In silico and in vitro tests can reveal promising anti-leishmania activity for natural products and their derivatives. The aim of this study was to investigate in silico the pharmacological activities of potential new chalcones and their leishmanicidal potential in vitro. The in silico study was carried out using the PASS, MolPredictX and Molegro Virtual Docker 6.0 programs. Antiparasitic activity was assessed in axenic promastigote and amastigote forms of Leishmania braziliensis. The cytotoxicity tests used the J77G8 cell line. The chalcones exhibited 50% cytotoxic concentration values (CC50) values > 50 μM. Chalcone 4 (named FERAI) presented the best activity with concentration for 50% of promastigotes and intracellular parasites forms (EC50) of 9.75 ± 1.7 and 10.13 ± 1.7 μM for promastigote and amastigote, respectively. Reactive oxygen species (ROS) testing presented increased ROS levels in the parasite at the FERAI concentrations of 10 μM (56.33%), 20 μM (61.76%) and 30 μM (67.13%). Molecular docking revealed interactions (binding energy) between FERAI and the enzymes UDP-glycosyl pyrophosphorylase (-56.8384), dihydroorotate-dehydrogenase (-132.276) and trypanothione-reductase (-151.281). Our results demonstrated the anti-leishmanial activity of chalcones, especially FERAI, with a noted raising of ROS levels in the parasite. Molecular docking revealed dihydroorotate dehydrogenase and trypanothione reductase as potential pharmacological targets for FERAI. antileishmania anti leishmania derivatives PASS 60 6 0 6. programs braziliensis JG J G J77G line CC50 CC (CC50 5 named EC50 EC (EC50 975 9 75 9.7 17 1 7 1. 1013 13 10.1 respectively (ROS 56.33%, 5633 56.33% , 56 33 (56.33%) 2 61.76% 6176 61 76 (61.76% 3 67.13%. 6713 67.13% . 67 (67.13%) binding energy UDPglycosyl UDP glycosyl 56.8384, 568384 56.8384 8384 (-56.8384) dihydroorotatedehydrogenase 132.276 132276 132 276 (-132.276 trypanothionereductase 151.281. 151281 151.281 151 281 (-151.281) antileishmanial leishmanial CC5 (CC5 EC5 (EC5 97 9. 101 10. 563 56.33 (56.33% 61.76 617 (61.76 671 67.13 (67.13% 56838 56.838 838 (-56.8384 132.27 13227 27 (-132.27 15128 151.28 15 28 (-151.281 (CC (EC 56.3 (56.33 61.7 (61.7 67.1 (67.13 5683 56.83 83 (-56.838 132.2 1322 (-132.2 1512 151.2 (-151.28 56. (56.3 61. (61. 67. (67.1 568 56.8 8 (-56.83 132. (-132. 151. (-151.2 (56. (61 (67. (-56.8 (-132 (-151. (56 (6 (67 (-56. (-13 (-151 (5 ( (-56 (-1 (-15 (-5 (-

Over the years the study of the quantitative structure-activity relationship (QSAR) has transformed from a simple regression analysis to the implementation of machine learning (ML) with multiple statistics. Today ML-based QSAR models are quite important and play a notable role in drug design and screening, property prediction, biological activity, etc. ML methods applied to QSAR build classification or regression models to describe/predict the complex relationships between the chemical structure of molecules and biological activity. Even with the increase in scientific publications addressing this topic written in Portuguese, there is still a shortage of scientific articles explaining ML techniques applied to QSAR, how to build models, the types of models, algorithms, for the Brazilian scientific community. And to fill this need, we intend to approach the subject in a simple and didactic way for students and researchers who are starting in this very promising and important area. We will describe the fully explained theory of machine learning by applying QSAR, abstracting the complexity, and well-illustrated. structureactivity activity (QSAR (ML statistics MLbased based screening prediction etc describepredict predict Portuguese algorithms community need area complexity wellillustrated. wellillustrated well illustrated. illustrated well-illustrated

