RESUMEN
ABSTRACT Keeping in mind the pharmacological importance of the 1,3,4-oxadiazole moiety, a series of new S-substituted derivatives, 5a-h, of 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3) were synthesized. The reaction of p-toluenesulfonyl chloride (a) and ethyl isonipecotate (b) produced ethyl 1-(4-tosyl)piperidin-4-carboxylate (1) which was further transformed into 1-(4-tosyl)piperidin-4-carbohydrazide (2) by hydrazine hydrate in methanol. Compound 2 was refluxed with CS2 in the presence of KOH to synthesize 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3). The desired compounds, 5a-h, were synthesized by stirring 3 with aralkyl halides, 4a-h, in DMF using NaH as an activator. The structures of synthesized compounds were elucidated by 1H-NMR, IR and EI-MS spectral studies. These compounds were further evaluated for enzyme inhibitory activity against lipoxygenase and alpha-glucosidase, along with antibacterial activity against Gram-negative and Gram-positive bacteria.
RESUMO Tendo em vista a importância farmacológica da porção 1,3,4-oxadiazol, sintetizou-se uma série de novos derivados S-substituídos, 5a-h, de 5-(1-(4-tosi)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). A reação do cloreto de p-toluenossulfonila (a), com isonipecotato de (b) etila forneceu 1-(4-tosil)piperidin-4-carboxilato de metila (1), que foi, em seguida, transformado em 1-(4-tosil)piperidin-4-carbo-hidrazida (2) por reação com hidrato de hidrazina em metanol. O composto 2 foi submetido a refluxo com CS2 na presença de KOH para se obter 5-(1-(4-tosil)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). Os compostos desejados, 5a-h, foram obtidos por agitação de 3 com haletos de aralquila, 4a-h, em DMF, na presença de NaH. As estruturas dos compostos sintetizados foram elucidadas através de análise dos espectros de 1H-MNR, IR e EI-MS. Estes compostos foram, ainda, avaliados quanto à inibição das enzimas lipoxigenase e alfa-glucosidase, juntamente com a atividade antibacteriana contra bactérias Gram positivas e Gram negativas.
Asunto(s)
Oxadiazoles/análisis , Inhibidores Enzimáticos/análisis , Antibacterianos/síntesis química , Sulfonamidas/análisis , Bacterias Gramnegativas , Bacterias GrampositivasRESUMEN
Antibiotic and non-antibiotic sulphonamides are often prescribed. Although chemical differences make cross-reactivity rare, reactions may be severe in patients allergic to sulphur. Adverse reactions are common with sulphonamides but low platelets and skin changes are rarely associated with eye-drops for glaucoma. A woman treated with dorzolamide and timolol presented with disseminated eruption. On admission, her physical examination was unremarkable except for the skin changes and severe thrombocytopaenia was detected. Skin biopsy showed hyperkeratosis, acanthosis, perivascular and periadnexal infiltrates with no vasculitis. After discontinuation of eye-drops, the eruption improved but low platelets persisted. Skin changes reappeared with use of dapsone which suggested sulphonamide cross-reactivity.
A menudo se prescriben sulfonamidas antibióticas y no-antibióticas. Aunque las diferencias químicas hacen que la reactividad cruzada sea algo raro, las reacciones pueden ser severas en los pacientes alérgicos al azufre. Las reacciones adversas son comunes con las sulfonamidas pero las plaquetas bajas y los cambios en la piel raramente se asocian con las gotas oculares para el glaucoma. A una mujer a quien se le hizo un tratamiento con dorzolamida y timolol, se le presentó una erupción diseminada. En el momento del ingreso, su examen físico fue común y corriente excepto por los cambios en la piel. Además se le detectó una trombocitopenia severa. La biopsia de la piel reveló hiperqueratosis, acanthosis, infiltrados perivasculares y periadnexales sin vasculitis. Tras descontinuar las gotas oculares, la erupción mejoró pero las plaquetas bajas persistieron. Los cambios de la piel reaparecieron con el uso de dapsona, lo que hizo pensar en una reactividad cruzada de la sulfonamida.