Amido-oligopyrroles/imidazoles and dimeric benzimidazoles are heterocyclic compounds which are nucleic acid minor groove binding agents. The targets for this project were symmetrical and unsymmetrical amide-linked di- and tri- and tetrameric benzimidazoles to evaluate as potential DNA binding agents. Syntheses involved linkage between C2 and C5 positions of 2-carboxy, 5-carboxy or 2,5-dicarboxy and 2-amino, 5-amino or 2,5-diamino-bearing benzimidazoles. This matrix of substrates could be coupled directly C2-C5 by amide linkage, or these same precursors could also be dimerized symmetrically using small bifunctional linkers (diamine or diacid), affording symmetrical C2-C2 or C5-C5 dimer types of orientation, such as head-to- head, and tail-to tail systems. Monomeric building block benzimidazoles were prepared by condensation of o- phenylene diamines with either aldehydes or carboxylic acids affording the corresponding C2 or C5 amino and C5 carboxybenzimidazoles. 2- Carboxybenzimidazoles were however prepared by condensation of o-phenylene diamines with trichloroacetimidate followed by hydrolysis. New different novel symmetrical and unsymmetrical-bis(benzimidazole) libraries (C2-C2, C5-C5 and C5- C2 orientation) were prepared via coupling of different aminobenzimidazoles with different carboxybenzimidazoles from the matrix of available monomers. Novel tris(benzimidazoles) with differently linked orientations were prepared either by coupling one equivalent of 2,5-dicarboxybenzimidazole with two equivalents of aminobenzimidazole or coupling one equivalent of 2,5-diaminobenzimidazole with two equivalents of carboxybenzimidazole. A second set of novel tris(benzimidazoles) was prepared via reduction of a nitro- to amino bearing dimer followed by coupling with another carboxybenzimidazole monomer. Novel symmetrical tetra(benzimidazoles) (C2-C2-C2-C2 and C5-C2-C2-C5 orientation) were synthesized via either coupling one equivalent 2-dicarboxy dimeric benzimidazole with two equivalents of 2 or 5-aminobenzimidazole or via coupling one equivalent of 2-diaminobis(benzimidazole) with two equivalents of 2 or 5- carboxybenzimidazoles. Novel symmetrical bis(benzimidazoles) piperidine derivatives were synthesized via coupling one equivalent of 2-dicarboxy dimericbenzimidazole with two equivalents of piperidine derivatives. Forty oligomeric benzimidazoles were evaluated using Surface Plasmon Resonance (SPR) for binding to a series of three oligonucleotides containing A2T2, or A3T3 or A4T4 sequences. Data are presented showing the identification of four optimum ligands from a screen of 40, primarily 2L2552L2 tetramers but also several 2L5 dimers and dimeric 5,5-units without terminal additional benzimidazoles.

