Characterization of heterogeneity and spatial distribution of phases in complex solid dispersions by thermal analysis by structural characterization and X-ray micro computed tomography

Purpose: This study investigated the effect of drug-excipient miscibility on the heterogeneity and spatial distribution of phase separation in pharmaceutical solid dispersions at a micron-scale using two novel and complementary characterization techniques, thermal analysis by structural characterization (TASC) and X-ray micro-computed tomography (XCT) in conjunction with conventional characterization methods. Method: Complex dispersions containing felodipine, TPGS, PEG and PEO were prepared using hot melt extrusion-injection moulding. The phase separation behavior of the samples was characterized using TASC and XCT in conjunction with conventional thermal, microscopic and spectroscopic techniques. The in vitro drug release study was performed to demonstrate the impact of phase separation on dissolution of the dispersions. Results: The conventional characterization results indicated the phase separating nature of the carrier materials in the patches and the presence of crystalline drug in the patches with the highest drug loading (30% w/w). TASC and XCT where used to provide insight into the spatial configuration of the separate phases. TASC enabled assessment of the increased heterogeneity of the dispersions with increasing the drug loading. XCT allowed the visualization of the accumulation of phase separated (crystalline) drug clusters at the interface of air pockets in the patches with highest drug loading which led to poor dissolution performance. Semi-quantitative assessment of the phase separated drug clusters in the patches were attempted using XCT. Conclusion: TASC and XμCT can provide unique information regarding the phase separation behavior of solid dispersions which can be closely associated with important product quality indicators such as heterogeneity and microstructure

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

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

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

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. [...

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

In previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness(MINEICO,ref.SAF2015-66690-R), the National Council for Scientific and Technological Development of Brazil (CNPq, ref. 301372/2015-2) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ,ref. E02/2017). The 911120 UCM-CEI Moncloa Research Group‘Epidemiología, Diagnóstico y Terapia Antiparasitaria’and the Spanish Ministry of Science, Innovation and Universities (MICIU, ref.RTI-2018-093940-B-I00) are also acknowledged. M.N.C.S. is a research fellowof CNPq and CNE researcher

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