The inhibition of the fatty acid amide hydrolase (FAAH), an endocannabinoid system component, emerged as a potentially new therapeutic target for a range of clinical disorders such as acute and chronic pain. Some α-ketoheterocycle derivatives demonstrated interesting analgesic and anti-inflammatory activities in vitro. Ligand-Based Drug Design techniques such as knowledge graph convolutional networks (kGCN) and hologram quantitative structure-activity relationship (HQSAR) using α-ketoheterocycle derivatives from five different datasets were generated to discover the relation between the chemical structures and the inhibition activity. Meanwhile, structure-based drug design simulations as interaction fields (MIF), molecular docking, and ligand sites studies (LSI) from FAAH were performed using Autogrid software and FTmap/FTsite servers. The results of both studies were merged to propose predictive models. The resulting kGCN model demonstrated adequate accuracy area under the curve by receiver operating characteristic (AUC-ROC 0.7922). From contribution maps of the Ligand-Based Drug Design (LBDD) models and the generated probes using MIF and LSI, it was observed that the oxazole ring, the ketone group, and the apolar chain present in the structures of the inhibitors are important, besides the evidence of the Cys269 and Val270 residues importance for the potential interaction, confirmed by carried docking studies. These fragments and structural information can be used to carry out new FAAH potential inhibitors studies and report kGCN as an accurate classification technique. FAAH, , (FAAH) component pain αketoheterocycle α ketoheterocycle antiinflammatory anti inflammatory vitro LigandBased Ligand Based (kGCN structureactivity structure activity HQSAR (HQSAR Meanwhile structurebased based MIF, (MIF) LSI (LSI FTmapFTsite FTmap FTsite servers AUCROC AUC ROC 0.7922. 07922 0.7922 . 0 7922 0.7922) LBDD (LBDD ring group important Cys Cys26 Val Val27 technique (FAAH (MIF 0792 0.792 792 Cys2 Val2 079 0.79 79 07 0.7 7 0.

The compound 2-hydrazinyl-4-(4-methoxyphenyl)thiazole (PD76) is a novel thiazolyl hydrazine derivative with proven antifungal activity against different fungal species, mainly Candida and Cryptococcus. Considering the advantages of oral route for clinical therapy, the aim of this work was to evaluate the potential intestinal permeability of this new antifungal drug. For the quantitation of PD76, a high-performance liquid chromatography method was developed and fully validated. The cytotoxicity of the compound in Caco-2 cells was analyzed and intestinal permeability of PD76 was assessed by means of the comparison of in vitro assay in Caco-2 cells and in silico platforms ADMETlab and admetSAR. Cell viability above 70% was obtained at all PD76 studied concentrations. Using Caco-2 cell model, the compound showed apparent permeability coefficients (Papp) of 5.25 × 10-6 and 23.28 × 10-6 cm s-1 in apical-basolateral and basolateral-apical directions, respectively. Experiments performed using verapamil as P-gp inhibitor demonstrated that PD76 is slightly susceptible to active efflux. Both in silico platforms inferred that PD76 presents permeability in Caco-2 cells, with Log P values of 2.82 (ADMETlab) and 2.10 (admetSAR). The results obtained in permeability studies showed that PD76 presents moderate intestinal permeability and a promising profile for clinical application. 2hydrazinyl44methoxyphenylthiazole hydrazinylmethoxyphenylthiazole 2 hydrazinyl 4 methoxyphenyl thiazole PD (PD76 species Cryptococcus therapy drug highperformance high performance validated Caco2 Caco Caco- PD7 admetSAR 70 concentrations model Papp (Papp 525 5 25 5.2 106 10 6 10- 2328 23 28 23.2 s1 s 1 s- apicalbasolateral apical basolateral basolateralapical directions respectively Pgp gp efflux 282 82 2.8 (ADMETlab 210 2.1 . (admetSAR) application methoxyphenylthiazole (PD7 7 52 5. 232 23. 8 2. 21 (admetSAR (PD

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl]-4-phenylthiazole) is a thiazolylhydrazone derivative with promising in vitro and in vivo antifungal activity. A stability indicating highperformance liquid chromatography with diode-array detection (HPLC-DAD) method was carried out using C18 end-capped column (250 × 4.6 mm, 5 μm) and a mobile phase composed of water and acetonitrile (15:85 v/v) at a flow rate of 1.2 mL min-1, injection volume 25 μL and DAD detection at 240 nm. The method showed to be selective, linear in the range of 20 to 240 μg mL-1, precise, accurate and robust. RN104 forced degradation study under different stress conditions (acidic, alkaline and neutral hydrolysis, oxidation, photolysis and thermolysis) was performed using the validated analytical method. The results showed that RN104 underwent significant degradation when subjected to alkaline hydrolysis and oxidation by metallic ions. Quantum mechanics calculations were carried out to assist in the structural elucidation of the formed degradation products. The obtained data may be useful for the development of future formulation based on RN104. RN RN10 22cyclohexylmethylenehydrazinyl4phenylthiazole cyclohexylmethylenehydrazinylphenylthiazole 2 cyclohexylmethylene hydrazinyl 4 phenylthiazole (2-[2-(cyclohexylmethylene)hydrazinyl]-4-phenylthiazole activity diodearray diode array HPLCDAD HPLC (HPLC-DAD C C1 endcapped end capped 250 (25 46 6 4. mm μm 1585 15 85 (15:8 v/v vv v 12 1 1. min1, min1 min 1, min-1 24 nm selective mL1, mL1 mL-1 precise robust acidic, acidic (acidic thermolysis ions products RN1 cyclohexylmethylenehydrazinyl (2 158 8 (15: min- mL- ( (15 (1

