, a series of 2-iminoimidazolin-4-ones could also be prepared in good yields from the reaction of aryl isothiocyanates with amino acid methyl esters.

Synthesis of Cyclic Guanidines Bearing N-Arylsulfonyl and N-Cyano Protecting Groups via Pd-Catalyzed Alkene Carboamination Reactions.

Palladium-catalyzed carboamination reactions of N-allylguanidines bearing cleavable N-cyano or N-arylsulfonyl protecting groups are described. The reactions afford cyclic guanidine products in good yield, and transformations of substrates bearing internal alkenes proceed with high diastereoselectivity. Deuterium labeling studies indicate these transformations proceed via anti-aminopalladation pathways.

Hypoglycemic potential of cyclic guanidine derivatives

Abstract Guanidine derivatives are widely used antidiabetic drugs. Metformin (biguanide) is the first-line therapy for the type 2 diabetes mellitus due to its multi-target and pleiotropic effects. Compounds that comprise guanidine moiety integrated in a heterocycle, i.e. cyclic guanidines, represent an increasing area of interest. We have synthesized and studied hypoglycemic effects of a range of cyclic guanidines, namely 2-aminobenzimidazoles and structurally related imidazo[1,2-a]-, pyrimido[1,2-a]-, pyrrolo[1,2-a]-, triazolo[1,5-a]benzimidazole tricyclic derivatives. We have determined the potential of these scaffolds using molecular modeling and QSAR analysis. Experimental studies have shown that N 9-(diethylamino)ethyl-2,3-dihydro-imidazo[1,2-a]benzimidazole (RU-254, diabenol) exhibits potent antidiabetic effects along with a low toxicity. We have found that diabenol exerts long-term glucose-lowering effects in prediabetic and diabetic animals, stimulates the first phase of insulin secretion and reduces the rate of liver glycogenolysis. Additionally, diabenol has been shown to exhibit antiplatelet, geroprotective and antitumor activities in animals. Clinical trials confirm that diabenol produces a range of antidiabetogenic effects such as improved glycemia, reduced HbA1c, stimulation of insulin secretion, decreased thrombogenic potential of blood and ameliorated hemorheology.