title: Synthesis and in vitro biological evaluation of aminoacridines and artemisinin-acridine hybrids.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Joubert
authors.affiliation: Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Smit
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences (PHARMCEN), North-West University, Potchefstroom 2520, South Africa.
authors.forename: Lissinda
authors.initials: L
authors.lastname: du Plessis
authors.affiliation: Department of Pharmacology, University of Cape Town, Groote Schuur Hospital, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences (PHARMCEN), North-West University, Potchefstroom 2520, South Africa. Electronic address: david.nda@nwu.ac.za.
authors.forename: David D
authors.initials: DD
authors.lastname: N'Da
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000166:Acridines; D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; C031327:artemisinin
keywords: Acridine; Apoptosis; Artemisinin; Cytotoxicity; Hybrids; Malaria