The coordination behaviour of 4-aminoantipyrine (H2pap) and its Schiff base derivatives with the oxorhenium(V) and tricarbonyl rhenium(I) cores are reported. The reactions of trans-[ReOX3(PPh3)2] (X = Cl, Br) with H2pap were studied, and the complexes cis-[ReX2(pap)(H2pap)(PPh3)](ReO4) were isolated. The ligand pap is coordinated monodentately through the doubly deprotonated amino nitrogen as an imide, and H2pap acts as a neutral bidentate chelate, with coordination through the neutral amino nitrogen and the ketonic oxygen. The reactions of trans-[ReOBr3(PPh3)2] and cis-[ReO2I(PPh3)2] with -(2-aminobenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (H2nap) and 4-(2-hydroxybenzylideneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (Hoap) are also reported. The complexes cis-[Re(nap)Br2(PPh3)]Br, [ReO(OEt)(Hnap)(PPh3)]I and [ReO(OMe)(oap)(PPh3)]I were isolated and structurally characterized. The reactions of the Schiff base derivatives 1,2-(diimino-4’-antipyrinyl)ethane (dae) and 2,6-bis(4-amino-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one)pyridine (bap) with [Re(CO)5X] (X = Br or Cl) produced fac-[Re(CO)3(dae)Cl] and fac-[Re(CO)3(bap)Br] respectively. A series of rhenium(I) tricarbonyl complexes containing bidentate derivatives of aniline was synthesized and structurally characterized. With 1,2-diaminobenzene (Hpda) the ‘2+1’ complex salt fac-[Re(CO)3(κ1-Hpda)(κ2-Hpda)]Br was isolated, but with 2-mercaptophenol (Hspo) the bridged dimer [Re2(CO)7(spo)2] was found. The neutral complex [Re(CO)3(ons)(Hno)] was isolated from the reaction of [Re(CO)5Br] with 2-[(2-methylthio)benzylideneimino]phenol (Hons; Hno = 2-aminophenol), with ons coordinated as a bidentate chelate with a free SCH3 group. In the complex [Re(CO)3(Htpn)Br] (Htpn = N-(2-(methylthio)benzylidene)benzene-1,2-diamine) the potentially tridentate ligand Htpn is coordinated via the methylthiol sulfur and imino nitrogen atoms only, with a free amino group. These rhenium(I) complexes, with the exception of [Re2(CO)7(spo)2], revealed broad emissions centred around 535 nm. The reactions of the rhenium(V) complex cis-[ReO2I(PPh3)2] with 2-aminothiophenol (H2atp), benzene-1,2-dithiol (H2tdt) and 2-hydroxybenzenethiol (H2otp) led to the formation of the rhenium(III) compounds [Re(Hatp)(ibsq)2].OPPh3, [Re(sbsq)3].OPPh3 and [Re(obsq)3].OPPh3 (ibsq = 2-iminothiobenzosemiquinonate, sbsq = 1,2-dithiobenzosemiquinonate, obsq = 2-hydroxothiobenzosemiquinonate) respectively. The complexes adopt a trigonal prismatic geometry around the rhenium centre with average twists angles between 3.20-26.10˚. The E1/2 values for the Re(III)/Re(IV) redox couple were found to be 0.022, 0.142 and 0.126 V for [Re(Hatp)(ibsq)2].OPPh3, [Re(sbsq)3].OPPh3 and [Re(obsq)3].OPPh3 respectively. The reactions of the benzoxazole ligands, 3-(benzoxazol-2-yl)pyridin-2-ol (Hbop) and 5-amino-2-(benzoxazol-2-yl)phenol (Habo) with a [ReO]3+ precursor led to the rhenium(III) complex, [ReCl2(bop)(PPh3)2], and the complex salt, [ReO(abo)I(PPh3)2]ReO4, respectively. A variety of benzothiazole and benzimidazole derivatives were reacted with [Re(CO)5Br]. In the case of bis(benzothiazol-2-ylethyl)sulfide (bts), the neutral complex fac-[Re(CO)3(bts)Br] was obtained. The dimeric complexes (μ-dbt)2[Re(CO)3]2 and (μ-mbt)2[Re(CO)3]2 were formed when 1,3-bis(benzothiazol-2-yl)thiourea (Hdbt) and 1-(benzothiazol-2-ylidene)-3-methylthiourea (Hmbt) were used as ligands. The reaction of 2,2’-(oxybis(methylene))bis(benzimidazole) (bmb) with [Re(CO)5Cl] resulted in the rhenium(I) complex salt fac-[Re(CO)3(bmb)]+, with the tri-μ-chlorohexacarbonyl dirhenate [Re2(CO)6Cl3]- as the counter anion. The neutral complex fac-[Re(CO)3(btp)Cl] was isolated from the reaction of the 2,9-bis(benzothiazol-2-yl)-1,10-phenanthroline (btp) ligand and [Re(CO)5Cl]. The reactions of trans-[ReOCl3(PPh3)2] with bis(benzimidazol-2-ylethyl)sulfide (btn) and 1-(benzothiazol-2-ylidene)-3-methylthiourea (Hmbt) led to the formation of the cationic compounds (μ-O)2[Re2O2(btn)2]I2 and [ReCl2(bte)(PPh3)2]Cl (bte = (benzothiazole-2-yl)-N-ethylidenemethanamine) respectively.

