Replacement of the 4'-hydroxy group of amodiaquine and amopyroquine by aromatic and aliphatic substituents: synthesis and antimalarial activity.

The prophylactic administration of amodiaquine (AQ), a 4-aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone-imine, an electrophilic metabolite. Replacement of the 4'-hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4'-position were synthesized using Csp(2)-Csp(2) and Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)-sensitive and CQ-resistant strains of P. falciparum, with IC(50) values in the range of 7-200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit beta-hematin formation in vitro. A detailed investigation of the structure-activity relationships for these new compounds was carried out; the 4'-methyl compound showed interesting in vivo antimalarial activity.

Antiplasmodial benzophenones from the trunk latex of Moronobea coccinea (Clusiaceae).

In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The methanol extract obtained from the latex of Moronobea coccinea exhibited a strong antiplasmodial activity (95% at 10microg/ml). The phytochemical investigation of this extract led to the isolation of eleven polycyclic polyprenylated acylphloroglucinols (PPAPs), from which eight showed potent antiplasmodial activity with IC50 ranged from 3.3microM to 37.2microM.

Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents.

A series of new piperazine derivatives of ursolic acid was synthesized and tested against Plasmodium falciparum strains. They were also tested on their cytotoxicity effects upon MRC-5 cells. Seven new piperazinyl analogues showed significant activity in the nanomolar range (IC(50)=78-167nM) against Plasmodium falciparum CQ-resistant strain FcB1. A possible mechanism of interaction implicating binding of these compounds to beta-hematin was supported by in vitro tests. Moreover, the importance of the hydrophilic framework attached at the terminal nitrogen atom of the bis-(3-aminopropyl)piperazine joined to the triterpene ring was also explored through molecular dynamic simulations.

Cytotoxic arylnaphthalene lignans from a Vietnamese acanthaceae, Justicia patentiflora.

One new norlignan (1) and five new lignans (2-6) were isolated from the leaves and stems of Justicia patentiflora by a bioassay-guided purification. Five known compounds, carinatone, diphyllin, justicidin A, taiwanin E, and tuberculatin, were also found in J. patentiflora. Most of the new compounds display significant activity in in vitro cytotoxic assays against KB, HCT116, and MCF-7 cancer cell lines and arrest the cell cycle in the G0/G1 phase.