Aryl Guanidines Research Articles

Platinum(ii) complexes of aryl guanidine-like derivatives as potential anticancer agents: between coordination and cyclometallation.

The preparation of a wide variety of Pt(ii) complexes with aryl guanidines and their potential application as anticancer agents have been explored. A relatively facile synthesis of cyclometallated Pt(ii) complexes of arylguanidines, preparation of Pt(ii) guanidine coordination complexes and an in situ activation of platinum arylguanidine complexes with acetonitrile to create a bidentate aryl iminoguanidine Pt(ii) complex were achieved. Cyclometallation methodology was extended to create a water-stable conjugate incorporating two Pt(ii) ions and a diaryl bis-guanidine DNA minor groove binder. Several crystal structures were obtained confirming these complexation modes. The cyclometallated Pt(ii) complexes were particularly stable to aqueous environments and were tested for Reactive Oxygen Species generation and anticancer activity in a leukaemia cancer cell line.

N‐Aroyl‐N′‐(1‐Naphthyl)‐N′′‐aryl guanidines as a New Entry to Urease Inhibitors: Synthesis, Kinetic Mechanism, Molecular Docking and MD Simulation Studies

AbstractA series of novel guanidines (6 a–j) was synthesized from corresponding thioureas using catalytic mercuric chloride in DMF. The synthesized compounds were characterized by spectroscopic techniques and appraised for Jack Bean Urease (JBU) inhibition. All compounds (6 a–j) exhibited strong potential against JBU whilst compound 6 b (IC50=0.0155±0.00087 μM) and 6 e (IC50=0.0091±0.00036 μM) displayed excellent urease inhibition compared to thiourea (IC50=18.27 μM) used as reference. The kinetic mechanism analyzed by Lineweaver‐Burk plots revealed that 6 b is a mixed‐type inhibitor while 6 e is a non‐competitive inhibitor. Thus, compounds 6 e and 6 b can serve as a structural model for the designing of super‐effective urease inhibitors. Binding affinity and interaction of N‐aryl guanidine analogs were evaluated through molecular docking studies. To evaluate the residual flexibility of receptor through MD simulation, RMSD and RMSF graphs were evaluated to determine the protein structural behavior. It is implied that compound 6 e can serve as a novel molecular template to medicinal chemists for designing more potent urease inhibitors.

Consecutive Utilization of Mechanochemical and Microwave Methods for the Synthesis of Boc‐2‐amino‐quinazolin‐4(3H)‐ones and DFT Study of Mechanism 6π‐Diazaelectrocyclization Process

AbstractTwo eco‐friendly synthetic methods were used consecutively in the preparation of quinazolin‐4(3H)‐one heterocycles. The first reaction step, synthesis of a series of aryl guanidines was carried out by solvent‐free mechanochemical milling of aryl amines with 1H‐pyrazole‐N,N‐di‐(tert‐butyloxycarbonyl)‐1‐carboxamidine. In the following synthetic step, aryl guanidines were converted into Boc‐2‐amino‐quinazolin‐4(3H)‐ones by microwave heating. The experimental studies were supplemented by detailed quantum chemical studies (DFT) of the reaction mechanism of 6π‐diazaelectrocyclization process, and the predicted reactivities and regioselectivities are consistent with the experimental observations.

Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections.

Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited antifungal efficacy equivalent to voriconazole (1e). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, 6h showed antifungal activity against azole-resistant A. fumigatus.

The utilization of ball milling in synthesis of aryl guanidines through guanidinylation and N-Boc-deprotection sequence

Solid state ball milling was used in guanidinylation reactions of aromatic amines with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine reagent. Reaction conditions are advantageous, and in general reactions proceed in significantly shorter reaction times and in higher yields than under the conventional solution conditions. Mechanochemical conditions were also successfully applied to the cleavage of N-Boc protecting group.

The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a mild electrocyclization of aryl guanidines

A new method for the preparation of 2-amino-4(3H)-quinazolinones and similar fused heterocycles is described. Simply warming a mixture of an aryl guanidine and carbonyl diimidazole in acetonitrile results in formation of a putative N-amidinoisocyanate intermediate which undergoes a 6π-electron electrocyclic reaction with the aryl ring to generate the quinazolinone ring system. The mild conditions are compatible with a variety of functional groups, and the reaction is shown to be successful on multigram scale.

Substituent effects on the basicity (pKa) of aryl guanidines and 2-(arylimino)imidazolidines: correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths

The AIBLHiCoS method accurately predicts the pKa values of 2-(arylimino)imidazolidines using only a single ab initio bond length.

