1,4-disubstituted-1,2,3-triazole compounds induce ultrastructural alterations in leishmania amazonensis promastigote: An in vitro antileishmanial and in silico pharmacokinetic study

Funding Information: This research was funded by the Coordination for the Improvement of Higher Education Personnel (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior do Brazil; CAPES) grant number Finance Code 001; and the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro; FAPERJ) grant number E-26/010.001759/2019. The APC was funded by the Oswaldo Cruz Institute (Instituto Oswaldo Cruz; IOC). Dr. Fernando Almeida-Souza is a postdoctoral researcher fellow of CAPES grant number 88887.363006/2019-00. Dra. Ana Lucia Abreu-Silva is a research productivity fellow of National Scientific and Technological Development Council (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; CNPq) grant number 309885/2017-5.The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.publishersversionpublishe

In vitro study of the inhibitory potential of hydroxy-1,2,3-triazoles on the replication of ZIKA and chikungunya arboviruses

Arboviruses, including Zika (ZIKV) and Chikungunya virus (CHIKV), replicate in both arthropods and vertebrates and are transmitted through mosquito, tick, and sandfly bites. The development of specific antiviral drugs and vaccines for these viruses is limited, highlighting the importance of investigating potential drug candidates. In this study, we examined the effects of hydroxy-triazole-based compounds on the in vitro replication of ZIKV and CHIKV. Hydroxy-1,2,3-triazoles were synthesized from 4-acyl-1,2,3-triazoles, previously prepared by the cycloaddition of enaminones and aryl azides, yielding good results. Cytotoxicity assessments using Vero cells showed low toxicity for the tested compounds, with a CC50 greater than 200 µM. Among these compounds, LSO150 and LSO163 demonstrated potent inhibitory effects against ZIKV, while LSO149, LSO151, LSO155, and LSO166 showed remarkable inhibitory effects on CHIKV. These molecules exhibited 99 % inhibition of viral replication at a concentration of 20 µM, with LSO163 and LSO149 particularly effective against ZIKV and CHIKV, respectively. The compounds maintained an inhibitory potential above 80 % when added to infected cells within 8 h after infection. Further investigation into the mechanism of action revealed that LSO163 had strong activity in viral adsorption, with a dose-dependent effect of over 90 % inhibition at a concentration of 20 µM. Additionally, when combined with suboptimal doses of Ribavirin (0.5 µM), the compound LSO149 showed a strong effect on CHIKV replication, inhibiting it by over 90 %. Our results suggest that LSO163 and LSO149 have high potential as drugs against ZIKV and CHIKV

The LQB-223 Compound Modulates Antiapoptotic Proteins and Impairs Breast Cancer Cell Growth and Migration

Drug resistance represents a major issue in treating breast cancer, despite the identification of novel therapeutic strategies, biomarkers, and subgroups. We have previously identified the LQB-223, 11a-N-Tosyl-5-deoxi-pterocarpan, as a promising compound in sensitizing doxorubicin-resistant breast cancer cells, with little toxicity to non-neoplastic cells. Here, we investigated the mechanisms underlying LQB-223 antitumor effects in 2D and 3D models of breast cancer. MCF-7 and MDA-MB-231 cells had migration and motility profile assessed by wound-healing and phagokinetic track motility assays, respectively. Cytotoxicity in 3D conformation was evaluated by measuring spheroid size and performing acid phosphatase and gelatin migration assays. Protein expression was analyzed by immunoblotting. Our results show that LQB-223, but not doxorubicin treatment, suppressed the migratory and motility capacity of breast cancer cells. In 3D conformation, LQB-223 remarkably decreased cell viability, as well as reduced 3D culture size and migration. Mechanistically, LQB-223-mediated anticancer effects involved decreased proteins levels of XIAP, c-IAP1, and Mcl-1 chemoresistance-related proteins, but not survivin. Survivin knockdown partially potentiated LQB-223-induced cytotoxicity. Additionally, cell treatment with LQB-223 resulted in changes in the mRNA levels of epithelial-mesenchymal transition markers, suggesting that it might modulate cell plasticity. Our data demonstrate that LQB-223 impairs 3D culture growth and migration in 2D and 3D models of breast cancer exhibiting different phenotypes

Fabrication of Lignocellulose-Based Microreactors: Copper- Functionalized Bamboo for Continuous-Flow CuAAC Click Reactions

The fabrication of a new copper-functionalized lignocellulosic microreactor (Cu-LμR) from bamboo culms is herein described together with its operation to perform a copper(I)-catalyzed 1,3-dipolar cycloaddition between azide and terminal alkyne (CuAAC). The bio-microfluidic device showed an easy prototyping and fast functionalization with copper ions. All reactions were carried out in flow regime with aqueous-methanol solvent and minimal leaching of copper, yielding a series of model 1,4-disubstitued triazole derivatives with good efficiency in a low-resource setting