Copper is an important micronutrient, and it is present in some protein structures, as well as participate in several important biological processes. Due to its importance, some ligands are used and studied like carriers of copper in the biological systems. This work has investigated the affinity of CuII by three ligands of biological interest: N, N, N, N’-tetrakis (2-pyridilmethyl) ethylenediamine (TPEN), triethylenetetramine (TRIEN), and diethyldithiocarbamate (Et2DTC), used for this purpose. The studies were performed by evaluating the CuII d-d band when complexed with these three ligands. The CuII d-d band in aqueous solution appears around 800 nm; when in the presence of TRIEN, this band displaces to 576 nm. TRIEN ligand is substituted by TPEN ligand (d-d band at 689 nm), and finally, in the presence of the Et2DTC ligand, the d-d band displaces to 665 nm. Theoretical calculations were used to obtain the binding energy and the values obtained were −481.85 kcal mol−1 for the CuII-TPEN, −417.80 kcal mol−1 for CuII-TRIEN and −726.72 kcal mol−1 for CuII-Et2DTC. Electrochemical studies showed an oxidation peak at 0.008 V to CuII-TRIEN complex, −0.135 V to CuII-TPEN and 0.150 V to CuII-Et2DTC. These results showed that CuII has a higher affinity by the Et2DTC ligand compared to the other ligands studied.

Activin-like kinase 5 (ALK-5) receptor represents an attractive object to treat cancer. Analyses on the quantitative structure-activity relationship were performed to explore the relationship between the molecular structure of 1,5-naphthyridine, pyrazole and quinazoline derivatives and the inhibition of the activin-like kinase 5. From a data set containing 59 compounds, various electronic descriptors were calculated using density functional theory (DFT) method; stereochemical descriptors (as molecular volume and area), polar surface area (PSA), log P and dragon descriptors were also calculated. The ordered predictor selection (OPS) algorithm, weighted principal component analysis (PCA) and Fisher's weights (FW), combined with sequential forward selection, were employed to select the most relevant descriptors to be employed in all partial least square regressions. Using this procedure, we selected the most informative descriptors and significant correlation coefficients were achieved (r2 = 0.74, q2= 0.83). Additional validation tests were carried out, indicating that the obtained model is robust and reliable and, consequently, it can be used to predict the biological activity of new compounds.

PPARδ é um receptor nuclear que, quando ativado, regula o metabolismo de carboidratos e lipídios, e está relacionado com diversas enfermidades, tais como síndrome metabólica e diabetes tipo 2. Para entender as principais interações entre alguns ligantes bioativos e o receptor PPARδ, modelos de QSAR 2D e 3D foram obtidos e comparados com mapas de potencial eletrostático (MEP) e dos orbitais de fronteira (HOMO e LUMO), assim como resultados de docagem molecular. Os modelos de QSAR obtidos apresentaram bons resultados estatísticos e foram utilizados para predizer a atividade biológica de compostos do conjunto-teste (validação externa), e os valores preditos estão em concordância com os resultados experimentais. Além disso, todos mapas moleculares foram utilizados para avaliar as possíveis interações entre os ligantes e o receptor PPARδ. Portanto, os modelos de QSAR 2D e 3D, assim como os mapas de HOMO, LUMO e MEP, podem fornecer informações sobre as principais propriedades necessárias para o planejamento de novos ligantes do receptor PPARδ.

PPARδ is a nuclear receptor that, when activated, regulates the metabolism of carbohydrates and lipids and is related to metabolic syndrome and type 2 diabetes. To understand the main interactions between ligands and PPARδ, we have constructed 2D and 3D QSAR models and compared them with HOMO, LUMO and electrostatic potential maps of the compounds studied, as well as docking results. All QSAR models showed good statistical parameters and prediction outcomes. The QSAR models were used to predict the biological activity of an external test set, and the predicted values are in good agreement with the experimental results. Furthermore, we employed all maps to evaluate the possible interactions between the ligands and PPARδ. These predictive QSAR models, along with the HOMO, LUMO and MEP maps, can provide insights into the structural and chemical properties that are needed in the design of new PPARδ ligands that have improved biological activity and can be employed to treat metabolic diseases.