Chagas disease, caused by the parasite Trypanosoma cruzi, occurs most commonly in Latin America. As the treatment is highly toxic and ineffective in the chronic phase of the disease, alternative treatments are needed. Through quantitative structure-activity relationship modeling (QSAR) analysis using ligand-based and structure-based virtual screening methods, we predicted the trypanocidal potential of 47 neolignans against three targets, the enzymes cruzain, trypanothione reductase, and sterol 14-alpha demethylase. A combined analysis allowed for the selection of potent inhibitors against Trypanosoma cruzi. Of these compounds, two were isolated and shown to inhibit the growth of epimastigotes at concentrations of 9.64 and 8.72 µM, and trypomastigote forms at 4.88 and 2.73 µM. Therefore, the compounds (2R, 3R)-2,3-dihydro-2 (4 methoxyphenyl)-3-methyl-5-(E)-propenylbenzofuran (46) and ottomentosa (47) may be a good option of growth inhibitors for the parasite stages and warrant additional study. disease cruzi America needed structureactivity structure activity QSAR (QSAR ligandbased ligand based structurebased methods 4 targets cruzain reductase 14alpha alpha 14 demethylase 964 9 64 9.6 872 8 72 8.7 µM 488 88 4.8 273 2 73 2.7 Therefore 2R, 2R R (2R 3R2,3dihydro2 3R23dihydro2 Rdihydro 3R 2,3 dihydro 3 3R)-2,3-dihydro- ( methoxyphenyl3methyl5Epropenylbenzofuran methoxyphenylmethylEpropenylbenzofuran methoxyphenyl methyl 5 E propenylbenzofuran 46 (46 (47 study 1 96 6 9. 87 7 8. 48 4. 27 2. 3R2 3dihydro2 3R2,3dihydro 3R23dihydro 23 2, 3R)-2,3-dihydro Epropenylbenzofuran 3dihydro

Abstract Acute lung injury is an inflammation that triggers acute respiratory distress syndrome with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex (TLR4/MD2) and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage. Due to the complexity of this pulmonary inflammation, a defined pharmacotherapy has not been established. Thus, this study evaluated the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an experimental model of lung inflammation. BALB/c mice were lipopolysaccharide-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar fluid, peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the cell migration (mainly neutrophils) to the alveoli, the pulmonary edema, and the cytokine levels (IL-1β, IL-6, TNF-α). The systemic IL-6 level was also reduced. The milonine docking analysis demonstrated hydrophobic interaction at TLR4/MD2 groove with Ile124 and Phe126 amino acids. Indeed, the alkaloid downregulated the kinase-Akt and NF-κB through TLR4/MD2. Therefore, milonine is an effective inflammatory modulator being a potential molecule for the treatment of lung inflammation.

The Annonaceae family of plants is one of the most anatomically and structurally uniform families. Chemotaxonomy is a common practice to determine the chemical patterns within these families at different phylogenetic levels. The aim of this study was to build a dataset of all the secondary metabolites isolated within the Annonaceae family and to perform the respective chemotaxonomic analysis using self-organizing maps (SOMs). This dataset is composed of 5321botanical occurrences and 1860 unique molecules present in all subfamilies of the Annonaceae. Diterpenes account for 366 unique compounds and 533 botanical occurrences seen in both Annonoideae and Malmeoideae subfamilies. The Annoneae, Xylopieae and Miliuseae tribes had the highest number of botanical occurrences and were therefore selected for the analysis. Molecular descriptors of the diterpenes and their respective botanical occurrences were used to generate the SOMs. These SOMs demonstrated clear and indicative tribe separations, with a match rate higher than 70%. Our results corroborate with the morphological and molecular data. These models can be used to predict the phylogenetic location of certain diterpenes and to accelerate the research of Annonaceae secondary metabolites and their biological potentials.

