El objetivo principal del trabajo presentado fue analizar el comportamiento farmacologico de un antihelmíntico de la familia de los benzimidazoles, el albendazol sulfóxido (ABZSO) y de sus enantiómeros, evaluando su capacidad para atravesar la barrera placentária y causar embriotoxicidad y malformaciones congénitas. Para ello se estudió la cinética metabólica en fluido ruminal, utilizando un modelo de fermentadores de doble flujo, y la cinética plasmática en ovejas. Posteriormente se analizó el paso placentario de los enantiómeros de ABZSO en ovejas y las concentraciones embrionarias en ratas. Las muestras colectadas en estos procesos se analizaron mediante una técnica de HPLC (High Performance Liquid Chromatography) para cuantificar la presencia de netobimin (NTB), albendazol (ABZ), ABZSO y sus enantiómeros y el metabolito albendazol sulfona (ABZSO2). El estudio de las malformaciones externas se llevó a cabo por observación directa, mientras que las malformaciones esqueléticas se analizaron mediante tinción con rojo de alizarina S y posterior transparentación de los tejidos blandos. En los fluidos ruminales se observó un predominio de los procesos de reducción de NTB a ABZ y de ABZSO a ABZ en comparación con los procesos de oxidación de ABZ a ABZSO y de éste a ABZSO2. Por otra parte, no fueron observados procesos enantioselectivos en el metabolismo de los enantiómeros de ABZSO. En el plasma de las ovejas se observó un predominio del (+)-ABZSO, mientras que en la rata los dos enantiómeros presentaron un perfil cinético semejante, sugiriendo la existencia de diferencias entre especies. En estos estudios no se observaron diferencias relacionadas con el sexo y la gestación en el perfil farmacocinético de los enantiómeros de ABZSO en ovejas. También se ha observado que los dos enantiómeros tienen capacidad de atravesar la barrera placentaria de las ratas y de las ovejas en elevadas concentraciones y que la placenta de la oveja impedía en cierto grado el paso de estas moléculas hacia el feto. Asimismo se observó un elevado poder embriotóxico y alta capacidad teratógena del ABZSO cuando se administró la forma racémica. Cuando se administraron los enantiómeros por separado se pudo observar que los dos son buenos substratos de la sulfonación y que siguen un perfil cinético similar. Asimismo no se ha observado una reracemización, indicando este hecho una gran estabilidad de los enantiómeros de ABZSO y una baja capacidad reductora en los fluidos gastrointestinales de la rata. / The main objective of this work was to analyse the pharmacological behaviour of a benzimidazole anthelmintic compound, albendazole sulphoxide (ABZSO) and its enantiomers, evaluating their ability to pass through the placental barrier and to produce developmental toxicity. The ruminal fluid kinetics of these compounds in artificial rumens, and the plasma kinetics in sheep was performed. The placental transfer and the embryo concentration of the ABZSO enantiomers were also studied in sheep and rats respectively. All the collected samples were analysed by HPLC (High Performance Liquid Chromatography) in order to determine netobimin (NTB), albendazole (ABZ), albendazole sulfoxide (ABZSO) and its enantiomers, and the metabolite sulfone (ABZSO2) concentration. The study of external abnormalities was performed by direct observation, whereas the skeletal malformation analysis was done using red alizarin S before transparentation of the smooth tissue. The reductive reations of the ruminal flora from NTB to ABZ and from ABZSO to ABZ were higher than the oxidation from ABZ to ABZSO and from ABZSO to ABZSO2. In other hand, no differences concerning the production or consumption of ABZSO enantiomers by the ruminal flora were observed, indicating that the ruminal bacteria metabolism was not enantioselective. In the sheep plasma there was a predominance of (+)-ABZSO, whereas in the rat plasma, both enantiomers showed similar kinetics profile, suggesting the existence of differences in ABZSO enantiomers plasma concentrations species. In our studies no pharmacokinetic differences of ABZSO enantiomers related to sex and pregnancy were observed in sheep. Both ABZSO enantiomers show the ability to pass through the placental barrier of rats and sheep, and that the sheep placenta impaired these compounds to reach the foetus. The ABZSO caused embrionary and teratogenic effects when administered in racemic form indicating that these effects were due to the presence of both enantiomers. When the enantiomers were administered separately, both enantiomers showed to be good substrates of sulfonation, and also to have a similar kinetic profile. Also, no reracemisation was observed after both enantiomers administration, indicating the high stability of ABZSO enantiomers, and the low reductive capacity of rat gastrointestinal fluid.

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.

