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 0.36–2.6 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.

Diterpenes as lead molecules against neglected tropical diseases

“…On the other hand, otostegindiol (25, 50, and 100 mg/kg) against Plasmodium berghei exhibited a significant chemosuppression effect (Endale et al, 2013). It should be mentioned that, till date, a number of promising diterpenes and their derivatives have been isolated from natural sources (Pouvelle et al, 1994;Uys et al, 2002;Riel et al, 2002;Kuria et al, 2002;Köhler et al, 2002;Clarkson et al, 2003;Wei et al, 2004;Loyola et al, 2004;Ospina et al, 2005;Kalauni et al, 2006;Ojo-Amaize et al, 2007;Koka et al, 2009;Lane et al, 2009;Wei et al, 2010;Lin et al, 2010;Wangchuk et al, 2010;Stout et al, 2010;Sebisubi et al, 2010;Stout et al, 2011;Cocquyt et al, 2011;Alasbahi and Melzig, 2012;Ebrahimi et al, 2013;Ehrhardt et al, 2013;Walter et al, 2013;Batista et al, 2013;González et al, 2014;Ma et al, 2014;Avilés et al, 2015;Gbedema et al, 2015;Annan et al, 2015;Sadashiva et al, 2015;Namukobe et al, 2015;Ahmad et al, 2016).…”

Antibacterial profiling of abietane-type diterpenoids

“…[8][9][10][11][12] Besides their activities against bacteria and fungi, 1, 1a and their semi-synthetic derivatives also show potential in the fight against malaria and other protozoan diseases. [13][14][15] While 1 itself is not toxic for human cells 14 , several derivatives of 1 and 1a -including some of their amino acid conjugates -exhibit moderate anti-proliferative properties against a panel of tumor cells lines. 16,17 However, their effect on microorganisms has not been elucidated yet.…”

Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines

“…5,6 Hence, development of new, effective antimalarial drugs is urgently needed. Towards this goal, our research group has recently reported the potential utility of 1,2-disubstituted-4-quinolones and abietane diterpenoids as new antimalarial agents, 7,8 and we have been continuing efforts to identify new classes of antimalarial agents.…”