Seventeen Schiff bases bearing 2-aminothiophene derivatives were designed and synthesized using molecular simplification. The resulting compounds (4a-4q) were evaluated for their in vitro antifungal activity against dermatophytes. Prediction of their druglikeness and pharmacokinetic properties, establishment of their structure-activity relationships (SAR), and cytotoxic evaluation of the most active compounds were performed. Using an eco-friendly procedure, microwave assisted synthesis resulted in compounds in good yields (35-85%). Compounds 4a-4q presented good druglikeness and pharmacokinetic profiles and no cytotoxicity for any cell line tested up to 100 µM. The compounds presenting the best antifungal profiles were 4e, 4f, 4g, 4k, 4l, 4m, 4o and 4p with more than one minimum inhibitory concentration (MIC) value occurring between 16-64 µg mL-1, thus, in some cases better than the reference drug (fluconazole). SAR testing indicated that the presence of halogens and nitro substituents increases antifungal activity. Taken together, the results demonstrate that 2-aminothiophene derivatives are promising lead compounds for the development of antifungal drugs.

This study describes a virtual screening performed for two series of selenides (28 compounds), derived from N-phenylacetamides chlorides and 7-chloro-quinoline, to determine their potential for leishmanicidal activity against Leishmania amazonensis and Leishmania donovani. Seven compounds were predicted as potential leishmanicides; therefore, they were synthesized from elemental selenium, as a precursor for the production of NaHSe, and subsequent reactions with 4,7-dichloro-quinoline and N-phenylacetamides chlorides were performed. The compounds were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR), and sent for in vitro cytotoxicity tests against L. amazonensis and were found to be active and selective, and two compounds presented half-maximal inhibitory concentrations (IC50) of 5.67 and 10.81 µg mL-1. They also presented good interaction energies in the docking study, suggesting that may exert their effects by inhibiting the N-myristoyltransferase and O-acetylserine sulfhydrylase enzymes in parasites.

The objective of this work was to carry out a bibliographic survey of secondary metabolites isolated from the Velloziaceae family, creating a bank of compounds. After the bank was created, four prediction models for potentially active compounds against pathogenic microorganisms (Candida albicans, Escherichia coli, Pseudomonas aeruginosa and Salmonella sp.) were obtained trying to identify which metabolites would be more active against the strains. Four sets of compounds with known activity for microorganisms were selected for the construction of predictive models from the CHEMBL database. Another bank with 163 unique molecules isolated from the Velloziaceae family was built. The Volsurf+ v.1.0.7 software obtained the molecular descriptors and Knime 3.5 generated the in silico model. The performances of the internal and external tests were also analyzed. The study contributed through the virtual screening of a bank of metabolites to select several compounds with potential antimicrobial activity, highlighting the biflavonoid amentoflavone which showed potential activity against the four strains.

The present study investigated the activity of pyrimidine derivatives against Aedes aegypti. Two compounds, 3c and 3d showed excellent larvicide activity. Additionally, quantitative structure-activity relationship (QSAR) models were built using multiple-linear regression and partial least squares with descriptors generated from Dragon and VolSurf+ software, respectively. The best model is obtained with multiple linear regression (MLR), leading to a robust model. Moreover, the QSAR model is validated by means of some internal validation techniques in order to check its reliability, quality and robustness for predicting the larvicidal activity against A. aegypti. The models confirmed that the three-dimensional structure of molecules, steric properties, hydrophobic polar surface area, log partition (logP) and a simple pattern of substituent groups as methyl, methoxy, and succinimide in the pyrimidine derivatives are responsible for the larvicidal activity of the pyrimidine derivatives. Even more, the activity decreases by an electron-withdrawing group in R1 and increases when it is replaced by an aromatic ring activator group. These findings will aid in further studies of new pyrimidine derivatives active against Aedes aegypti.

The chemistry of natural products in Brazil has experienced a rapid development during the 21st century, with a diversification of lines of research, methodological approaches, exploration of diverse natural sources for the isolation of secondary metabolites and establishment of several multidisciplinary initiatives. These topics are critically discussed, evidencing achievements and new challenges to be faced for the future of Brazilian natural products chemistry.

