We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.

Owing to valuable biological activities of 1,3,4-oxadiazole, sulfamoyl and piperidine functionalities, some new 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl) thio]methyl}benzene sulfonyl)-4-methylpiperidine (6a-o) derivatives have been introduced. The target molecules were synthesized from different aralkyl/aryl carboxylic acids, 1a-o, through a series of steps. First the compounds, 1a-o, were converted to heterocyclic 1,3,4-oxadiazole nucleophiles, 4a-o. Second an electrophile as 1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (5) was synthesized from 4-methylpiperidine. Finally the target compounds, 6a-o, were prepared by reacting 4a-o with 5 in DMF and LiH. The final compounds were structurally elucidated by spectral data of IR, ¹H-NMR and EI-MS. All the compounds were screened for their antibacterial evaluation and found to exhibit valuable results.

ABSTRACT A series of molecules bearing multiple functional groups were synthesized to study their antibiotic effect against Gram-positive and Gram-negative bacteria and lipoxygenase activity as well. 2,4-Dimethylcarbolic acid (1) was refluxed with ethyl 2-bromoacetate to synthesize ethyl 2-(2,4-dimethylphenoxy)acetate (2). Compound 2 was converted to the corresponding hydrazide 3, again on refluxing with hydrazine. The compound 5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-thiol (4) was synthesized by the reaction of 3 and CS2 in the presence of KOH. Compound 4 was further converted to the corresponding ester 5 and then 2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide (6). The final molecules N'-substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide, 8a-m, bearing ether, 1,3,4-oxadiazole, thioether, hydrazone and azomethine functional groups were synthesized by stirring the aryl carboxaldehydes 7a-m with 6 in methanol at room temperature. The depicted structures of all synthesized molecules were corroborated by IR, 1H-NMR and EIMS spectral data analysis. 8m and 8i showed substantial antibacterial activity and lipoxygenase inhibitory activity, respectively.

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.

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.

The synthesis of poly-functional moieties as one unit has been under consideration by the synthetic chemists to search out new potent molecules. 2-Chlorobenzoic acid (1) was converted to 5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-thiol (4) through a series of steps. This nucleophile was attached with different electrophiles, prepared by the reaction of aryl/alkyl amines with 2-bromoacetylbromide, in NaH/DMF to synthesize N-substituted-2-((5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-yl)sulfanyl)acetamide, 7a-f. The molecule 4 was stepped to ethyl ester and carbohydrazide. The carbohydrazide was made to react with aryl carboxaldehydes in methanol to synthesize N'-substituted-2-(5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-ylthio)acetohydrazide, 11a-i. The structures of all the molecules were corroborated through IR, ¹H-NMR and EI-MS spectral data. Both the series were screened for antibacterial and enzyme inhibition activity.

INTRODUCTION: In research projects such as vaccine trials, accurate and complete surveillance of all outcomes of interest is critical. In less developed countries where the private sector is the major health-care provider, the private sector must be included in surveillance systems in order to capture all disease of interest. This, however, poses enormous challenges in practice. The process and outcome of recruiting private practice clinics for surveillance in a vaccine trial are described. METHODS: The project started in January 2002 in two urban squatter settlements of Karachi, Pakistan. At the suggestion of private practitioners, a phlebotomy team was formed to provide support for disease surveillance. Children who had a reported history of fever for more than three days were enrolled for a diagnosis. RESULTS: Between May 2003 and April 2004, 5540 children younger than 16 years with fever for three days or more were enrolled in the study. Of the children, 1312 (24%) were seen first by private practitioners; the remainder presented directly to study centres. In total, 5329 blood samples were obtained for microbiology. The annual incidence of Salmonella typhi diagnosed by blood culture was 407 (95% confidence interval (95% CI), 368-448) per 100 000/year and for Salmonella paratyphi A was 198 (95% CI, 171-227) per 100 000/year. Without the contribution of private practitioners, the rates would have been 240 per 100 000/year (95% CI, 211-271) for S. typhi and 114 (95% CI, 94-136) per 100 000/year for S. paratyphi A. CONCLUSION: The private sector plays a major health-care role in Pakistan. Our experience from a surveillance and burden estimation study in Pakistan indicates that this objective is possible to achieve but requires considerable effort and confidence building. Nonetheless, it is essential to include private health care providers when attempting to accurately estimate the burden of disease in such settings.