Benzimidazole and its derivatives have attracted many organic chemists due to their interesting biological activities. These include activities against viruses such as, HIV, RNA, herpes (HSV-1), influenza, and cytomegalovirus (HCMV); antimicrobial and antitumor activities. Even though a lot of research has been conducted on the synthesis of benzimidazoles, factors such as, drug resistance present a need for synthesis of more structural analogues of these compounds. In chapter three, the synthesis of 2-aryl-1Hbenzimidazoles (46a-c) and 2-aryl-1-arylmethyl-1H-benzimidazoles (49a-d) is described. The yields for these products ranged from 44-79 % and 62-72 %, respectively. The synthesis of novel bisbenzimidazole derivatives is described in chapter four. Direct condensation of 3,3'-diaminobenzidine (1 mmol) with 2-thiophenecarboxyaldehyde (2 mmol) afforded 2, 2’-di-2-thienyl-5,5-Bi-1H-benzimidazole (52) in 65 % yield. Except in the case of 2-furancarboxyaldehyde, the acid catalyzed condensation of 3,3'- diaminobenzidine (1 equivalent) and heteroaromatic aldehydes (4 equivalents) gave novel bisbenzimidazoles where the aldehyde added three times to 3,3'-diaminobenzidine. The four times addition product, 1,2-di-2-furanylmethyl-2,2-di-2-furanyl benzimidazole (53) was obtained in 53 % yield. On the other hand, the three times addition product, 1,2-di-2- pyrrolylmethyl-2,2-di-2-pyrrolyl (54); 1,2-di-2-thienylmethyl-2,2-di-2-thienyl (55); and 1,2-di-2-pyridylmethyl-2,2-di-2-pyridyl benzimidazoles (56) were obtained in 85, 12 and 10 %, respectively. Full characterization of bisbenzimidazoles (54-56) was achieved by 1H, 13C NMR and LCMS spectra. Although benzimidazoles have been proven to be active against various cancers, their use as ligands for platinum (II) has been reported to enhance this activity. Three new benzimidazole Pt (II) complexes were synthesized. N, N, N-bound Pt (II) complexes of 2- quinolyl-1-quinolylmethyl-1H-benzimidazole (60) and 2-pyridyl-1-pyridylmethyl-1Hbenzimidazole (63) were obtained in excellent yields of 82 and 72 %, respectively. S, Nbound Pt (II) complex of 2-thienyl-1-thienylmethyl-1H-benzimidazole (64) was isolated in 63 % yield. From 195Pt NMR spectra analysis, it was concluded that the method reported by Morgan and Burstall is more efficient for the synthesis of these complexes. In addition to 195Pt NMR, platination was also confirmed using 1H and 13C NMR spectra. / Thesis (PhD.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

The mechanism of benzimidazole (BZ) anthelmintic resistance in Haemonchus contortus was investigated. The total binding (TB), low-affinity binding (LAB) and high-affinity (specific) binding (HAB) of ($ sp3$H) BZs (mebendazole (MBZ), oxibendazole (OBZ), albendazole (ABZ) and oxfendazole (OFZ)) in supernatants derived from BZ-susceptible (S) and BZ-resistant (R) strains were examined and compared. The TB of all ($ sp3$H) BZs was reduced for the R strain. The TB of OBZ, MBZ and ABZ was separated into LAB and HAB. However, OFZ bound with low-affinity. The binding affinity, K$ sb{ rm a},$ and maximum binding, B$ sb{ rm max},$ for the HAB of OBZ and MBZ were calculated using computer programs. Compared with the S strain, the B$ sb{ rm max}$ of the R strain was reduced but the K$ sb{ rm a}$ was not affected. LAB to parasite preparations devoid of tubulin was observed but HAB occurred to preparations containing tubulin only. The HAB per mg protein decreased from egg through larva to adult stage. It was shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot and enzyme-linked immunosorbent assay (ELISA) analysis that the tubulin content per mg protein decreased from egg, through larva to adult worm. The ability of various BZs--OBZ, MBZ, ABZ, OFZ, fenbendazole (FBZ), albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO$ sb2),$ and thiabendazole (TBZ)--to bind tubulin was compared by displacement analysis and their IC$ sb{50}$ ( (BZ) required to inhibit 50% of the ($ sp3$H) BZ binding) and K$ sb{ rm a}$ values were determined. The IC$ sb{50}$ and K$ sb{ rm a}$ values approximately correlated with the known anthelmintic potency (recommended therapeutic doses) of the BZs except for OFZ and ABZSO. Tubulin bound BZs at 4$ sp circ$C with lower K$ sb{ rm a}$ than at 37$ sp circ$C. Western blot of tubulin separated by 2-dimensional electrophoresis showed that the $ beta$-tubulin isoform pattern of the S and R strains were dissimilar whil

Thesis (Ph.D.) --Murdoch University, 2003. / Thesis submitted to the Division of Veterinary and Biomedical Sciences. Includes bibliographical references (leaves 160-196).

Thesis (M.Sc. (Physical Chemistry))--Mahidol University, 1982.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1956. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 92-96).

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Chemistry and Chemical Biology." Includes bibliographical references (p. 162-175).

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