nifurtimox and Leishmaniasis--Visceral

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

We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.

Topics: Amides; Apoptosis; Blood Platelets; Cells, Cultured; Chagas Disease; Flow Cytometry; Heterocyclic Compounds; Humans; Imidazoles; In Vitro Techniques; Leishmania donovani; Leishmaniasis, Visceral; Molecular Structure; Monocytes; Platelet Activation; Sulfonamides; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

A series of 25 N,N'-substituted diamines were prepared by controlled reductive amination of free aliphatic diamines with different substituted benzaldehydes. The library was screened in vitro for antiparasitic activity on the causative agents of human African trypanosomiasis, Chagas' disease and visceral leishmaniasis. The most potent compounds were derived from a subset of diamines that contained a 4-OBn substitution, having a 50% parasite growth inhibition in the submicromolar (against Trypanosoma cruzi) or nanomolar (against Trypanosoma brucei and Leishmania donovani) range. We conclude that members of this series of N,N'-substituted diamines provide new lead structures that have potential to treat trypanosomal and leishmanial infections.

Topics: Animals; Antiprotozoal Agents; Chagas Disease; Diamines; Humans; Inhibitory Concentration 50; Kinetoplastida; Leishmaniasis, Visceral; Molecular Structure; Small Molecule Libraries; Trypanosomiasis, African

The action of 16 newly synthesized metal complexes having the general structure cis-Pt-(II)-Xn-Ln have been tested in vitro against the promastigote forms of Leishmania donovani. The metal complexes at 24 h and maximum dosages inhibited growth from 0%, e.g. in cis-Pt-nifurtimox, to 100%, e.g. in cis-Pt-(2,3,4,5,6-pentafluoroaniline)2Br2 or cis-Pt-pentamidine-I2. A study of the cytotoxicty of these latter complexes on the phagocytic cell line J-774 showed neither high cytotoxicity nor cytolysis. At the maximum dosage after 24 h of permanent contact with the cells (extreme, non-physiological conditions), cytolysis did not exceed 30%. For most of the compounds, cytolysis ranged from 0%, for cis-Pt-oxamniquine-Cl2 to 27.7%, for cis-Pt-pentamidine-I2. The compound cis-Pt-(2,3,4,5,6-pentafluoroaniline)2-Br2 caused up to 1.4% cytolysis under the above conditions. Parasites exposed to cis-Pt-pentamidine-I2 showed notably reduced DNA, RNA and protein synthesis, unlike those exposed to other compounds. Parasites examined by electron microscopy showed effects mainly on the nucleus, though in some cases the mitochondria were affected, altering the internal membranes of the cytoplasmic organelles. The in-vivo activity of the complex cis-Pt-guanethidine-Cl2 was evaluated in parasitized Wistar rats, in which the number of amastigotes per gram of spleen was reduced by 75% compared with controls.

Topics: Animals; Chromatin; Cricetinae; DNA, Protozoan; Drug Evaluation, Preclinical; Guanethidine; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mice; Mitochondria; Nifurtimox; Organometallic Compounds; Organoplatinum Compounds; Oxamniquine; Rats; Rats, Wistar; RNA, Protozoan; Spleen; Structure-Activity Relationship; Toxicity Tests

Topics: Animals; Antiprotozoal Agents; Chlorpromazine; Clofazimine; Electron Transport; Leishmania donovani; Leishmania mexicana; Leishmaniasis; Leishmaniasis, Visceral; Methylene Blue; Methylphenazonium Methosulfate; Mice; Mice, Inbred BALB C; Naphthoquinones; Nifurtimox; Vitamin K