Amidinoquinoxaline N-oxides: synthesis and activity against anaerobic bacteria.

We present herein an in-depth study on the activity of amidinoquinoxaline N-oxides 1 against Gram-positive and Gram-negative anaerobic bacteria. Based on 5-phenyl-2,3-dihydropyrimidoquinoxaline N-oxide 1a, the selected structural variations included in our study comprise the substituents α- to the N-oxide function, the benzofused ring, substitution and quaternization of the amidine moiety, and the amidine ring size. Compounds 1 showed good to excellent antianaerobic activity, evaluated as the corresponding CIM50 and CIM90 values, and an antimicrobial spectrum similar to metronidazole. Six out of 13 compounds 1 had CIM90 values significantly lower than the reference drug. Among them, imidazoline derivatives 1i-l were the most active structures. Such compounds were synthesized by base-promoted ring closure of the corresponding amidines. The N-oxides under study showed no significant cytotoxicity against RAW 264.7 cells, with high selectivity indexes. Their calculated ADME properties indicate that the compounds are potentially good oral drug candidates. The antianaerobic activity correlated satisfactorily with the electron affinity of the compounds, suggesting that they may undergo bioreductive activation before exerting their antibacterial activity.

Polyphosphoric Acid Esters Promoted Synthesis of Quinazolin-4(3H)-imines from 2-Aminobenzonitrile.

A novel method for the synthesis of quinazolin-4(3H)-imines (QIs) by trimethylsilyl polyphosphate (PPSE) promoted reaction of 2-aminobenzonitrile with secondary amides is reported. The reaction is general and allows for the synthesis of N3-aryl and N3-alkyl QIs with variable 2-substituents affording high yields. The procedure was extended to derivatives bearing additional functional groups. The method is operationally simple, involves easily available starting materials and a mild dehydrating agent, with wide functional group tolerance. The reaction procedure proved to be suitable for scaling-up. A possible reaction path via an intermediate nitrilium ion is proposed on the basis of literature data and experimental observations.

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol.

A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido alcohols promoted by trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of several hitherto unreported seven-membered iminothioethers bearing 2-aryl, alkenyl, aralkyl and alkyl substituents. The cyclodehydration reaction is likely to involve an SN2-type displacement and affords good to excellent yields of the desired heterocycles in very short reaction times.

Conformational and Stereodynamic Behavior of Five- to Seven-Membered 1-Aryl-2-iminoazacycloalkanes.

The stereodynamic behavior of 1-arylpyrrolidin-2-imines, having a Caryl-N stereogenic axis, has been studied by means of dynamic nuclear magnetic resonance and density functional theory calculations, evaluating the steric effect of ortho-aryl substituents. The rotational barrier due to E/Z isomerism about the -C=N-H bond was also determined. The dynamic stereochemistry of homologous six- and seven-membered iminoazacycloalkane rings and their oxo-analogues was also comparatively investigated, evidencing a ring size effect. It was found that the seven-membered heterocycle shows additional dynamic features because of ring inversion.

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N 3 -aryl derivatives with electron-withdrawing groups.

The sequential N-functionalization of 2-aminobenzylamine (2-ABA) followed by cyclodehydration allowed for a straightforward and efficient synthesis of 3,4-dihydroquinazolines with N-aryl substituents bearing electron-withdrawing groups. The sequence involves an initial SNAr displacement, N-acylation and MW-assisted ring closure. Remarkably, the uncatalyzed N-arylation of 2-ABA led to the monosubstitution product using equimolar amounts of both reagents. The individual steps were optimized achieving good to excellent overall yields of the desired heterocycles, avoiding additional protection and deprotection steps. A mechanistic interpretation for the cyclodehydration reaction promoted by trimethylsilyl polyphosphate (PPSE) is also proposed on the basis of literature data and our experimental observations.

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids.

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

Amidinoquinoxaline N-oxides: spin trapping of O- and C-centered radicals.

Amidinoquinoxaline N-oxides represent a novel family of heterocyclic spin traps. In this work, their ability to trap O- and C-centered radicals was tested using selected derivatives with different structural modifications. All the studied nitrones were able to trap radicals forming persistent spin adducts, also in the case of OH and OOH radicals which are of wide biological interest as examples of ROS. The stability of the adducts was mainly attributed to the wide delocalization of the unpaired electron over the whole quinoxaline moiety. The nitroxide spectral parameters (hfccs and g-factors) were analyzed and the results were supported by DFT calculations. The N-19 hfccs and g-factors were characteristic of each aminoxyl and could aid in the identification of the trapped radical. The enhanced stability of the OH adducts under the employed reaction conditions could be ascribed to their possible stabilization by IHBs with two different acceptors: the N-O˙ moiety or the amidine functionality. DFT calculations indicate that the preferred IHB is strongly conditioned by the amidine ring size. While five membered homologues show a clear preference for the IHB with the N-O˙ group, in six membered derivatives this stabilizing interaction is preferentially established with the amidine nitrogen as an IHB acceptor.

Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine.

A straightforward strategy for the synthesis of dihydroquinazolines is presented, which allows for the preparation of 3,4- and 1,4-dihydroquinazolines with different substitution patterns from 2-aminobenzylamine (2-ABA) as common precursor. The required functionalization of both amino groups present in 2-ABA was achieved by different routes involving selective N-acylation and cesium carbonate-mediated N-alkylation reactions, avoiding protection/deprotection steps. The heterocycles were efficiently synthesized in short reaction times by microwave-assisted ring closure of the corresponding aminoamides promoted by ethyl polyphosphate (PPE).

