benzothiophene and steroidal derivatives of aminoquinoline

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..

Botoks - upotreba i zloupotreba

Botulinum toxin is a neurotoxic protein, produced by bacterium Clostridium botulinum. This toxin specifically cleaves the SNAP-25 protein, required for vesicle fusion, that releases neurotransmitters from the axon endings (in particular acetylcholine). Although botulinum toxin is a lethal naturally occurring substance, it can be used as an effective and powerful medication, in the treatment of different types of spasms and dystonias, and also in cosmetics, but potential side effects do exist. Commercially it is known as BotoxR.Botulinski toksin je izuzetno otrovna supstanca koju proizvodi bakterija Clostridum botulinum. Deluje na periferne nervne završetke, blokirajući oslobađanje neurotransmitera acetilholina. Interesantan je po tome što može da izazove oboljenje (botulizam), ali i da služi za lečenje mnogih bolesti (na primer, cervikalna distonija). U današnje vreme se koristi u različitim kozmetičkim tretmanima. Prekomerna upotreba izaziva neželjene efekte, a može dovesti do smrti

Botoks - upotreba i zloupotreba

Botulinum toxin is a neurotoxic protein, produced by bacterium Clostridium botulinum. This toxin specifically cleaves the SNAP-25 protein, required for vesicle fusion, that releases neurotransmitters from the axon endings (in particular acetylcholine). Although botulinum toxin is a lethal naturally occurring substance, it can be used as an effective and powerful medication, in the treatment of different types of spasms and dystonias, and also in cosmetics, but potential side effects do exist. Commercially it is known as BotoxR.Botulinski toksin je izuzetno otrovna supstanca koju proizvodi bakterija Clostridum botulinum. Deluje na periferne nervne završetke, blokirajući oslobađanje neurotransmitera acetilholina. Interesantan je po tome što može da izazove oboljenje (botulizam), ali i da služi za lečenje mnogih bolesti (na primer, cervikalna distonija). U današnje vreme se koristi u različitim kozmetičkim tretmanima. Prekomerna upotreba izaziva neželjene efekte, a može dovesti do smrti

Supplementary data for article : Konstantinović, J. M.; Selaković, M.; Srbljanovic, J.; Djurkovic-Djakovic, O.; Bogojević, K.; Sciotti, R.; Šolaja, B. A. Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners. Molecules 2017, 22 (3). https://doi.org/10.3390/molecules22030343

Supplementary material for: [https://doi.org/10.3390/molecules22030343]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2441

Supplementary data for article : Konstantinović, J. M.; Selaković, M.; Srbljanovic, J.; Djurkovic-Djakovic, O.; Bogojević, K.; Sciotti, R.; Šolaja, B. A. Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners. Molecules 2017, 22 (3). https://doi.org/10.3390/molecules22030343

Supplementary material for: [https://doi.org/10.3390/molecules22030343]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2441

Supplementary data for the article: Marković, O. S.; Cvijetić, I. N.; Zlatović, M. V.; Opsenica, I. M.; Konstantinović, J. M.; Terzić Jovanović, N. V.; Šolaja, B. A.; Verbić, T. Ž. Human Serum Albumin Binding of Certain Antimalarials. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy 2018, 192, 128–139. https://doi.org/10.1016/j.saa.2017.10.061

Supplementary material for: [https://doi.org/10.1016/j.saa.2017.10.061]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2085

Taeniosis and cysticercosis in Serbia, 1990-2018: Significance of standard of living

Objectives: As is the case for all of Southeast Europe, Serbia is an area traditionally endemic for Taenia saginata and Taenia solium infections. This study was performed to analyse the epidemiological data on taeniosis and cysticercosis in Serbia for the period 1990-2018. Methods: Data on cases of T. saginata and T. solium infection were collected via a systematic search of published articles, the grey literature, and official reports, as well as by performing clinical observational studies of patients treated in the departments for infectious diseases of hospitals and university clinics in Serbia. Results: A total of 212 cases of taeniosis were reported, all between 1997 and 2004 when taeniosis was notifiable (incidence range 0.04-0.9/100 000 population/year). From 1990 to 2018, 170 cases of cysticercosis (all but one of neurocysticercosis), were registered (incidence range 0-0.29/100 000 population/year), with a strong decrease since 2000 and a single case in the last 9 years. The annual number of cases of both taeniosis (Pearson's r = 0.914, p = 0.001) and cysticercosis (Pearson's r = 0.582, p = 0.014) correlated with the consumer price index. Conclusions: In Serbia, T. saginata and T. solium infections are autochthonous but occur only sporadically. However, the potential for re-emergence exists, depending on the socio-economic state of the country

Supplementary data for the article: Konstantinović, J.; Videnović, M.; Orsini, S.; Bogojević, K.; D’Alessandro, S.; Scaccabarozzi, D.; Terzić Jovanović, N.; Gradoni, L.; Basilico, N.; Šolaja, B. A. Novel Aminoquinoline Derivatives Significantly Reduce Parasite Load in Leishmania Infantum Infected Mice. ACS Medicinal Chemistry Letters 2018, 9 (7), 629–634. https://doi.org/10.1021/acsmedchemlett.8b00053

Supplementary material for: [https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00053]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2209]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/2948

Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors

Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a submicromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates

POPULATION PHARMACOKINETICS OF 2-OXO-CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies