First-Row Transition 7-Oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes: Antiparasitic Activity and Release Studies.

Leishmaniasis and Chagas disease are still considered neglected illnesses due to the lack of investment in research, despite the fact that almost one million new cases are reported every year. Four 7-oxo-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (HftpO) first-row transition complexes (Cu, Co, Ni, Zn) have been studied for the first time in vitro against five different species of Leishmania spp. (L. infantum, L. braziliensis, L. donovani, L. peruviana and L. mexicana) as well as Trypanosoma cruzi, showing higher efficacy than the reference commercial drugs. UV and luminescence properties were also evaluated. As a proof of concept, anchoring of a model high-effective-metal complex as an antiparasitic agent on silica nanoparticles was carried out for the first time, and drug-release behaviour was evaluated, assessing this new approach for drug vehiculation.

The Bioactivity of Xylene, Pyridine, and Pyrazole Aza Macrocycles against Three Representative Leishmania Species.

Due to the urgent need for finding effective and free of secondary effect treatments for every clinical form of Leishmaniasis, a series of synthetic xylene, pyridine and, pyrazole azamacrocycles were tested against three Leishmania species. A total of 14 compounds were tested against J774.2 macrophage cells which were models for host cells, and against promastigote and amastigote forms of each studied Leishmania parasite. Amongst these polyamines, one proved effective against L. donovani, another one for L. braziliensis and L. infantum, and another one was selective solely for L. infantum. These compounds showed leishmanicidal activity and reduced parasite infectivity and dividing ability. Action mechanism studies gave a hint that compounds were active against Leishmania due to their ability to alter parasite metabolic pathways and reduce (except Py33333) parasitic Fe-SOD activity.

Heterocyclic Diamines with Leishmanicidal Activity.

Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention, and outdated drugs hamper treatment. Therefore, research aimed at developing new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, here, we present 10 new compounds made up by linking alkylated ethylenediamine units to pyridine or quinoline heterocycles with promising in vitro and in vivo efficacy against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani, and Leishmania braziliensis species. Three compounds (2, 4, and 5) showed a selectivity index much higher in the amastigote form than the reference drug glucantime. These three derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing alterations in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy due to their effectiveness and their ready synthesis.

In vitro Leishmanicidal and Trypanosomicidal Properties of Imidazole-Containing Azine and Benzoazine Derivatives.

Leishmaniasis and Chagas diseases are two of the most important parasitic diseases in the world. Both belong to the category of Neglected Tropical Diseases, and they cannot be prevented by vaccination. Their treatments are founded in outdated drugs that possess many pernicious side-effects and they're not easy to administer. With the aim of discovering new compounds that could serve as anti-trypanosomal drugs, an antiparasitic study of a synthetic compound family has been conducted. A series of new 1,4-bis(alkylamino)- and 1-alkylamino-4-chloroazine and benzoazine derivatives 1-4 containing imidazole rings have been synthesized and identified. Their structures showed a possible interest based on previous work. Their in vitro anti-Leishmania infantum, anti-L. braziliensis, anti-L. donovani and anti-T. cruzi activity were tested, as well as the inhibition of Fe-SOD enzymes. It was found that some of them exhibited quite relevant values indicative of being worthy of future more detailed studies, as most of them showed activity to more than only one parasite species, especially compound 3 c was active for the three studied Leishmania species and also for T. cruzi, which is a very interesting trait as it covers a wide spectrum.

First Example of Antiparasitic Activity Influenced by Thermochromism: Leishmanicidal Evaluation of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine Metal Complexes.

BACKGROUND: The World Health Organization catalogues illnesses such as Leishmaniasis as neglected diseases, due to low investment in new drugs to fight them. The search of novel and non-side effects anti-parasitic compounds is one of the urgent needs for the Third World. The use of triazolopyrimidines and their metallic complexes has demonstrated hopeful results in this field. OBJECTIVE: This work studies the antiparasitic efficacy of a series of 5,7-dimethyl-1,2,4- triazolo[1,5-a]pyrimidine first row transition metal complexes against three leishmania spp. strains. METHODS: The in vitro antiproliferation of promastigote forms of different strains of leishmania spp. (L. infantum, L. braziliensis and L donovani) and the cytotoxicity in macrophage host cells are reported here. The antiparasitic assays have been complemented with enzymatic tests to elucidate the mechanisms of action. New crystal structure description, thermal analysis, magnetic susceptibility and magnetization experiments have also been carried out in order to present a whole characterization of the studied compounds and interesting physical properties besides the biological tests. RESULTS: The results of antiproliferation screening and cytotoxicity show great antiparasitic efficacy in the studied complexes. The superoxide dismutase enzymatic assays exhibit a different behaviour according to the thermochromic triazolopyrimidine form tested. CONCLUSION: Antiproliferative assays and enzymatic tests corroborate the synergetic leishmanicidal effect present in coordination triazolopyrimidine complexes. The changes in coordination sphere derived from thermochromism affect the physical properties as well as the biological efficacy.