This study aimed to prepare a complex of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 6CN10, a poorly water soluble 2-aminothiophene derivative with antifungal properties, by freeze-drying technique. The complex was characterized by thermal analysis, infrared/Raman spectroscopy, X-ray diffraction and scanning electron microscopy. In addition, we used the data of the phase solubility study, 1H, and 2D NMR spectroscopy and molecular modeling in order to investigate the interactions between 6CN10 and HP-β-CD. The apparent solubility of 6CN10 with HP-β-CD increased more than 29 fold. The phase solubility assay in water at 25 ºC showed an AP-type curve, with an apparent stability constant K1:1 and K1:2 of 96 and 0.1989 M-1, respectively. The results of IR, NMR and docking indicate that 6CN10 is able to form complexes with HP-β-CD (1:1 and 1:2 stoichiometric ratios), generating the formation of inclusion and preferably, non-inclusion complexes. The antifungal activity against Cryptococcus neoformans demonstrated the superior performance of the complex (46.66 µg mL-1) when compared with the free drug (166.66-333.33 µg mL-1). The present study provides useful information for the potential application of complexation with low soluble compounds and about the type of complex formation between 6CN10 and HP-β-CD.

O perfil metabólito baseado na aplicação de análises multivariadas (análise de componentes principais, PCA) dos dados de espectrometria de massas com ionização electrospray (ESIMS) no modo positivo e de ressonância magnética nuclear (RMN) do ¹H de extratos brutos de espécies de Piper destacou algumas espécies caracterizadas pela produção de lignanas (P. solmsianum, P. truncatum e P. cernuum), neolignanas (P. regnellii) e cromenos (P. gaudichaudianum). Análises específicas em conjunto de espécies caracterizadas morfologicamente por apresentarem inflorescências pêndulas e globosas (P. caldense, P. carniconnectivum, P. bowiei e P. permucronatum) ou em espécies que produzem amidas indicaram o potencial mais significativo para tais análises como critério para estudos fitoquímicos posteriores. Análises intraespecíficas de plântulas das espécies P. solmsianum, P. regnellii e P. gaudichaudianum indicaram uma composição química nas folhas baseada na presença dos fenilpropanóides dilapiol e apiol, diferentemente do que produzem as plantas adultas. No caso das espécies que produzem amidas, a composição apresentou-se relativamente constante independentemente do estágio de desenvolvimento.

The metabolomic profiling based on the application of multivariate analysis (principal component analysis, PCA) of positive mode electrospray ionization mass spectrometric (ESIMS) and ¹H nuclear magnetic resonance (NMR) data of crude extracts highlighted some species characterized by lignans (P. solmsianum, P. truncatum and P. cernuum), neolignans (P. regnellii) and chromenes (P. gaudichaudianum). A specific analysis focusing on species having pendant and globular inflorescences (P. caldense, P. carniconnectivum, P. bowiei and P. permucronatum) or amides-producing species indicated higher potential of the methodology in determining similarities and establishing priorities for further phytochemical investigation. Such intraspecific analysis applied to analyzed seedling leaves of the P. solmsianum, P. regnellii and P. gaudichaudianum species revealed the production of dillapiole and apiole instead of lignans, neolignans or prenylated benzoic acid, produced by the adult leaves, respectively. In case of amides-producing species, a similar profile was observed regardless the developmental stage.

Aldose Reductase (AR) is the polyol pathway key enzyme which converts glucose to sorbitol. High glucose availability in insulin resistant tissues in diabetes leads into an accumulation of sorbitol, which has been associated with typical chronic complications of this disease, such as neuropathy, nephropathy and retinopathy. In this study, 71 flavonoids AR inhibitors were subjected to two methods of SAR to verify crucial substituents. The first method used the PCA (Principal Component Analysis) to elucidate physical and chemical characteristics in the molecules that would be essential for the activity, employing VolSurf descriptors. The rate obtained explained 53% of the system total variance and revealed that a hydrophobic-hydrophilic balance in the molecules is required, since very polar or nonpolar substituents decrease the activity. Artificial Neural Networks (ANNs) was also employed to determine key substituents by evaluating substitution patterns, using NMR data. This study had a high success rate (85% accuracy in the training set and 88% accuracy in the test set) and showed polihydroxilations are essential for high activity and methoxylations and glicosilations primarily at positions C7, C3' and C4' decrease the activity.