La agroindustria cítrica argentina, que incluye producción, empaque, transporte, tratamiento por frío y producción de jugos concentrados, aceites esenciales, etc.; constituye una de las actividades de fundamental importancia en la economía nacional y regional. Los mercados importadores del mundo y consumidores de productos frescos o industrializados en general, han incrementado considerablemente sus exigencias respecto a los niveles de tolerancia de residuos de agroquímicos en los productos, lo que demanda controles y estrategias de producción adecuadas. Dentro de la amplia gama de plaguicidas de uso corriente en la producción citrícola, los benzimidazoles constituyen un grupo importante de fungicidas sistémicos, que son empleados para el control y tratamiento de enfermedades en citrus. El contenido de residuos de estos fungicidas, constituye un importante parámetro de calidad a controlar al momento de comercializar los frutos, tanto para el consumo fresco como para su empleo como materia prima en la industria cítrica. Las metodologías analíticas tradicionales para la determinación de benzimidazoles, son en general complejas, de elevado costo y tiempo de análisis; lo que llevó a plantear como objetivo del presente trabajo el desarrollo de metodologías alternativas para el análisis de fungicidas benzimidazólicos en matrices cítricas. La propuesta incluyó la aplicación y optimización de metodologías analíticas para la determinación de tiofanato, metiltiofanato y thiabendazole por microextracción en fase sólida y cromatografía gaseosa con detector de nitrógeno-fósforo en frutas, jugos concentrados y productos cítricos fermentados; y la determinación de thiabendazole y carbendazim por extracción en fase sólida y cromatografía líquida de alta resolución con detector de arreglo de diodos en aceites esenciales cítricos. / Visciglio, SB. (2011). Desarrollo de metodologías alternativas para el análisis de fungicidas benzimidazólicos en matrices cítricas [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/14978 / Palancia

An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further attempted synthetic approaches to calixindoles using new leaving groups led to uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane- 2,2'-dicarbaldehydes gives potential for further ligand design and metal complex formation. In addition, 4,6-dimethoxyindole-7- carbaldehydes have been effectively converted to a range of 6-methoxyindole-4,7-diones by Dakin oxidation. Various electrophilic substitution reactions have been performed on the 4,6-dimethoxybenzimidazoles. Formylation, acylation, acid catalyzed addition of formaldehyde and nitration revealed that the activated benzimidazoles are less reactive at the specified C-7 position compared to the analogous indoles. The key starting material for a potential calixbenzimidazole was synthesized by the selenium dioxide oxidation of 2-methyl-7-formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy- 2-styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless, attempted preparation of calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy benzimidazole led to formation of a dibenzimidazolyl ether. The synthesis of some novel activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were incorporated into new ligand systems which have led to a wide range of acyclic quadridentate neutral metal complexes. Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a radical cation followed by multielectron oxidations. On the other hand, the nickelII and cobaltII benzimidazole metal complexes investigated showed one electron ligand centered reversible reduction. Irreversible radical cation oxidation followed by multielectron oxidation of the metal complexes further demonstrates the rich electrochemical nature of the 4,6-dimethoxybenzimidazoles. Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one and triflic anhydride and an alternate procedure afforded 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles from activated indoles and 2-benzimidazolinone. Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles were synthesized via Jacobson cyclization. The two strategically placed electron donating methoxy groups activate these benzothiazoles to undergo various electrophilic substitutions at the 4- and 7- positions respectively.

