Peroksidni antimalarici

The problem of endemic malaria continues unabated globally. Malaria affects 40 % of the global population, causing an estimated annual mortality of 1.5-2.7 million people. The World Health Organization (WHO) estimates that 90 % of these deaths occur in sub-Saharan Africa among infants under the age of five. While a vaccine against malaria continues to be elusive, chemotherapy remains the most viable alternative towards treatment of the disease. During last years, the situation has become urgent in many ways, but mainly because of the development of chloroquine-resistant (CQR) strains of Plasmodium falciparum (Pf). The discovery that artemisinin (ART, 1), an active principle of Artemisia annua L., expresses a significant antimalarial activity, especially against CQR strains, opened new approaches for combating malaria. Since the early 1980s, hundreds of semi-synthetic and synthetic peroxides have been developed and tested for their antimalarial activity, the results of which were extensively reviewed. In addition, in therapeutic practice, there is no reported case of drug resistance to these antimalarial peroxides. This review summarizes recent achievements in the area of peroxide drug development for malaria chemotherapy.Širenje malarije je stalno prisutan problem na globalnom nivou. Od malarije godišnje oboli 40 % svetske populacije i oko 1,5-2,7 miliona ljudi umre. Prema podacima Svetske zdravstvene organizacije, 90 % smrtnih slučajeva je u zemljama podsaharske Afrike, među kojima dominiraju deca starosti do 5 godina. Usled nemogućnosti razvoja vakcine, hemoterapija ostaje kao jedini pouzdan oblik lečenja od ove bolesti. Poslednjih godina problem borbe protiv malarije postaje urgentan iz brojnih razloga, među kojima je najznačajniji razvoj hlorokin-rezistentnih sojeva parazita. Otkriće da artemizinin (ART, 1) i njegovi derivati pokazuju izuzetnu efikasnost prema hlorokin-rezistentnim sojevima otvorilo je velike mogućnosti u borbi protiv malarije. Od tada, posebno tokom 80-tih godina, sintetisan je veliki broj jedinjenja i rezultati njihove aktivnosti opisani su u mnogim naučnim publikacijama. Osim toga, u kliničkoj praksi nisu zabeleženi primeri pojave rezistencije parazita prema ovoj klasi antimalarika. U ovom revijalnom radu opisani su najnoviji rezultati u razvoju peroksidnih antimalarika

Peroksidni antimalarici

The problem of endemic malaria continues unabated globally. Malaria affects 40 % of the global population, causing an estimated annual mortality of 1.5-2.7 million people. The World Health Organization (WHO) estimates that 90 % of these deaths occur in sub-Saharan Africa among infants under the age of five. While a vaccine against malaria continues to be elusive, chemotherapy remains the most viable alternative towards treatment of the disease. During last years, the situation has become urgent in many ways, but mainly because of the development of chloroquine-resistant (CQR) strains of Plasmodium falciparum (Pf). The discovery that artemisinin (ART, 1), an active principle of Artemisia annua L., expresses a significant antimalarial activity, especially against CQR strains, opened new approaches for combating malaria. Since the early 1980s, hundreds of semi-synthetic and synthetic peroxides have been developed and tested for their antimalarial activity, the results of which were extensively reviewed. In addition, in therapeutic practice, there is no reported case of drug resistance to these antimalarial peroxides. This review summarizes recent achievements in the area of peroxide drug development for malaria chemotherapy.Širenje malarije je stalno prisutan problem na globalnom nivou. Od malarije godišnje oboli 40 % svetske populacije i oko 1,5-2,7 miliona ljudi umre. Prema podacima Svetske zdravstvene organizacije, 90 % smrtnih slučajeva je u zemljama podsaharske Afrike, među kojima dominiraju deca starosti do 5 godina. Usled nemogućnosti razvoja vakcine, hemoterapija ostaje kao jedini pouzdan oblik lečenja od ove bolesti. Poslednjih godina problem borbe protiv malarije postaje urgentan iz brojnih razloga, među kojima je najznačajniji razvoj hlorokin-rezistentnih sojeva parazita. Otkriće da artemizinin (ART, 1) i njegovi derivati pokazuju izuzetnu efikasnost prema hlorokin-rezistentnim sojevima otvorilo je velike mogućnosti u borbi protiv malarije. Od tada, posebno tokom 80-tih godina, sintetisan je veliki broj jedinjenja i rezultati njihove aktivnosti opisani su u mnogim naučnim publikacijama. Osim toga, u kliničkoj praksi nisu zabeleženi primeri pojave rezistencije parazita prema ovoj klasi antimalarika. U ovom revijalnom radu opisani su najnoviji rezultati u razvoju peroksidnih antimalarika

Sinteza dendrimerskog steroidnog jezgra

Synthesis of a steroidal dendrimercore possessing various functional termini, such as ester, carboxy and hydroxy, is presented. The approach described enables further simple manipulations for the introduction of more complex functionalities.U ovom radu prikazana je sinteza dendrimerskog steroidnog jezgra sa estarskim karboksilnim i hidroksilnim završecima. Opisani pristup sintezi omogućava dalju, kompleksniju funkcionalizaciju jednostavnim manipulacijama

