Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation.

The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.

Número de células CD34+ circulantes como predictor de recolección exitosa de progenitores hematopoyéticos por aféresis en trasplante autólogo / Number of circulating CD34+ cells as a predictor of successful collection of hematopoietic progenitors by apheresis in autologous transplantation

RESUMEN Introducción. El trasplante autólogo de células progenitoras hematopoyéticas es una terapia eficaz en neoplasias malignas hematológicas. El número de células que CD34+ en sangre periférica es el mejor predictor del rendimiento de recolección de células progenitoras hematopoyéticas. Objetivo. Determinar el número de células CD34+ en sangre periférica asociado al éxito de recolección de progenitores hematopoyéticos por aféresis en trasplante autólogo. Métodos. Se evaluó retrospectivamente los datos de 236 procedimientos de aféresis de células progenitoras hematopoyéticas para el trasplante autólogo en el Hospital Edgardo Rebagliati Martins (Lima, Perú) de julio del 2020 a julio del 2023. Se utilizó la curva ROC (características operativas del receptor) para determinar el número de células CD34+ en sangre periférica necesario para lograr una recolección por aféresis ≥ 2 x 106 células CD34+/kg. Resultados. El 61% fueron hombres, con mediana de edad de 58 años, el valor de corte fue de 18,38 células CD34+/μL (sensibilidad de 94,1% y especificidad de 96,9%). Conclusión. El número de células CD34+ sangre periférica para una recolección exitosa de células progenitoras hematopoyéticas para el trasplante autólogo fue de 18,38 células CD34+/μL.

ABSTRACT Introduction. Autologous hematopoietic progenitor cell transplantation is an effective therapy in hematological malignancies, the number of CD34+ cells in peripheral blood is the best predictor of hematopoietic progenitor cell harvesting performance. Objective. To determine the number of CD34+ cells in peripheral blood associated with the successful collection of hematopoietic progenitors by apheresis in autologous transplantation. Methods. The data of 236 hematopoietic progenitor cell apheresis procedures for autologous transplantation at the Edgardo Rebagliati Martins Hospital (Lima, Peru) were retrospectively evaluated from July 2020 to July 2023. The ROC (receiver operating characteristics) curve was used to determine the number of CD34+ cells in peripheral blood necessary to achieve an collection by apheresis ≥ 2 x 106 CD34+ cells/kg. Results. 61% were men, with a median age of 58 years, the cut-off value was 18.38 CD34+ cells/μL (sensitivity of 94.1% and specificity of 96.9%). Conclusion. The number of peripheral blood CD34+cells for successful collection of hematopoietic progenitor cells for autologous transplantation was 18.38 CD34+ cells/μL.

A step towards development of promising trypanocidal agents: Synthesis, characterization and in vitro biological evaluation of ferrocenyl Mannich base-type derivatives.

Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T. cruzi strains of the parasite and their cytotoxicity on Vero cells to calculate the selectivity index (SI). Compound 2, 1-ferrocenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one, stood out as the most promising derivative showing a half maximal inhibitory concentration (IC50) value around 5 µM in both amastigote and trypomastigote forms of T. cruzi and SI values higher than 13, being the best value on the trypomastigote forms of the Arequipa strain (SI = 41.7). Moreover, 2 decreased the number of infected cells and was not genotoxic. Furthermore, its possible mechanism of action was studied through the alteration of the metabolites excreted by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase (SOD). Finally, docking studies were executed to analyze the binding mode of the studied compounds to Fe-SOD enzyme.

Organometallic compounds in the discovery of new agents against kinetoplastid-caused diseases.

The development of safe and affordable antiparasitic agents effective against neglected tropical diseases is a big challenge of the drug discovery. The drugs currently employed have limitations such as poor efficacy, drug resistance or side effects. Thus, the search for new promising drugs is more and more crucial. Metal complexes and, in particular, organometallic compounds may expand the list of the drug candidates due to the peculiar attributes that the presence of the metal core add to the organic fragment (e.g., redox and structural features, ability to interact with DNA or protein targets, etc.). To date, most organometallic compounds tested as anti-neglected tropical diseases are based on similarities or activity of the organic ligands against other diseases or parasites and/or consist in modification of existing drugs combining the features of the metal moiety and the organic ligands. This review focuses on recent studies (2012-2017) on organometallic compounds in treating kinetoplastid-caused diseases such as Human African trypanosomiasis, Chagas disease and leishmaniasis. This field of research, however, still lacks exhaustive studies to identify of parasitic targets and quantitative structure-activity relationships for a rational drug design.

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.

Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 µM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.

Challenges in Chagas Disease Drug Discovery: A Review.

Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process.