2 resultados para SUBSTITUENT POSITION,SPACER GROUPS

em Digital Commons at Florida International University


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The issue of institutional engineering has gained a renewed interest with the democratic transitions of the Central and Eastern European countries, as for some states it has become a matter of state survival. The four countries examined in the study – Macedonia, Slovakia, Romania and Bulgaria – exemplify the difficulty in establishing a stable democratic society in the context of the resurgence of national identity. The success of ethnonational minorities in achieving the desired policies affirming or expanding their rights as a group was conditioned upon the cohesion of the minority as well as the permissiveness of state institutions in terms of participation and representation of minority members. The Hungarian minorities in Slovakia and Romania, the Turkish minority in Bulgaria, and the Albanian minority in Macedonia, formed their political organizations to represent their interests. However, in some cases the divergence of strategies or goals between factions of the minority group seriously impeded its ability to obtain the desired concessions from the majority. The difficulty in the pursuit of policies favoring the expansion of minority rights was further exacerbated in some of the cases by the impermissiveness of political institutions. The political parties representing the interest of ethnonational minorities were allowed to participate in elections, although not without suspicions about their intent and even strong opposition from majority groups, but participation in elections and subsequent representation in legislative bodies did not translate into adoption of the desired policies. The ethnonational minorities' inability to effectively influence the decision-making process was the result of the inadequacy of democratic institutions to process these demands and channel them through the normal political process in the absence of majority desire to accommodate them. Despite the promise of democratic institutions to bring about a major overhaul of the policies of forceful assimilation and disregard for minority rights, the four cases analyzed in the study demonstrate that in effect ethnonational minorities continued to be at the mercy of the majority, especially if the minority was unable to position itself as a balancing actor.

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Quorum sensing (QS) is a population-dependent signaling process bacteria use to control multiple processes including virulence, critical for establishing infection. There are two major pathways of QS systems. Type 1 is species specific or intra-species communication in which N-acylhomoserine lactones (Gram-negative bacteria) or oligopeptides (Gram-positive bacteria) are employed as signaling molecules (autoinducer one). Type 2 is inter-species communication in which S-4,5-dihydroxy-2,3-pentanedione (DPD) or its borate esters are used as signaling molecules. The DPD is biosynthesized by LuxS enzyme from S-ribosylhomocysteine (SRH). Recent increase in prevalence of bacterial strains resistant to antibiotics emphasizes the need for the development of new generation of antibacterial agents. Interruption of QS by small molecules is one of the viable options as it does not affect bacterial growth but only virulence, leading to less incidence of microbial resistance. Thus, in this work, inhibitors of both N-acylhomoserine lactone (AHL) mediated intra-species and LuxS enzyme, involved in inter-species QS are targeted. The γ-lactam and their reduced cyclic azahemiacetal analogs, bearing the additional alkylthiomethyl substituent, were designed and synthesized targeting AHL mediated QS systems in P. aeruginosa and Vibrio harveyi. The γ-lactams with nonylthio or dodecylthio chains acted as inhibitors of las signaling in P. aeruginosa with moderate potency. The cyclic azahemiacetal with shorter propylthio or hexylthio substituent were found to strongly inhibit both las and rhl signaling in P. aeruginosa at higher concentrations. However, lactam and their azahemiacetal analogs were found to be inactive in V. harveyi QS systems. The 4-aza-S-ribosyl-L-homocysteine (4-aza-SRH) analogs and 2-deoxy-2-substituted-S-ribosyl-L-homocysteine analogs were designed and synthesized targeting Bacillus subtilis LuxS enzyme. The 4-aza-SRH analogs in which oxygen in ribose ring is replaced by nitrogen were further modified at anomeric position to produce pyrrolidine, lactam, nitrone, imine and hemiaminal analogs. Pyrrolidine and lactam analogs which lack anomeric hydroxyl, acted as competitive inhibitors of LuxS enzyme with KI value of 49 and 37 µM respectively. The 2,3-dideoxy lactam analogs were devoid of activity. Such findings attested the significance of hydroxyl groups for LuxS binding and activity. Hemiaminal analog of SRH was found to be a time-dependent inhibitor with IC50 value of 60 µM.