Supplementary data for article: Božinović, N. S.; Opsenica, I.; Šolaja, B. A. Double Palladium-Catalyzed Synthesis of Azepines. Synlett 2013, 24 (1), 49–52. https://doi.org/10.1055/s-0032-1317667

Supporting information for: [https://doi.org/10.1055/s-0032-1317667]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1597

Supplementary data for the article: Božinović, N.; Šolaja, B. A.; Opsenica, I. M. Microwave-Assisted Synthesis of Azepines via Nucleophilic Aromatic Substitution. J. Serb. Chem. Soc. 2016, 81 (11), 1225–1230. https://doi.org/10.2298/JSC160824074B

Supplementary material for: [https://doi.org/10.2298/JSC160824074B]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2354

Antimalarijska, antimikobakterijska i antiproliferativna aktivnost fenil-supstituisanih tetraoksana

Mixed tetraoxanes of the 4"-phenyl-substituted cyclohexyl-spirotetraoxacyclohexyl-spirocholate series have been prepared and evaluated as possible antimalarials, anti-proliferatives and antimycobacterials. The activity of the (4"R or S)-phenyl series against P falciarum D6 and W2 strains was found to be at the level of artemisinin. with two compounds. the acid 4 and the amide 6, exhibiting encouraging anti-TB activity as well. Very promising in vitro results of the said tetraoxanes were obtained against solid tumours and, in some instances. the activity against a selected number of cell lines was higher than that of the antitumor drug paclitaxel.U ovom radu prikazana je sinteza serije mešovitih tetraoksana 4"-fenil-supstituisanih cikloheksil-spirotetraoksacikloheksil-spiroholata, a ispitana je i njihova in vitro aktivnost kao mogućih antimalarika, anti-TBC agenasa i antiproliferativnih jedinjenja. Aktivnost (4"R ili S)-fenil serije na D6 i W2 sojeve P. falciparum vrlo je slična aktivnosti poznatog antimalarika artemizinina. Izraženu anti-TBC aktivnost iskazala su jedinjenja 4 i 6, čija antiproliferativna in vitro aktivnost prema nekim kompaktnim tumorima prevazilazi aktivnost leka paklitaksela

QSAR izučavanje steroidnih 1,2,4,5-tetraoksanskih antimalarika računarskim modelovanjem

A three-dimensional QSAR pharmacophore model for antimalarial activity of steroidal 1,2,4,5-tetraoxanes was developed from a set of 17 substituted antimalarial derivatives out of 27 analogues that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and one hydrophobic (aliphatic) feature, was found to map well onto the potent analogues and many other well-known antimalarial trioxane drugs including artemisinin, arteether, artesunic acid, and tetraoxanes. The presence of at least one hydrogen bond acceptor in the trioxane or the tetraoxane moiety appears to be necessary for potent activity of this class of compounds. Docking calculations of some of these compounds with heme are consistent with the above observation as the proximity of the heme iron to the oxygen atom of the trioxane or the tetraoxane moiety favors potent activity of the compounds. Electron transfer from the oxygen of trioxane or the tetraoxane appears to be crucial for mechanism of action of the compounds. This information together with the pharmacophore should enable search for new peroxide containing antimalarial candidates from databases and custom designed synthesis of more efficacious and safer analogues.Izvršeno je trodimenzionalno modelovanje farmakofore za antimalarijsku aktivnost steroidnih 1,2,4,5-tetraoksana na osnovu struktura 17 supstituisanih derivata, izdvojenih iz grupe od 27 analoga koji pokazuju izuzetnu in vitro antimalarijsku aktivnost (ispod 100 ng/mL) prema osetljivim i rezistentnim sojevima Plasmodium falciparum-a. Utvrđeno je da se farmakofora, koju čine dva akceptora vodonične veze (lipidni) i jedno hidrofobno mesto (alifatično), dobro preklapa sa strukturama aktivnih analoga kao i sa strukturama nekih poznatih trioksanskih antimalarika, uključujući artemizinin, arteetar, artesunatnu kiselinu kao i sa strukturama nekih drugih tetraoksana. Za dobru aktivnost ove klase jedinjenja važno je prisustvo bar jednog akceptora vodonične veze na trioksanskom ili tetraoksanskom delu strukture. Izračunavanja interakcija nekih od ovih jedinjenja sa hemom saglasna su sa prethodno iznetim zaključkom da je blizina gvožđa iz hema i trioksanskog ili tetraoksanskog atoma kiseonika važna za dobru aktivnost ovih jedinjenja. Izgleda da je prenos elektrona sa trioksanskog ili tetraoksanskog atoma kiseonika osnova mehanizma dejstva ovih jedinjenja. Izvršena modelovanja farmakofore i interakcija ovih jedinjenja se hemom mogu biti od pomoći u sintezi novih i efikasnijih peroksidnih antimalarika