Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.</p

Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug

Chagas disease chemotherapy, currently based on only two drugs, nifurtimox and benznidazole, is far from satisfactory and therefore the development of new antichagasic compounds remains an important goal. On the basis of antichagasic properties previously described for some 1,2-disubstituted 5-nitroindazolin-3- ones (21, 33) and in order to initiate the optimization of activity of this kind of compounds, we have prepared a series of related analogs (22-32, 34-38, 58 and 59) and tested in vitro these products against epimastigote forms of Trypanosoma cruzi. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23) and 2-benzyl-1-butyl (24) derivatives have shown high trypanocidal activity and low unspecific toxicity. Other indazole derivatives with different substitution patterns (1-substituted 3-alkoxy-1H-indazoles and 2-substituted 3-alkoxy-2H-indazoles), arising from the synthetic procedures used to prepare the mentioned indazolinones, have moderate to low effectiveness. The exploration of SAR information using the concept of an activity landscape has been carried out with SARANEA software. We have also searched for structural similarities between 225 known antiprotozoan drugs and compound 22. The results confirm that compounds 22-24 constitute promising leads and that 5-nitroindazolin-3-one system is a novel anti-T. cruzi scaffold which may represent an important therapeutic alternative for the treatment of Chagas disease. © 2012 Elsevier Masson SAS. All rights reserved.Peer Reviewe

Trypanocidal Activity of Long Chain Diamines and Aminoalcohols

Thirteen aminoalcohols and eight diamines were obtained and tested against Trypanosoma cruzi epimastigotes strains MG, JEM and CL-B5 clone. Some of them were equal or more potent (1.0–6.6 times) than the reference compound nifurtimox. From them, three aminoalcohols and two diamines were selected for amastigotes assays. Compound 5 was as potent as the reference drug nifurtimox against amastigotes of the CL-B5 strain (IC50 = 0.6 µM), with a selectivity index of 54

Exploring the potential activity spectrum of two 5-nitroindazolinone prototypes on different Trypanosoma cruzi strains

Submitted by sandra infurna ([email protected]) on 2016-03-22T17:16:07Z No. of bitstreams: 1 mariane_vasconcelos_etal_IOC_2015.pdf: 462658 bytes, checksum: fb088563cf7c4096be045521175938bd (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-03-22T17:27:09Z (GMT) No. of bitstreams: 1 mariane_vasconcelos_etal_IOC_2015.pdf: 462658 bytes, checksum: fb088563cf7c4096be045521175938bd (MD5)Made available in DSpace on 2016-03-22T17:27:09Z (GMT). No. of bitstreams: 1 mariane_vasconcelos_etal_IOC_2015.pdf: 462658 bytes, checksum: fb088563cf7c4096be045521175938bd (MD5) Previous issue date: 2015UCM-UPM & CSIC. CEI Campus Moncloa. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitologia. Madrid, Spain.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.UCM-UPM & CSIC. CEI Campus Moncloa. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitologia. Madrid, Spain.UCM-UPM & CSIC. CEI Campus Moncloa. Madrid, Spain / Consejo Superior de Investigaciones Científicas (CSIC). Instituto de Química Médica (IQM),. Madrid, Spain.UCM-UPM & CSIC. CEI Campus Moncloa. Madrid, Spain / Universidad Complutense de Madrid. Facultad de Farmacia. Departamento de Parasitologia. Madrid, Spain.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.In the present study, the potential activity of two 5-nitroindazole derivatives previously proposed as suitable antichagasic prototypes was further evaluated on diverse Trypanosoma cruzistrains belonging to two discrete typing units (DTUs) frequently associated with human infection (i.e. DTUs TcII and TcVI). The trypanocidal profile that both 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives achieved on Tulahuen amastigotes (IC50 = 3·56 ± 0·99 and 6·31 ± 1·04 µM, respectively) correlates with that of formerly obtained on CL Brener, corroborating an outstanding activity on DTU TcVI parasites. Moreover, a sequential screening on extracellular and intracellular stages of T. cruzi Y (DTU TcII) demonstrated also the effectiveness of 22 and 24 over this strain on a similar range of activity (IC50 epimastigotes = 3·55 ± 0·47 and 7·92 ± 1·63 µM, IC50 amastigotes = 2·80 ± 0·46 and 9·02 ± 5·26 µM, respectively). These results, supported by a lack of toxicity registered over either L929 fibroblasts or primary cultures of cardiomyocytes, confirm that 5-nitroindazolinones 22 and 24 display great selectivity on both drug-sensitive (CL and Tulahuen) and drug-moderately resistant (Y) T. cruzi strains, and therefore, represent an important outcome in the research of Chagas disease chemotherapy

Activity of 2-benzyl-1-(2-hydroxyethyl)-5-nitroindazolin-3-one on Trypanosoma cruzi Bloodstream Trypomastigotes (Y strain): In Vitro and In Vivo Studies

Benznidazole and nifurtimox, the currently available drugs for the specific treatment of Chagas disease, show limited effectiveness and high toxicity that prompt the identification of therapeutic alternatives. [...

Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi

The phenotypic activity of two 5-nitroindazolinones, i.e. 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives, previously proposed as anti-Trypanosoma cruzi prototypes, was presently assayed on bloodstream trypomastigotes (BT) of the moderately drug-resistant Y strain. Further exploration of putative targets and cellular mechanisms involved in their activity was also carried out. Therefore, transmission electron microscopy, high-resolution respirometry and flow cytometry procedures were performed on BT treated for up to 24 h with the respective EC50 value of each derivative. Results demonstrated that although 22 and 24 were not as active as benznidazole in this in vitro assay on BT, both compounds triggered important damages in T. cruzi that lead to the parasite death. Ultrastructural alterations included shedding events, detachment of plasma membrane and nuclear envelope, loss of mitochondrial integrity, besides the occurrence of a large number of intracellular vesicles and profiles of endoplasmic reticulum surrounding cytoplasmic organelles such as mitochondrion. Moreover, both derivatives affected mitochondrion leading to this organelle dysfunction, as reflected by the inhibition in oxygen consumption and the loss of mitochondrial membrane potential. Altogether, the findings exposed in the present study propose autophagic processes and mitochondrial machinery as part of the mode of action of both 5-nitroindazolinones 22 and 24 on T. cruzi trypomastigotes.2030-01-0

Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl- 5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2Hindazoles

Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.58-4.19 μM for epimastigotes; compounds 6, 19-21 and 24: IC50 = 0.22-0.54 μM for amastigotes) being as potent as the reference drug benznidazole. SAR analysis suggests that electron-donating groups at position 1 of indazolinone ring are associated with an improved antichagasic activity. Moreover, compounds of series A displayed low unspecific toxicities against an in vitro model of mammalian cells (fibroblasts), which were reflected in high values of the selectivity indexes (SI). Compound 20 was also very efficient against amastigotes from Tulahuen and Y strains of T. cruzi (IC50 = 0.81 and 0.60 μM, respectively), showing low toxicity towards cardiac cells (LC50 > 100 μM). In what concerns compounds of series B, some of them displayed moderate activity against trophozoites of a metronidazole-sensitive isolate of T. vaginalis (35 and 36: IC50 = 9.82 and 7.25 μM, respectively), with low unspecific toxicity towards Vero cells. Compound 36 was also active against a metronidazole-resistant isolate (IC50 = 9.11 μM) and can thus be considered a good prototype for the development of drugs directed to T. vaginalis resistant to 5-nitroimidazoles

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2-Benzyl-5-nitroindazole-Derived Amines

Three different series of new 5-nitroindazole derivatives—1-(ω-aminoalkyl)-2-benzylindazolin-3-ones (series A; ten compounds), 3-(ω-aminoalkoxy)-2-benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)—have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi. Some compounds in series A, after successfully passing the preliminary screening for epimastigotes, exhibited activity values against amastigotes of several T. cruzi strains that were better than or similar to those shown by the reference drug benznidazole and displayed low nonspecific toxicity against mammalian cells. On the other hand, preliminary studies against promastigotes of L. amazonensis showed high leishmanicidal activity for some derivatives of series A and C. With regard to activity against T. vaginalis, some indazoles of series B and C were rather efficient against trophozoites of a metronidazole-sensitive isolate and showed low nonspecific toxicities toward Vero cell cultures. Additionally, some of these compounds displayed similar activity against metronidazole-sensitive and resistant isolates, showing the absence of cross-resistance between these derivatives and the reference drug.This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINEICO; ref. SAF2015-66690-R), by the 911120 UCM-CEI Moncloa research group (E-Health Cluster), by the National Council for Scientific and Technological Development of Brazil (CNPq; ref. 301372/2015-2) and by the Fundaçao Carlos Chagas Filho de Amparo / Pesquisa do Estado do Rio de Janeiro (FAPERJ; ref. E02/2017). M.N.C.S. is a research fellow of CNPq and CNE. The authors thank the Program for Technological Development in Tools for Health (PDTIS-FIOCRUZ) for use of their facilities.Peer Reviewe