Correction: Substituent effects on the basicity (pKa) of aryl guanidines and 2-(arylimino)imidazolidines: correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths

Correction for ‘Substituent effects on the basicity (pKa) of aryl guanidines and 2-(arylimino)imidazolidines: correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths’ by Christophe Dardonville et al., New J. Chem., 2017, DOI: 10.1039/c7nj02497e.

SYNTHESIS OF SOME NEW 1, 3-DI METHYL SUBSTITUTED GUANIDINE WITH POSSIBLE ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY

The compounds containing thiazole, thiadiazole, oxazole, oxadiazole, imidazole, pyrimidine, pyridine & benzothiazole rings have been found to exhibit broad spectrum of biological activities.Derivatives of 1, 2, 4-thiadiazole and 1, 2, 4-thiadiazolidines exhibit antibacterial and antifungal activity1. Thiazolyl guanidines2 and various substituted aryl guanidine’s have been found to exhibit antibacterial & antifungal activities3.Keeping all these views in mind attempts were made to synthesized some new 1,3-di methyl Substituted Guanidine.In the present work 2,4 Dimethyl -3,5-(di Aryl imino)-1,2,4-thiadiazolidines were prepared by nitrous acid oxidation of N-methyl –N Aryl thiourea4 & 2,4 dimethyl-3,5-(diaryl imino)-1,2,4-thiazolidines were converted to corresponding 1,3 di methyl substituted guanidine’s by their acid catalyzed re-arrangment5.(Scheme-1)Antibacterial & Antifungal activity of the title compounds were evaluated against two bacteria, E.coli & lactobacillus & two fungi, A.Brassicicola & Aspergillus Niger. N=methyl-N`-Aryl thiourea (1-10) were prepared by refluxing a mixture of different 2-Amino Heterocyclic moieties with methyl iso thiocyanate in Ethanol.A mixture of compound (1-100 and conc. HCl, ethanol was added drop wise & under stirring to a solution of NaNO2 in water afforded 2, 4-dimethyl-3,5-(di Aryl imino)-1,2,4-thiadiazolidine (11-20) afforded 1,3 di methyl substituted guanidine’s (21-30). Structures of the compounds were established by elemental analysis & spectral data.

Copper-Catalyzed Oxidative Three-Component Synthesis of N, N′,N″-Trisubstituted Guanidines

A copper-catalyzed three-component synthesis of trisubstituted N-aryl guanidines involving cyanamides, arylboronic acids, and amines has been developed. This operationally simple oxidative process, which is performed in the presence of K2CO3, a catalytic amount of CuCl2·2H2O, bipyridine, and oxygen (1 atm), allows the rapid assembly of N,N',N″-trisubstituted aryl guanidines.

Copper(I)-catalyzed intramolecular C-N coupling reactions toward 1-cyanobenzoimidazoles

Employing a CuI/2,2'-biimidazole catalyst system, the intramolecular C-N coupling reactions of various substituted aryl guanidines could be successfully carried out under mild conditions. A variety of 1-cyanobenzimidazoles were synthesized in good to excellent yields.

Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds

The syntheses of the triazinyl-based bis-aryl phosphates 2 and 3, and of the aminopyrimidyl-based aryl phosphate 4 are described. Each compound contains a diaryl ether-phosphate structural motif. The synthetic route to bis-aryl phosphates 2 and 3 consisted in two nucleophilic substitution reactions with amines from cyanuric chloride, followed by a Suzuki coupling with the resulting 2,4-diamino-6-chloro-1,3,5-triazine derivative 12 to introduce the diaryl ether functionality. Aryl phosphate 4 was obtained via condensation of aryl guanidine 34 with aryloxyphenyl butenone 31. These de novo-designed aryl phosphates were evaluated as potential inhibitors of the Grb2-SH2 domain using an ELISA assay. The water-soluble sodium salt 26 of 3 gave an IC 50 value in the high micromolar range. Molecular modeling studies were subsequently performed upon modifying the 1,3,5-trisubstituted triazine scaffold of 3. Non-phosphate derivatives encompassing cyclopropane, pyrrole, keto-acid, and IZD fragments were thus step-wise designed and their Grb2-SH2 complexes were modeled by molecular dynamics. Some derivatives gave rise to an enriched pattern of H-bonds and cation–π interactions with Grb2-SH2.

EIN NEUER WEG ZU 2H-1,2,4-BENZOTHIADIAZINDERIVATEN

Abstract 2-Substituted 2H-1,2,4-benzothiadiazine-1-oxides are prepared by reaction of aryl guanidines with SOCl2 in presence or without Lewis acids. The scope of this reaction and some transformations of the products are investigated.