Microwave-Assisted Synthesis of 2-Aryl-2-oxazolines, 5,6-Dihydro-4H-1,3-oxazines, and 4,5,6,7-Tetrahydro-1,3-oxazepines.

The first general procedure for the synthesis of 5- to 7-membered cyclic iminoethers by microwave-assisted cyclization of ω-amido alcohols promoted by polyphosphoric acid (PPA) esters is presented. 2-Aryl-2-oxazolines and 5,6-dihydro-4H-1,3-oxazines were efficiently prepared using ethyl polyphosphate/CHCl3. Trimethylsilyl polyphosphate in solvent-free conditions allowed for the synthesis of hitherto-unreported 4,5,6,7-tetrahydro-1,3-oxazepines. The method involves good to excellent yields and short reaction times.The reaction mechanism and the role of PPA esters were investigated in a chiral substrate.

Microwave-assisted cyclizations promoted by polyphosphoric acid esters: a general method for 1-aryl-2-iminoazacycloalkanes.

The first general procedure for the synthesis of 5 to 7-membered 1-aryl-2-iminoazacycloalkanes is presented, by microwave-assisted ring closure of ω-arylaminonitriles promoted by polyphosphoric acid (PPA) esters. 1-Aryl-2-iminopyrrolidines were easily prepared from the acyclic precursors employing a chloroformic solution of ethyl polyphosphate (PPE). The use of trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of 1-aryl-2-iminopiperidines and hitherto unreported 1-aryl-2-iminoazepanes. The cyclization reaction involves good to high yields and short reaction times, and represents a novel application of PPA esters in heterocyclic synthesis.

Atropisomerism in amidinoquinoxaline N-oxides: effect of the ring size and substituents on the enantiomerization barriers.

The atropisomerism of novel 2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-oxides 1 bearing dissymmetric (ortho-substituted) 5-aryl residues and the homologous 1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxides 2 was investigated. The existence of a chiral axis was demonstrated for compound 1a by X-ray diffraction and by DFT calculations of the ground state geometry. The resolution of the atropisomeric enantiomers on chiral stationary phases is reported. The barriers to enantiomerization were determined by off-line racemization studies and/or by treatment of the plateau-shaped chromatograms during chromatography on chiral support. A clear ring size effect was evidenced. In all cases, six-membered amidine derivatives 1 showed higher barriers than the corresponding lower homologues 2, which also display lower sensitivity to the substituent size. Transition states for the interconversion of the atropisomers were located using DFT calculations, and involved the interaction of the ortho substituent with the formally sp(2) nitrogen in the amidine moiety. In contrast, in the most favored enantiomerization transition state of the 2-nitro derivative the ortho substituent is close to the N-oxide group.

Drug-excipient compatibility studies in binary mixtures of avobenzone.

During preformulation studies of cosmetic/pharmaceutical products, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the active and the excipients of interest that might interfere with safety and/or efficacy of the final product. Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of avobenzone with some currently used cosmetic excipients. In the first phase of the study, DSC was used as a tool to detect any interaction. Based on the DSC results alone, cetearyl alcohol, isopropyl myristate, propylparaben, diethylhexyl syringylidene malonate, caprylic capric triglyceride, butylated hydroxytoluene (BHT), glycerin, cetearyl alcohol/ceteareth 20, cetearyl alcohol/sodium lauryl sulfate/sodium cetearyl sulfate, and paraffinum liquidum exhibit interaction with avobenzone. Stressed binary mixtures (stored at 50°C for 15 days) of avobenzone and excipients were evaluated by high-performance liquid chromatography. Binary mixtures were further investigated by infrared (IR) spectroscopy. Based on DSC, isothermal stress testing, and fourier transform infrared results; avobenzone is incompatible with caprylic capric triglyceride, propylparaben, and BHT.

A comparison of the electron ionization and electrospray behaviour of some N,N'-disubstituted hexahydropyrimidines.

The behaviour of some N,N'-disubstituted hexahydropyrimidines, a class of naturally occurring compounds of biological and biomedical interest, has been studied in both electron ionization (EI) and electrospray ionization (ESI) modes coupled with collisional experiments (ESI-MSn). In both techniques, the [M-H]+ ions are highly abundant, even if their formation is generated by two different mechanisms, i.e. H. loss from the M+. species in the case of EI and hydride (H-) abstraction from the molecules in the case of ESI. Furthermore, due to the low, step-by-step internal energy deposition typical of collisional experiments performed in an ion trap mass spectrometer, different fragment ions were observed in EI and ESI-MSn collisions. In both cases, the ions can be related to the original structure and allow us to identify the positions in which the different substituents are present.

Separation of atropisomeric 1,4,5,6-tetrahydropyrimidinium salts by chiral HPLC and determination of their enantiomerization barriers.

Chiral HPLC separation of a series of novel atropisomeric quaternary (1) and ternary (2) 1,2-disubstituted 1,4,5,6-tetrahydropyrimidinium salts bearing disymmetric aryl groups in positions 1 and/or 2 is described. A screening of different polysaccharide stationary phases (OD-R, OJ-R and AD-RH) and chromatographic conditions allowed for partial or baseline resolution of 16 over 26 compounds. When a semi-preparative separation was achieved, the corresponding enantiomerization barriers were determined employing the off-column method. The experimental data were compared inter se in order to establish the factors influencing the magnitude of the barriers and with those corresponding to the parent amidines.