Artemisinins and synthetic peroxides as highly efficient antimalarials

Malaria is devastating disease and global public health problem, with nearly half world population exposed to risk. Illness is caused by five Plasmodium species, P falciparum, P ovale, P viva; P malaria and P knowlesi, from which P falciparum is the most serious one causing cerebral malaria and is the major reason for malaria mortality. Vaccine against malaria is not expected in the near future and chemotherapy remains as most feasible alternative for treatment of the disease. The development of widespread drug-resistance to chloroquine (CQ), the most successful antimalarial drug up to date, has resulted in severe health issues for countries in malaria endemic regions. Organic peroxides, like artemisinins, 1,2,4-trioxanes, 1,2,4-trioxolanes, 1,2,4,5-tetraoxanes and their chimeras, are the best choice for malaria treatment nowadays. These therapeutics are fast acting, non-toxic, low costing and without reported data of parasite resistance. Stability of peroxide bonds enables synthetic comfort and resulting in diversity of synthesized structures. The most important classes of peroxide antimalarials with promising representatives are reviewed and possible mechanisms of action were presented in details

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

Reaction of Cross-Conjugated Systems With Diisobutylaluminium-Hydride and Oxygen

After discovering that conjugated ketones may be converted to syn-epoxy-alcohols by DIBAH and oxygen, the investigation was expanded to cross-conjugated dienone systems, i. e. «-santonln and adrosta-1,4-diene-3,17-dione. The addition of 1 M DIBAH in toluene converted these dienones to intermediate aluminoxy derivatives which, after passing oxygen through the reaction mixture and continuous addition of DIBAH, gave the corresponding syn-epoxy-alcohols. No formation of diepoxy and anti-epoxy-alcohols was observed

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

Steroidal Analogue of Deoxyvernolepin. Synthesis of d-Lactone Key Intermediate

Sesquiterpene lactones of elemanolide type vernolepin 1 and deoxyvernolepin 2 exhibit a pronounced antitumor activity against the Walker intramuscular carcinosarcoma 256 and CCRF - CEM human lymphoblastic leukemia cells in culture and were therefore, subjects of many partial and total syntheses. The synthesis of the steroidal analogue of deoxyvernolepin 3, i. e., its key interrnediate, d-lactone 28-hydroxy-2-oxa-5a,10a- cholest-6-en-3-one 4 starting from cholesterol is the subject of this report. Known reactions, as well as modified ones, were used in the synthesis. A new reaction for the preparation of dimethyl acetals with pyridinium chlorochromate and methanol was also developed. It was found that the acetalization reaction using pyridinium chlorochromate and methanol could be performed without affecting an acid-sensitive functional groups such as the oxirane ring