amphotericin-b and artemisinin

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

Leishmaniasis is a neglected tropical disease affecting thousands worldwide, especially in developing countries where it co-exists with malaria. Only a handful of drugs are clinically available to treat the disease, but significant limitations threaten their very use. New, safe and effective drugs, including those against malaria-leishmaniasis co-infections, are thus imperative. We assessed the in vitro anti-infective potential of previously synthesized, potent antimalarial artemisinin derivatives. Analogue esters featuring 1,1'-biphenyl and thiophenyl moieties were as much as 30-fold more potent than clinical artemisinins against L. donovani parasites, qualifying them as antipromastigote hits for further investigation in the search for malaria-leishmaniasis co-infection therapies.

Topics: Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Leishmania; Molecular Structure; Parasitic Sensitivity Tests; Structure-Activity Relationship

Currently available artemisinin-based combination therapies (ACTs) for malaria are inadequate. There remains an enormous unmet need for alternate artemisinin-based combination therapies. One of the fastest methods to identify promising artemisinin-based combination therapies is to look for synergistic or additive antimalarial interaction between artemisinin and an alternate drug against P. falciparum in vitro. Amphotericin B and clotrimazole are known drugs for treatment of human fungal infections. We repurposed clotrimazole or heat-treated amphotericin B in fixed ratio combination with artemisinin for antimalarial properties. Isobologram results show synergistic/additive interaction in both of the cases at therapeutically safe concentrations. Artemisinin, clotrimazole, and their synergistic combinations also decrease hemozoin production in parasitized erythrocytes. New permeation pathways induced in infected cells remain unaffected by drug combinations as indicated by sorbitol lysis. It would be interesting to extend the studies' in vivo system.

Topics: Amphotericin B; Animals; Antimalarials; Artemisinins; Chloroquine; Clotrimazole; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Hot Temperature; Plasmodium falciparum

Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.

Topics: Animals; Anti-Infective Agents; Artemisinins; Calcium-Transporting ATPases; Parasitic Sensitivity Tests; Sesquiterpenes; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

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

Artemisinin and its derivative alpha, beta-arteether have been evaluated for activity against experimental primary amoebic meningoencephalitis. In vivo experiments have shown that amphotericin B at dose of 2.5 mg/kg for 5 days produced 100% protection. Artemisinin and alpha, beta-arteether, even when tested at a high doses (60-120 mg/kg x 5 days and 90-180 mg/x 5 days) respectively, were not curative and showed only slight protection as indicated by extension of mean survival time.

Topics: Amebiasis; Amebicides; Amphotericin B; Animals; Artemisinins; Meningoencephalitis; Mice; Naegleria fowleri; Sesquiterpenes

Artemisinin and its derivatives, beta-arteether and sodium artesunic acid, have been evaluated for activity against experimental primary amebic meningoencephalitis and the efficacy of these compounds has been compared with that of the standard drug amphotericin B. In vivo experiments in Swiss mice have shown that amphotericin B at a dose of 2.5 mg/kg for 5 days produced 100% protection in the mice infected intranasally with Naegleria fowleri. Artemisinin, beta-arteether, and sodium artesunic acid, even when tested at high doses (60-180 mg/kg x 5 days), were not curative and showed only slight protection as indicated by extension of mean survival time.

Topics: Amebiasis; Amebicides; Amphotericin B; Animals; Artemisinins; Artesunate; Dose-Response Relationship, Drug; Meningoencephalitis; Mice; Naegleria fowleri; Sesquiterpenes

Topics: Amoeba; Amphotericin B; Animals; Artemisinins; Sesquiterpenes