INTRODUCCIÓN: En proyectos de investigación como los ensayos de vacunas, es fundamental aplicar una vigilancia exhaustiva de todos los resultados de interés. En los países poco desarrollados donde el sector privado constituye el principal proveedor de atención sanitaria, dicho sector debe formar parte de los sistemas de vigilancia si se desea detectar todas las enfermedades pertinentes. Sin embargo, en la práctica esto plantea grandes retos. Se describen aquí los procedimientos y los resultados de la contratación de consultorios privados con fines de vigilancia en el ensayo de una vacuna. MÉTODOS: El proyecto comenzó en enero de 2002 en dos asentamientos ilegales urbanos de Karachi, Pakistán. Por sugerencia de algunos médicos privados, se formó a un equipo de flebotomía para que apoyara las actividades de vigilancia de la morbilidad. Se reclutó para diagnóstico a los niños que presentaban una historia de fiebre de más de tres días. RESULTADOS: Entre mayo de 2003 y abril de 2004 se reclutó para el estudio a 5540 niños menores de 16 años con una historia de fiebre de al menos tres días de duración. De ellos, 1312 (24%) fueron examinados por primera vez por médicos privados; los otros acudieron directamente a los centros de estudio. En total se obtuvieron 5329 muestras de sangre para análisis microbiológico. La incidencia anual de Salmonella typhi diagnosticada mediante hemocultivo fue de 407 (intervalo de confianza del 95% (IC95%): 368 - 448) por 100 000/año, y la de Salmonella paratyphi A, de 198 (IC95%: 171 - 227) por 100 000/año. Sin la ayuda de los médicos privados, las tasas habrían sido de 240 (IC95%: 211 - 271) por 100 000/año para S. typhi y de 114 (IC95%: 94 - 136) por 100 000 /año para S. paratyphi A. CONCLUSIÓN: El sector privado cumple una importante función de atención sanitaria en el Pakistán. La experiencia de nuestro estudio de vigilancia y estimación de la morbilidad en el pais indica que el objetivo planteado se puede lograr pero requiere un considerable esfuerzo y medidas que estimulen la confianza. No obstante, si se desea estimar con precisión la carga de morbilidad en esas circunstancias, la participación de proveedores de salud privados es fundamental.

INTRODUCTION: Pour les projets de recherche tels que les essais vaccinaux, une surveillance précise et exhaustive de l'ensemble des résultats intéressants revêt une importance critique. Dans les pays moins développés, où le secteur privé est le principal prestataire de soins de santé, il faut faire collaborer ce secteur à l'activité des systèmes de surveillance afin de bien prendre en compte toutes les maladies à suivre. Dans la pratique cependant, la mise en place de cette collaboration pose d'énormes difficultés. L'article décrit le processus de recrutement des établissements privés en vue de leur participation à la surveillance dans le cadre d'un essai vaccinal et les résultats de ce processus. MÉTHODES: Le projet a débuté en janvier 2002 dans deux lotissements urbains spontanés de Karachi (Pakistan). A l'initiative de praticiens privés, une équipe spécialisée dans les prélèvements veineux a été constituée pour apporter un appui à la surveillance des maladies. Les enfants ayant des antécédents signalés de fièvre pendant plus de trois jours ont été recrutés dans l'étude pour faire l'objet d'un diagnostic. RÉSULTATS: Entre mai 2003 et avril 2004, 5540 enfants de moins de 16 ans ayant présenté de la fièvre pendant trois jours ou plus ont été recrutés dans l'étude. Parmi ces enfants, 1312 (24 %) ont été vus d'abord par des praticiens privés, les autres ayant été présentés directement aux centres d'étude. Au total, 5329 échantillons de sang ont été prélevés pour examen microbiologique. L'hémoculture a permis d'évaluer l'incidence annuelle de Salmonella typhi à 407 cas [intervalle de confiance (IC) à 95 % : 368-448 ] pour 100 000 enfants appartenant à la tranche d'âges considérée et celle de Salmonella paratyphi A à 198 (CI à 95 % : 171-227) pour 100 000 enfants appartenant à la tranche d'âges considérée par an. Sans la contribution des praticiens privés, ces taux auraient été évalués à 240 pour 100 000 enfants de l'âge considéré et par an (CI à 95 % : 211 - 271) pour S. typhi et à 114 (CI à 95 % : 94-136) pour 100 000 enfants appartenant à la tranche d'âges considérée et par an pour S. paratyphi A. CONCLUSION: Le secteur privé joue un rôle majeur dans la dispensation de soins de santé au Pakistan. L'expérience tirée de cette étude de surveillance et d'estimation de la charge de morbidité au Pakistan indique qu'il serait possible d'atteindre l'objectif d'amélioration de la surveillance grâce à la collaboration du secteur privé, mais que cela nécessiterait des efforts considérables et un renforcement de la confiance. Quoi qu'il en soit, il est essentiel de prendre en compte les dispensateurs de soins privés lorsqu'on tente d'estimer avec précision la charge de morbidité dans de tels pays.