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Abstract: In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC50 of 200–400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure–activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones. [ABSTRACT FROM AUTHOR]

Carvalho, G.V.; Cabral, M.M.; de Oliveira, A.L.S.C.; Garção, H.F., and Pellegrini, J.A.C., 2020. Methodology to evaluate the coastal susceptibility to oil spills originated in large marine areas – Costa Norte Project. In: Malvárez, G. and Navas, F. (eds.), Global Coastal Issues of 2020. Journal of Coastal Research, Special Issue No. 95, pp. 1344–1348. Coconut Creek (Florida), ISSN 0749-0208. Within Costa Norte Project – an R&D project focused on improving the understanding of the vulnerability of mangrove forests to oil spills in the Brazilian Equatorial Margin - the vulnerability concept is understood as composed by three factors: sensitivity, resiliency, and susceptibility. The latter is defined as the exposure level to oil spills and should consider all possible sources of this pollutant. This work presents a methodology to assess the susceptibility of an asset to oil spills that may occur anywhere within a large marine area. It benefits from the development of a multi-source stochastic oil dispersion algorithm to enable the modeling of oil spills originated from hundreds of sources and the development of a methodology to integrate multiple scales with increasingly higher resolutions. Once stored, the results allow the identification of susceptible areas considering a single or a subset of spill sources and the identification of potential origins of spills that may affect specific areas. The choices of the spill sources and the coastal areas to be considered are defined during post-processing, granting flexibility and interactivity exploring the results. The developed methodology presents the potential to assist public management and is illustrated by an offshore scale simulation considering 1,138 oil spill sources distributed along the Brazilian Equatorial Margin integrated to an estuarine scale model, forced by 1-year of metocean data. [ABSTRACT FROM AUTHOR]

The potential impact of drill cuttings on the two deep water calcareous red algae Mesophyllum engelhartii and Lithothamnion sp. from the Peregrino oil field was assessed. Dispersion modelling of drill cuttings was performed for a two year period using measured oceanographic and discharge data with 24 h resolution. The model was also used to assess the impact on the two algae species using four species specific impact categories: No, minor, medium and severe impact. The corresponding intervals for photosynthetic efficiency (Φ PSIImax ) and sediment coverage were obtained from exposure–response relationship for photosynthetic efficiency as function of sediment coverage for the two algae species. The temporal resolution enabled more accurate model predictions as short-term changes in discharges and environmental conditions could be detected. The assessment shows that there is a patchy risk for severe impact on the calcareous algae stretching across the transitional zone and into the calcareous algae bed at Peregrino. [ABSTRACT FROM AUTHOR]

The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the ( 6a–f ) series, which presents phthalyl and thiazolidinone groups. [ABSTRACT FROM AUTHOR]

The present work reports on the synthesis, anti- Trypanosoma cruzi activities and docking studies of a novel series of 2-(pyridin-2-yl)-1,3-thiazoles derived from 2-pyridine thiosemicarbazone. The majority of these compounds are potent cruzain inhibitors and showed excellent inhibition on the trypomastigote form of the parasite, and the resulting structure–activity relationships are discussed. Together, these data present a novel series of thiazolyl hydrazones with potential effects against Chagas disease and they could be important leads in continuing development against Chagas disease. [ABSTRACT FROM AUTHOR]

We modified the thiazolidinic ring at positions N3, C4,and C5,yielding compounds 6–24. Compoundswith a phenyl at position N3, 15–19, 22–24, exhibited better inhibitoryproperties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidalcompound, 2-minothiazolidin-4-one 18, which inhibitedthe activity of cruzain and the proliferation of epimastigotes andwas cidal for trypomastigotes but was not toxic for splenocytes. Havinglocated some of the structural determinants of the trypanocidal properties,we subsequently wished to determine if the exchange of the thiazolidinefor a thiazole ring leaves the functional properties unaffected. Wetherefore tested thiazoles 26–45andobserved that they did not inhibit cruzain, but they exhibited trypanocidaleffects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocyclescan lead to useful cidal agents for Chagas disease. [ABSTRACT FROM AUTHOR]

Abstract: As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors. [ABSTRACT FROM AUTHOR]

• Spiro-acridine AMTAC-01 was complexed with 2-hydroxypropryl-β-cyclodextrin (HPβCD). • HPβCD complexed with AMTAC-01 in a 1:1 molar ratio as shown by molecular modeling. • ¹H NMR, FT-IR, Raman, SEM, XRD, and fluorescence confirmed the inclusion complex. The spiro-acridine derivative (E)-1′-(benzylideneamino)-5′-oxo-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4-carbonitrile (AMTAC-01) is a synthetic compound with limited water solubility, which restricts its physiological activities and therapeutic applications. Hence, we investigated the complexation of AMTAC-01 with 2-hydroxypropyl‑β‑cyclodextrin (HPβCD) using the freeze-drying method. Complex formation was characterized by scanning electron microscopy, X-ray diffractometry(XRD), nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, and fluorescence spectrophotometry. Additionally, molecular modeling and phase solubility studies were performed. Molecular modeling demonstrated the most stable inclusion model, and phase solubility studies indicated that AMTAC-01 and HPβCD formed a 1:1 inclusion complex with an apparent stability constant of 1145.3 M −1. XRD and spectroscopy results suggest intermolecular interactions between AMTAC-01 and HPβCD, with the formation of a 1:1 inclusion complex demonstrating an amorphous pattern and alterations in band distribution intensities compared with free drug. Image, graphical abstract [ABSTRACT FROM AUTHOR]