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Abstract
The antimalarial activity of some bisbenzylisoquinoline (BBIQ) alkaloids were studied using in vitro culture of both chloroquine (CQ)-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The combination of chloroquine and tetrandrine gave a 44 fold potentiation of malarial killing. Fangchinoline, hernandezine, pycnamine, berbamine and isotetrandrine had similar antimalarial activity as tetrandrine against the sensitive strain of P. falciparum malaria. Hernandezine, isotetrandrine, berbamine, fangchinoline and methoxyadiantifoline had similar antimalarial activity as tetrandrine against a strain of chloroquine-resistant falciparum malaria. Based on structure/ activity analysis, we concluded that the stereochemistry of C-1E¹ (S ring) of the BBIQ structure played an important role in selective action against resistant malaria. The stereochemistry of C-1 (left ring) and a substituent of C-12 appeared to have little influence on the selectivity. The point of attachment of the ether bridges to the rings also exerts an important influence on selective antimalarial activity. Tetrandrine (TT) penetrates both the erythrocyte and parasite membranes and inhibits the synthesis and activity of the (MDR) pump and likely the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) since it inhibits the calcium channel. These observations likely account for the fact TT potentiates the activity of chloroquine more than 40 fold against chloroquine resistant falciparum malaria.
Highlights
Our previous work revealed that tetrandrine (TT) possessed surprising antimalarial activity, because it exerted a selective action against the chloroquine-resistant strain of P. falciparium malaria in vitro [1]; TT was found to greatly potentiate antimalarial activity of chloroquine (CQ) or qinghaosu when used in combination [2]
The purpose of displaying this data is that it represents the synergistic power of the correct combinations of chloroquine and terandrine against a chloroquine resistant strain of falciparum malaria
Most of the other drugs have similar potentiating activity but tetrandrine is probably the drug of choice to accompany chloroquine to reverse chloroquine resistance since it is very effective against chloroquine resistance with little toxicity at the low concentrations utilized
Summary
Our previous work revealed that tetrandrine (TT) possessed surprising antimalarial activity, because it exerted a selective action against the chloroquine-resistant strain of P. falciparium malaria in vitro [1]; TT was found to greatly potentiate antimalarial activity of chloroquine (CQ) or qinghaosu (artemesinin) when used in combination [2]. Two aporphinebenzylisoquinoline alkaloids – thalicarpine (TH) and methoxyadiantifoline (ME) – were selected for testing The former reportedly has antitumor activity [6], increased the antitumor effect of cyclophosphamide when used in combination [7], and affected the cardiovascular system [8]. ME is a relatively new alkaloid isolated from Thalictrum omeiense [9] which affects the cardiovascular system by increasing coronary blood flow and producing negative inotropic, chronotropic [10], and antiarrhythmic effects [11]. These biological activities likely result from inhibition of calcium channels [10,11]. Owing to similarities in chemical structure and biological activities between these alkaloids and bisbenzylisoquinolines; e.g., TT, CE and hernandezine (HE), were investigated for antimalarial activities of TH and ME against a chloroquine sensitive and a resistant strain of P. falciparum malaria
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