An alternate approach to the synthesis of calix[3]indoles has been demonstrated, but further attempted synthetic approaches to calixindoles using new leaving groups led to uncharacterized polymeric products. The synthesis of new 7,7'-diindolylmethane- 2,2'-dicarbaldehydes gives potential for further ligand design and metal complex formation. In addition, 4,6-dimethoxyindole-7- carbaldehydes have been effectively converted to a range of 6-methoxyindole-4,7-diones by Dakin oxidation. Various electrophilic substitution reactions have been performed on the 4,6-dimethoxybenzimidazoles. Formylation, acylation, acid catalyzed addition of formaldehyde and nitration revealed that the activated benzimidazoles are less reactive at the specified C-7 position compared to the analogous indoles. The key starting material for a potential calixbenzimidazole was synthesized by the selenium dioxide oxidation of 2-methyl-7-formyl-4,6-dimethoxybenzimidazole and by oxidative cleavage of 4,6-dimethoxy- 2-styrylbenzimidazole by Lemieux-Johnson reagent followed by reduction. Nevertheless, attempted preparation of calixbenzimidazole from 2-hydroxymethyl-4,6-dimethoxy benzimidazole led to formation of a dibenzimidazolyl ether. The synthesis of some novel activated bisbenzimidazoles has been developed. Furthermore, benzimidazoles were incorporated into new ligand systems which have led to a wide range of acyclic quadridentate neutral metal complexes. Activated benzimidazoles overall illustrate one electron irreversible oxidation to form a radical cation followed by multielectron oxidations. On the other hand, the nickelII and cobaltII benzimidazole metal complexes investigated showed one electron ligand centered reversible reduction. Irreversible radical cation oxidation followed by multielectron oxidation of the metal complexes further demonstrates the rich electrochemical nature of the 4,6-dimethoxybenzimidazoles. Some novel 7-(indol-2-yl)-4,6-dimethoxybenzimidazoles were prepared with indolin-2-one and triflic anhydride and an alternate procedure afforded 2-(4,6-dimethoxyindol-7-yl)-benzimidazoles from activated indoles and 2-benzimidazolinone. Two new isomeric series of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles were synthesized via Jacobson cyclization. The two strategically placed electron donating methoxy groups activate these benzothiazoles to undergo various electrophilic substitutions at the 4- and 7- positions respectively.

En esta Memoria se informa el estudio de la interacción en solución de nuevas moléculas benzimidazólicas, 2-(o-nitrofenil)-benzimidazol (NB) y N-benzoil-2-(onitrofenil)-benzimidazol (BNB) con ADN. Para esto, se trabajó con moléculas de ADN de simple hebra (ssADN) y doble hebra (dsADN). Mediante voltamperometría de pulso diferencial sobre un electrodo de carbono vítreo se obtuvo una señal analítica para NB y BNB correspondiente a la reducción del grupo nitro presente en cada una de las estructuras estudiadas. Ambos compuestos presentaron una disminución en la intensidad de corriente en presencia de ambos tipos de ADN. Se determinó que cada molécula de ADN, ssADN o dsADN, une un mayor número de moléculas de NB que de BNB y que la constante de equilibrio del complejo formado también es mayor para el caso de NB. Al estudiar el efecto de la fuerza iónica sobre el mecanismo de interacción se pudo determinar que los compuestos interaccionan en forma electrostática con ambos tipos de ADN y que no existe una reactividad preferencial por alguna de las estructura nucléicas estudiadas. Mediante espectroscopía UV-Vis, se observó que los espectros de absorción de ambos compuestos presentan variaciones tanto en la intensidad como en el máximo de absorción en presencia de diferentes concentraciones (50 – 250 ppm) de ADN, confirmando la interacción entre las moléculas. Por otro lado, se estudió la interacción de los nitrocompuestos con ADN mediante biosensores electroquímicos. Para ello, se modificaron electrodos de carbono vítreo con nanotubos de carbono dispersos en una solución de quitosano, sobre los cuales se adsorbió finalmente dsADN (CV/CNT/ADN). La señal analítica de seguimiento fue la señal electroquímica de reducción de cada nitrocompuesto adsorbido sobre el biosensor, determinándose un tiempo óptimo de acumulación de 10 minutos. Bajo estas condiciones la respuesta del biosensor fue lineal con la concentración de nitrocompuesto en un rango de 20 a 80 µM. Finalmente al generar el biosensor con diferentes concentraciones de dsADN (20-100 ppm), se observó una rápida saturación de la superficie del electrodo para ambos compuestos. En conclusión, estas moléculas son capaces de interactuar con el ADN, lo que abre la posibilidad de causar daño a estas estructuras como mecanismo de acción farmacológico.

