Joubert J.P., Smit F.J., Du Plessis L., Smith P.J., N'da D.D.
Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences (PHARMCEN), North-West University, Potchefstroom 2520, South Africa; Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa
Joubert, J.P., Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa; Smit, F.J., Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa; Du Plessis, L., Centre of Excellence for Pharmaceutical Sciences (PHARMCEN), North-West University, Potchefstroom 2520, South Africa; Smith, P.J., Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa; N'da, D.D., Centre of Excellence for Pharmaceutical Sciences (PHARMCEN), North-West University, Potchefstroom 2520, South Africa
During this study, 9-aminoacridine and artemisinin-acridine hybrid compounds were synthesized and the in vitro for antimalarial activity against both the chloroquine sensitive but also gametocytocidal strain (NF54), and chloroquine resistant (Dd2) strains of Plasmodium falciparum was determined. In vitro cytotoxicity against CHO cells, apoptosis of HepG2 and SH-SY5Y as well as anticancer activity against HeLa cell lines were assessed. The hybrids were synthesized, using a microwave-assisted radiation method by covalently linking artemisinin and acridine pharmacophores by means of a liable, aminoethyl ether linker. The synthesized compounds were found active against both the Plasmodium strains and displayed superior selective toxicity towards the parasitic cells. Hybrid 7, however, containing ethylenediamine linker, proved the most active of all of the synthesized compounds. It had seven-fold higher antigametocytocidal activity compared to chloroquine and was also found to be seven-fold more potent than chloroquine against the Dd2 strain, with highly selective action towards the parasitic cells. This hybrid also showed favourable anti-cancer activity against the HeLa cells, three- and eight-fold higher than those of chloroquine and melphalan, respectively. This hybrid may therefore stand as drug candidate for further investigation in the search for new and effective drugs against malaria and cervical cancer. © 2014 Elsevier B.V. All rights reserved.
6 chloro 2 methoxy 9 (2 methylpiperazin 1 yl)acridine 2 (10 beta dihydroartemisinoxy)ethane; 6 chloro 2 methoxy 9 (3 methylpiperazin 1 yl)acridine; 6 chloro 2 methoxy 9 (piperazin 1 yl)acridine; 6 chloro 2 methoxy 9 (piperazin 1 yl)acridine 2 (10 beta dihydroartemisinoxy)ethane; 6 chloro 2 methoxy n [2 (piperazin 1 yl)ethyl]acridin 9 amine; 6 chloro 2 methoxy n [2 (piperazin 1 yl)ethyl]acridin 9 amine 2 (10 beta dihydroartemisinoxy)ethane; [3 [(6 chloro 2 methoxyacridin 9 yl)amino]propyl](methyl) amine; [3 [(6 chloro 2 methoxyacridin 9 yl)amino]propyl](methyl) amine 2 (10 beta dihydroartemisinoxy)ethane; [n (2 aminoethyl) 6 chloro 2 methoxyacridin 9 amine] 2 (10 beta dihydroartemisinoxy)ethane; acridine derivative; aminoacridine derivative; antimalarial agent; antineoplastic agent; artemisinin derivative; chloroquine; ether; ethylenediamine; melphalan; n (2 aminoethyl) 6 chloro 2 methoxyacridin 9 amine; unclassified drug; acridine derivative; antimalarial agent; antineoplastic agent; artemisinin; artemisinin derivative; animal cell; antimalarial activity; antineoplastic activity; apoptosis; article; CHO cell; controlled study; drug cytotoxicity; drug screening; drug synthesis; HeLa cell; human; human cell; hybrid; in vitro study; microwave radiation; nonhuman; nucleophilicity; pharmacophore; phase transition; physical chemistry; Plasmodium falciparum; priority journal; X ray analysis; animal; cell survival; chemistry; CHO cell line; Cricetulus; drug effects; synthesis; tumor cell line; Acridines; Animals; Antimalarials; Antineoplastic Agents; Apoptosis; Artemisinins; Cell Line, Tumor; Cell Survival; CHO Cells; Cricetulus; Humans; Plasmodium falciparum