Synthesis and antimalarial activity of urenyl Bis-chalcone in vitro and in vivo.

Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, ß-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3',4'-N-(urenylphenyl)-3-(3″,4″,5″-trimethoxyphenyl)]-2-propen-1-one 5, with a percentage of inhibition of heme polymerization of 87.05 ± 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria.

Synthesis of chlorovinyl sulfones as structural analogs of chalcones and their antiplasmodial activities.

The synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity against cultured Plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and murine malaria model are described. Compounds were prepared via Claisen-Schmidt condensation from available chloromethylphenyl sulfones with substituted aldehydes. Antiplasmodial IC(50) activity of these compounds ranged between 0.025 and 10 microM, those that blocked P. falciparum development at low micro molar concentrations were tested in a murine Plasmodium berghei model, and these compounds delayed the progression of malaria but did not eradicate infections. Much effort and attention are needed for discovery and development of new and less toxic antimalarial drugs.

Synthesis and evaluation of sulfonylurea derivatives as novel antimalarials.

We have synthesized a series of sulfonylureas and have tested their antimalarial activities, including inhibition of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, in vitro hemoglobin hydrolysis, hemozoin formation, and development of Plasmodium berghei in murine malaria. The most active antimalarial compound was (E)-1-[4'-(3-(2,4-difluorophenyl)acryloyl)phenyl]-3-tosylurea (22) with an IC(50) of 1.2microM against cultured P. falciparum parasites. Biological results suggest a fairly potent antimalarial activity for this derivative, but also imply that its activity may arise from an unknown mechanism. Indeed, these compounds may act against malaria parasites through multiple mechanisms.

Synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives.

Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.

Synthesis and antimalarial activity of sulfonamide chalcone derivatives.

A series of sulfonamide chalcone derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation in vitro and their activity against cultured Plasmodium falciparum parasites. Inhibition of beta-hematin formation was minimal in the aromatic ring of the chalcone moiety as it appeared for compounds 4b, 4d-f, and greatest with compounds 4g (IC50 0.48 microM) and 4k (IC50 0.50 microM) with a substitution of 3,4,5-trimethoxyl and 3-pyridinyl, respectively. In this study, the most active compound resulted 1[4'-N(2'',5''-dichlorophenyl) sulfonyl-amidephenyl]-3-(4-methylphenyl)-2-propen-1-one 4i, effective as antimalarial by the inhibition of cultured P. falciparum parasites (1 microM). These studies open up the novel possibility of development of sulfonamide derivatives as antimalarials that target beta-hematin formation and the inhibition of the development of cultured P. falciparum parasites, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that chalcones exert their antimalarial activity via multiple mechanisms.