Flavonóides são considerados bons marcadores químicos da família Asteraceae. Nesse artigo 4700 ocorrências de flavonóides (cerca de 800 substâncias) foram utilizadas em um sistema especialista desenvolvido para estudos taxonômicos. Através do uso de Mapas Auto-Organizáveis foram estabelecidas relações filogenéticas entre as subfamílias e as tribos de Asteraceae, as quais foram classificadas com base no número de ocorrências e nos padrões de oxidação de flavonóides. Os resultados obtidos permitiram a diferenciação das duas subfamílias de Asteraceae a correlação de tribos na subfamília Cichiroideae de acordo com a árvore topológica proposta por Karis o agrupamento de tribos de acordo com a árvore baseada em dados de CpDNA proposta por Jansen e separar as subtribos de Asteroideae bem como as tribos de acordo com o grau de metoxilação x glicosilação de flavonóides. A partir desses resultados pode-se afirmar que o método descrito com dados químicos pode ser utilizado como uma ferramenta complementar na classificação de plantas.

Flavonoids have shown good chemical markers for Asteraceae. In this paper, 4,700 occurrences of flavonoids (about 800 compounds) were considered in an expert system developed for taxonomic purposes. Through the use of Self-Organizing Maps (SOM) phylogenetic relationships among the subfamilies and tribes of Asteraceae were established. These taxa were classified on the basis of their occurrences and oxidation patterns of the flavonoids. The obtained results show the separation between the two subfamilies of Asteraceae the correlation among the tribes of the Cichiroideae subfamily according to the topological tree proposed by Karis the clustering of the tribes according to the tree proposed by Jansen based on CpDNA and the separation of the tribes classified in the Asteroideae subfamily as well as the tribes based on the methoxylation x glycosylation level in flavonoids. From these results one can affirm that the method applied with chemical data can be used as a complementary tool in plant classification.

Esse trabalho descreve um método para previsão dos deslocamentos químicos de RMN de 125Te e 13C de diorgano-teluretos baseado em uma abordagem tridimensional. Para tanto, 150 substâncias foram selecionadas da literatura e tiveram suas respectivas geometrias otimizadas através do método semi-empírico PM3. A partir desses dados, as estruturas foram codificadas através do programa FOCOS, que descreve o ambiente químico de cada átomo presente na estrutura, num total de 1411 focos para as substâncias. O método descrito foi testado com dez diorgano teluretos não inseridos na base de dados e mostrou uma exatidão maior na previsão de deslocamentos químicos de RMN de 125Te e 13C do que os dados previstos por um programa comercial. Os dados e os parâmetros estatísticos obtidos nesse estudo demonstram que o método aplicado foi capaz de prever com sucesso os deslocamentos químicos de RMN de 125Te e 13C dos diorgano teluretos.

This work describes a method to predict the 125Te and 13C NMR chemical shifts of diorgano tellurides based in a three-dimensional approach. For that, a collection of 150 compounds were selected from the literature and had their geometry optimized using the PM3 semi-empirical method. From this data, the structures were coded by the FOCOS program which described the chemical environment for each atom present in the structure, totalizing 1411 focos for the substances. The method developed was tested with ten diorgano tellurides not inserted in the database showing a higher accuracy in the prediction of 125Te and 13C NMR chemical shifts than those predicted by the commercial program. The chemical shifts and the statistical parameters obtained in this work demonstrate that the method applied was able to predict successfully the 13C and 125Te NMR chemical shifts of the diorgano tellurides.