title: A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.
abstract: Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA; Department of Chemistry, University of Mysore, Manasagangothri, Mysore, 570 006, India. Electronic address: mpsadashiva@gmail.com.
authors.forename: Maralinganadoddi P
authors.initials: MP
authors.lastname: Sadashiva
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Gajanan S
authors.initials: GS
authors.lastname: Inamdar
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Kuzu
authors.affiliation: Department of Chemistry, University of Mysore, Manasagangothri, Mysore, 570 006, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: gowda@psu.edu.
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D001549:Benzamides; D052160:Benzothiazoles; D002460:Cell Line; D045744:Cell Line, Tumor; D003959:Diamines; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology; D005347:Fibroblasts / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D020128:Inhibitory Concentration 50; D009930:Organic Chemicals; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines; D013329:Structure-Activity Relationship
chemical_list: D045784:Abietanes; D000962:Antimalarials; D001549:Benzamides; D052160:Benzothiazoles; D003959:Diamines; D005456:Fluorescent Dyes; C000600820:N-dehydroabietylbenzamide; D009930:Organic Chemicals; D011804:Quinolines; C098022:SYBR Green I; C000600819:dehydroabietylamine; C023710:abietic acid
keywords: Abietane diterpenoids; Abietic acid derivatives; Antimalarial activity; Dehydroabietylamine derivatives