In vitro assessment of 3-alkoxy-5-nitroindazole-derived ethylamines and related compounds as potential antileishmanial drugs.

Leishmaniasis is a widespread neglected tropical disease complex that is responsible of one million new cases per year. Current treatments are outdated and pose many problems that new drugs need to overcome. With the goal of developing new, safe, and affordable drugs, we have studied the in vitro activity of 12 different 5-nitroindazole derivatives that showed previous activity against different strains of Trypanosoma cruzi in a previous work. T. cruzi belongs to the same family as Leishmania spp., and treatments for the disease it produces also needs renewal. Among the derivatives tested, compounds 1, 2, 9, 10, 11, and 12 showed low J774.2 macrophage toxicity, while their effect against both intracellular and extracellular forms of the studied parasites was higher than the ones found for the reference drug Meglumine Antimoniate (Glucantime®). In addition, their Fe-SOD inhibitory effect, the infection rates, metabolite alteration, and mitochondrial membrane potential of the parasites treated with the selected drugs were studied in order to gain insights into the action mechanism, and the results of these tests were more promising than those found with glucantime, as the leishmanicidal effect of these new drug candidates was higher. The promising results are encouraging to test these derivatives in more complex studies, such as in vivo studies and other experiments that could find out the exact mechanism of action.

Synthesis and biological evaluation of new long-chain squaramides as anti-chagasic agents in the BALB/c mouse model.

Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their 1H and 13C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC50 values. Compounds 4 and 7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound 7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments.

New polyamine drugs as more effective antichagas agents than benznidazole in both the acute and chronic phases.

Despite the continuous research effort that has been made in recent years to find ways to treat the potentially life threatening Chagas disease (CD), this remains the third most important infectious disease in Latin America. CD is an important public health problem affecting 6-7 million people. Since the need to search for new drugs for the treatment of DC persists, in this article we present a panel of new polyamines based on the tripodal structure of tris(2-aminomethyl)amine (tren) that can be prepared at low cost with high yields. Moreover, these polyamines present the characteristic of being water-soluble and resistant to the acidic pH values of stomach, which would allow their potential oral administration. In vitro and in vivo assays permitted to identify the compound with the tren moiety functionalized with one fluorene unit (7) as a potential antichagas agent. Compound 7 has broader spectrum of action, improved efficacy in acute and chronic phases of the disease and lower toxicity than the reference drug benznidazole. Finally, the action mechanisms studied at metabolic and mitochondrial levels shows that the trypanocidal activity of compound 7 could be related to its effect at the glycosomal level. Therefore, this work allowed us to select compound 7 as a promising candidate to perform preclinical evaluation studies.

Synthesis and Biological in vitro and in vivo Evaluation of 2-(5-Nitroindazol-1-yl)ethylamines and Related Compounds as Potential Therapeutic Alternatives for Chagas Disease.

Chagas disease, a neglected tropical disease caused by infection with the protozoan parasite Trypanosoma cruzi, is a potentially life-threatening illness that affects 5-8 million people in Latin America, and more than 10 million people worldwide. It is characterized by an acute phase, which is partly resolved by the immune system, but then develops as a chronic disease without an effective treatment. There is an urgent need for new antiprotozoal agents, as the current standard therapeutic options based on benznidazole and nifurtimox are characterized by limited efficacy, toxicity, and frequent failures in treatment. In vitro and in vivo assays were used to identify some new low-cost 5-nitroindazoles as a potential antichagasic therapeutic alternative. Compound 16 (3-benzyloxy-5-nitro-1-vinyl-1H-indazole) showed improved efficiency and lower toxicity than benznidazole in both in vitro and in vivo experiments, and its trypanocidal activity seems to be related to its effect at the mitochondrial level. Therefore, compound 16 is a promising candidate for the development of a new anti-Chagas agent, and further preclinical evaluation should be considered.

Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi.

Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.

In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives.

Leishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

Library of Seleno-Compounds as Novel Agents against Leishmania Species.

The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives.

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.