Sinteza i biološko djelovanje novih 1-benzil i 1-benzoil 3-heterocikličkih derivata indola

Starting from 1-benzyl- (2a) and 1-benzoyl-3-bromoacetyl indoles (2b) new heterocyclic, 2-thioxoimidazolidine (4a,b), imidazolidine-2,4-dione (5a,b), pyrano(2,3-d)imidazole (8a,b and 9a,b), 2-substituted quinoxaline (11a,b–17a,b) and triazolo(4,3-a)quinoxaline derivatives (18a,b and 19a,b) were synthesized and evaluated for their antimicrobial and anticancer activities. Antimicrobial activity screening performed with concentrations of 0.88, 0.44 and 0.22 g mm2 showed that 3-(1-substituted indol-3-yl)quinoxalin-2(1H)ones (11a,b) and 2-(4-methyl piperazin-1-yl)-3-(1-substituted indol-3-yl) quinoxalines (15a,b) were the most active of all the tested compounds towards P. aeruginosa, B. cereus and S. aureus compared to the reference drugs cefotaxime and piperacillin, while 2-chloro-3-(1-substituted indol-3-yl)quinoxalines (12a,b) were the most active against C. albicans compared to the reference drug nystatin. On the other hand, 2-chloro-3-(1-benzyl indol-3-yl) quinoxaline (12a) display potent efficacy against ovarian cancer xenografts in nude mice with tumor growth suppression of 100 0.3 %.U radu je opisana sinteza, antimikrobno i antitumorsko djelovanje heterocikličkih derivata indola. Polazeći iz 1-benzil- i 1-benzoil-3-bromacetil indola (2a i 2b) sintetizirani su novi heterociklički spojevi 2-tioksoimidazolidini (4a,b), imidazolidin-2,4-dioni (5a,b), pirano(2,3-d)imidazoli (8a,b i 9a,b), 2-supstituirani kinoksalini (11a,b–17a,b) i triazolo(4,3-a)kinoksalini (18a,b i 19a,b). Sintetizirani spojevi testirani su na antimikrobno i antitumorsko djelovanje. Ispitivanje antimikrobnog djelovanja provedeno je s koncentracijama otopina 0,88, 0,44 i 0,22 g mm2 i uspoređeno s referentnim lijekovima cefotaksimom i piperacilinom. Rezultati pokazuju da su 3-(1-supstituirani indol-3-il)kinoksalin-2(1H)oni (11a,b) i 2-(4-metil piperazin-1-il)-3-(1-supstituirani indol-3-il) kinoksalini (15a,b) najaktivniji spojevi na sojeve P. aeruginosa, B. cereus i S. aureus, dok su 2-klor-3-(1-supstituirani indol-3-il)kinoksalini (12a,b) najaktivniji na C. albicans (usporedba s nistatinom). Osim toga, 2-klor-3-(1-benzil indol-3-il) kinoksalin (12a) pokazuje veliku učinkovitost na tumore ovarija miševa (supresija rasta tumora 100 0,3 %)

Dopamine transport function is elevated in cocaine users

Dopaminergic transmission has been suggested to be a primary mechanism mediating reinforcement, withdrawal and craving associated with psychostimulant addiction. Pyscho-stimulants attenuate dopamine transporter (DAT) clearance efficiency, resulting in a net increase in synaptic dopamine levels. Re-uptake rate is determined by the number of functional DAT molecules at the membrane surface. Previous in vivo imaging studies in humans and in vitro studies in post-mortem human brain have demonstrated that chronic cocaine abuse results in a neuroadaptive increase in DAT-binding site density in the limbic striatum. Whether this increase in DAT availability represents an increase in the functional activity of the transporter is unknown. Here, we present evidence that DAT function is elevated by chronic cocaine abuse. The effect of increasing post-mortem interval on the functional viability of synaptosomes was modeled in the baboon brain. Baboon brains sampled under conditions similar to human brain autopsies yielded synaptosomal preparations that were viable up to 24 h post-mortem. Dopamine (DA) uptake was elevated twofold in the ventral striatum from cocaine users as compared to age-matched drug-free control subjects. The levels of [3H]DA uptake were not elevated in victims of excited cocaine delirium, who experienced paranoia and marked agitation prior to death. In keeping with the increase in DAT function, [3H]WIN 35,428 binding was increased in the cocaine users, but not in the victims of excited delirium. These results demonstrate that DA uptake function assayed in cryopreserved human brain synaptosomes is a suitable approach for testing hypotheses of the mechanisms underlying human brain disorders and for studying the actions of addictive drugs in man