amphotericin-b and Malaria--Falciparum

Topics: Amphotericin B; Antimalarials; Antiprotozoal Agents; Artemisinins; Humans; Leishmaniasis, Visceral; Malaria, Falciparum; Parasitic Diseases; Praziquantel; Schistosomiasis japonica; Schistosomicides; Sesquiterpenes

We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC

Topics: Antiprotozoal Agents; Humans; Hydrazines; Leishmania infantum; Leishmaniasis, Visceral; Malaria, Falciparum; Plasmodium falciparum; Quinoxalines; Structure-Activity Relationship

In our search for new protein farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and parasite farnesyltransferases, and their anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of parasite proliferation in the submicromolar range. The structure of the best inhibitors was parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox.

Topics: Alkyl and Aryl Transferases; Animals; Antiparasitic Agents; Cell Line; Enzyme Inhibitors; Humans; Imidazoles; Leishmania donovani; Leishmaniasis, Visceral; Malaria, Falciparum; Mice; Parasitic Sensitivity Tests; Plasmodium falciparum; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Artemisinins; Clone Cells; Drug Design; Inhibitory Concentration 50; L-Lactate Dehydrogenase; Leishmania donovani; Malaria, Falciparum; Models, Molecular; Molecular Conformation; Plasmodium falciparum; Sesquiterpenes; Static Electricity; Stereoisomerism; Structure-Activity Relationship