o:18090 Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum doktorska disertacija benzothiophene and steroidal derivatives of aminoquinoline : doctoral dissertation sr Botulinum neurotoksini su najjaĉi poznati prirodni otrovi i izazivaĉi botulizma – potencijalno smrtonosne neuroparalitiĉke bolesti. U poslednje vreme, sve veći broj studija je usmeren ka pronalaţenju inhibitora botulinum neurotoksina serotipa A (BoNT/A) aktivnih unutar ćelije, jer terapija antitelima ima uspeha jedino pre nego što toksin uĊe u neuron. U okviru ove doktorske disertacije izvršena je sinteza i detaljno ispitivanje inhibitorne aktivnosti novih steroidnih i benzo[b]tiofenskih derivata 4-aminohinolina prema kratkom nizu (BoNT/A LC) i holotoksinu BoNT/A. U istraţivanju je korišćen proteolitiĉki in vitro esej i ćelijski esej u motornim neuronima razvijenim iz embrionalnih matiĉnih ćelija miša (mES-MN). Dodatno, molekulsko modelovanje i uklapanje novih derivata u aktivno mesto enzima izvršeno je korišćenjem programa Schr dinger Suite 2016-4. U in vitro proteolitiĉkom eseju, sintetisana jedinjenja su ostvarila do 85% inhibicije BoNT/A LC pri koncentraciji 20 μM, dok su IC50 vrednosti bile u opsegu 0,7– 10,2 μM. U preintoksikacionom modelu u motornim neuronima razvijenim iz embrionalnih matiĉnih ćelija miša (mES-MN) novi derivati su vršili zaštitu proteina SNAP-25i do 88%, u niskim mikromolarnim koncentracijama i u dozno-zavisnom reţimu. Najaktivniji derivati su testirani u postintoksikacionom modelu, u kome se jedinjenja dodaju ćelijskoj kulturi 30 ili 60 minuta posle holotoksina. U oba modela je uoĉena korelacija procenta zaštite SNAP-25 i primenjene koncentracije jedinjenja. Jedinjenje 17 (JK141) je pokazalo 99% zaštite SNAP-25 kada se administrira 30 minuta posle BoNT/A... Botulinum neurotoxins are the most poisonous (biological) substances known and causative agents of botulism – serious and potentially fatal neuroparalytic illness. Recently, the majority of efforts have focused on identification of botulinum neurotoxin serotype A (BoNT/A) inhibitors with intracellular activity, because antibody-based treatments are successful only before toxin enters a neuron. In this doctoral dissertation synthesis and detailed evaluation of inhibitory potencies of new steroidal and benzo[b]thiophene 4-aminoquinoline derivatives against BoNT/A light chain (LC) and full length BoNT/A is reported. Both in vitro proteolytic assay and cell-based assay using mouse embryonic stem cell derived motor neurons (mES-MNs) were employed. To rationalize the inhibitory potencies of the new derivatives, structure-based docking simulations were performed using Schr dinger Suite 2016-4 and the modules therein. Using in vitro HPLC-based assay, the newly synthesized molecules have shown BoNT/A LC inhibition up to 85% at 20 μM and IC50 values ranging from 0.7–10.2 μM. Compounds tested during BoNT/A challenge in mES-MNs in preintoxication model were found to protect SNAP-25 proteinii by up to 88% at low μM concentrations and in dose-dependent manner. The most effective derivatives were also tested in a postexposure model, where compounds were added 30 or 60 minutes following holotoxin administration. In both pre- and postintoxication models, dose-dependent behavior was observed. Compound 17 (JK141) showed 99% of SNAP-25 cleavage protection when administrated 30 minutes after BoNT/A... Prirodne nauke - Organska hemija, medicinska hemija / Life sciences- Organic chemistry, medicinal chemistry Datum odbrane: 07.05.2018. botulinum neurotoksin, mali molekuli kao inhibitori, aminohinolin,steroid, benzotiofen, antimalarici, Plasmodium falciparum, farmakokinetika botulinum neurotoxin, small molecule inhibitors, aminoquinoline, steroid,benzotiophene, antimalarials, Plasmodium falciparum, pharmacokinetics 547 yes 50361871 91552101 5940 91552100 50361871 2018-09-05T12:20:50.053Z 45 no 46 mentor Jelena M., 1988- Konstantinović 2018 63 mentor Bogdan A., 1951- Šolaja 2018 63 član komisije Dragana, 1967- Milić 2018 63 član komisije Igor, 1977- Opsenica 2018 63 član komisije Olgica. Đurković-Đaković 2018 63 član komisije Vladimir S., 1953- Kostić 2018 63 član komisije Velimir, 1951- Popsavin 2018 259 listova 8387474 http://phaidrabg.bg.ac.rs/o:18090 no yes 4 2018-09-05T12:20:50.320Z 70 11 1066775 1066794 botulinum neurotoksin, mali molekuli kao inhibitori, aminohinolin,steroid, benzotiofen, antimalarici, Plasmodium falciparum, farmakokinetika botulinum neurotoxin, small molecule inhibitors, aminoquinoline, steroid,benzotiophene, antimalarials, Plasmodium falciparum, pharmacokinetics 547 1738 11A19 2018