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

Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized compounds were evaluated for their antimalarial activity and toxicity, in vitro and in mice. Benzothiophenes presented in this paper showed improved activities against a chloroquine susceptible (CQS) strain, with potencies of IC50 = 6 nM, and cured 5/5 Plasmodium berghei infected mice when dosed orally at 160 mg/kg/day x 3 days. In the benzothiophene series, the examined antiplasmodials were more active against the CQS strain D6, than against strains chloroquine resistant (CQR) W2 and multidrug-resistant (MDR) TM91C235. For the thiophene series, a very interesting feature was revealed: hypersensitivity to the CQR strains, resistance index (RI) of lt 1. This is in sharp contrast to chloroquine, indicating that further development of the series would provide us with more potent antimalarials against CQR strains

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

Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falcipanim. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of gt = 5% were further examined in vitro to determine the 50% inhibitory concentration (IC50) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium herghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded gt = 60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines

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 material for the article: Manzano, J. I.; Konstantinović, J.; Scaccabarozzi, D.; Perea, A.; Pavić, A.; Cavicchini, L.; Basilico, N.; Gamarro, F.; Šolaja, B. A. 4-Aminoquinoline-Based Compounds as Antileishmanial Agents That Inhibit the Energy Metabolism of Leishmania. European Journal of Medicinal Chemistry 2019, 180, 28–40. https://doi.org/10.1016/j.ejmech.2019.07.010

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2019.07.010]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/3287

Allelopathic effect of Xanthium strumarium L. and Abuthilon theophrasti Med. extracts on germination of maize and soybean seed

During 2014 allelopathic effects of Xanthium strumarium L. and Abutilon theophrasti Med. extracts to germination and initial development of maize (Zea mays L.), and soybean (Glycine max L.) were studied in laboratory conditions. In addition to the Water extracts out of dry mass of the tested weed species, extracts made by use of hexane, ethyl acetate and methanol in different concentrations were also used. The applied concentrations were 10, 20, 30 and 40 g/l of dry matter made out of weed species in the 3-4 leaf stage of development. Inhibiting effect of water extract from dry matter of X. strumarium and methanol extract from which methanol part was evaporated to maize seed epicotyls and hypocotyls length was established. In comparison to the control, the maximum concentration of 40 g / l of the extract made from Water solution of A. theophrasti showed inhibitory effect on soybean seed epicotyls and hypocotyls length. The applied extracts made out of dry matter of the both of the studied weed species X. strumarium and A. theophrasti reduced maize seed germination for 14.8-26.83% and soybean seed germination for 18.5-35.82%, in comparison to the control in which it was 95% and 92%, respectively. After germination in a climate chamber, epicotyls’ and hypocotyls’ length of maize and soybean seeds was measured three, six and ten days following spraying by extracts

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