En esta Memoria se presenta el desarrollo y la puesta punto de metodologías analíticas reproducibles y selectivas, y su posterior aplicación en estudios de degradación de 2-(o-nitrofenil)-benzimidazol (NB) y N-benzoil-2-(o-nitrofenil)-benzimidazol (BNB). Dichos estudios se llevaron a cabo usando las técnicas de polarografía de pulso diferencial (PPD), polarografía tast (PTAST), voltametría cíclica (VC), espectrofotometría UV-Vis, cromatografía líquida de alta eficiencia (HPLC) y además estudios computacionales de modelamiento molecular.

El objetivo del estudio, fue evaluar la efectividad terapéutica de la combinación fenbendazol-praziquantel contra nemátodes y céstodes en perros; en dosis única, por vía oral de 100 mg. de fenbendazol y 5 mg. de praziquantel por Kg. de peso vivo. Se emplearon 10 cachorros machos y hembras, de 12 a 14 semanas de edad, infectados naturalmente con Toxocara canis y Dipylidium caninum, los cuales fueron divididos en dos grupos, control no tratado y tratado, de 5 animales cada uno. La necropsia de los animales se realizó al 4º día post tratamiento, obteniéndose una efectividad 92.5% y 100% frente a estadios adultos de T. canis y D. caninum, respectivamente. Este resultado demuestra que la combinación fenbendazol-praziquantel a la dosis descrita, es altamente efectiva contra los parásitos en mención, además de ser muy segura al no presentar efectos adversos ante su administración. / --- The objective of the study was to evaluate the therapeutic effectiveness of the combination fenbendazole-praziquantel against nematode and cestode in dogs; in the only dose, for oral route of 100 mg. of fenbendazole and 5 mg. of praziquantel for kg of body weight. Ten female/male pups was used, from 12 until 14 weeks of age, infected naturally with Toxocara canis and Dipylidium caninum, which were divided in two groups, control non treated and treated, of 5 animals each one. The necropsy of the animals was made the 4th day of treatment, obtaining an effectiveness of 92.5% and 100% opposite to adult stadiums of T. canis and D. caninum, respectively. This result demonstrates that the combination fenbendazole-praziquantel to the described dose is highly effective against the parasites in mention, in addition to being very sure on not having presented adverse effects before his administration.

Pas de résumé fourni / No summary available

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of biophysics and physical chemistry Candidate: Šárka Slezáková Supervisor: Ing. Vladimír Kubíček, CSc. Title of diploma thesis: HPLC Determination of Benzimidazoles In this thesis we have investigated the possibility of establishing benzimidazole with HILIC chromatography using a chromatographic column Ascentis Express HILIC 10.0 cm x 3.0 mm; 2.7 microns. Two groups of benzimidazoles were tested. The first one was focused on albendazole and its metabolites. Experiments with these substances did not produce satisfactory results, because the mobile phase composition which enables separation of the studied analytes was not found. The second group was formed by flubendazole and its reduced and hydrolyzed form. In this case, several mobile phase compositions were tested. Finally, distribution of individual analytes in a mixture, using a mobile phase ACN:HCOOH 0.03 mol/l (90:10), was successfully achieved. Ricobendazol was chosen as an internal standard. When separation conditions were found, calibration curve for the determination of reduced flubendazole in biological samples was subsequently constructed using ricobendazol as the internal standard with the use of fluorescence detection. Keywords: HILIC, HPLC, albendazole,...